bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of patients with borderline-resectable pancreatic cancer treated with FOLFIRINOX versus gemcitabine plus nab-paclitaxel.
Authors: Templeton Shaina D'Lee , Moser Michael , Chalchal Haji I. , Shaw John , Luo Yigang , Zaidi Adnan , Ahmed Shahid
Published: January 2019

299

Background: Pancreatic cancer is a major cause of cancer-related death. Less than 20% of patients have resectable disease at diagnosis. Patients with borderline-resectable pancreatic cancer (BRPC) are at high risk of incomplete resection with upfront surgery. Currently there is no standard induction chemotherapy regimen exists for BRPC. Both FOLFIRINOX (5-FU, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) have shown better efficacy than gemcitabine in advanced pancreatic cancer. The current study aims to assess outcomes of real-world patients with BRCP who received induction FOLFIRINOX or GnP. Methods: In this population-based multicenter retrospective cohort study patients with biopsy proven BRPC as defined by the pancreatic surgical team diagnosed from 2011-2017, in the province of Saskatchewan, Canada, who received FOLFIRINOX or GnP were assessed. Kaplan Meier methods and log rank tests were performed for survival analyses. Results: Of 161 patients with pancreatic cancer who received FOLFIRINOX or GnP during the study period, 20 eligible patients with BRPC, with median age of 65 yrs (54-79) and M:F 14:6, were identified. 85% had pancreatic head tumours with a median CA19-9 of 470 u/mL. Of eligible patients, 10 each received FOLFIRINOX or GnP. No significant differences were found between the two groups, except more patients in FOLFIRINOX group had a WHO performance status of 0 (50% vs. 10%, p = 0.057) and had a higher body mass index (27.0 vs. 23.0, p = 0.027). Eleven patients showed partial response (5–FOLFIRINOX and 6–GnP), three progressed during treatment. Five patients (4–FOLFIRINOX, 1–GnP, p = NS) underwent curative surgery. Five patients (1–FOLFIRINOX, 4–Gnp) had radiation and four underwent Nanoknife procedure (3–FOLFIRINOX, 1–GnP). The median progression free survival was 17 months in FOLFIRINOX (95% CI: 5.3-28.6) versus nine months (3.0-15) in GnP group (p = 0.26). The median overall survival was 32 months in FOLFIRINOX (not reach) versus 16 months (9.3-22.7) in GnP group (p = 0.15). Conclusions: The current study suggests that patients with BRPC who received FOLFIRINOX tends to have better outcomes. Future study are warranted to establish a preferred systemic therapy for BRPC.
Integrated population pharmacokinetic (PopPK) modeling of cabozantinib (C) in patients (pts) with various cancer types including hepatocellular carcinoma (HCC).
Authors: Nguyen Linh Thuy , Chapel Sunny , Meyer Tim , Cheng Ann-Lii , El-Khoueiry Anthony B. , Kelley Robin Kate , Abou-Alfa Ghassan K. , Lacy Steven
Published: January 2019

305

Background: C significantly improved overall survival vs placebo in pts with previously treated advanced HCC in the phase 3 CELESTIAL trial (NCT01908426). In a previous single dose PK study, increased C exposure was observed in healthy volunteers (HV) with mild or moderate hepatic impairment (Nguyen, J Clin Pharmacol, 2016). An integrated PopPK model was recently developed to characterize C concentration data from HV and pts with various cancers, including renal cell carcinoma, castration-resistant prostate cancer, and medullary thyroid cancer (MTC) (Lacy, Cancer Chemother Pharmacol, 2018). Here, we update the model to include data for pts with advanced HCC from CELESTIAL and a prior phase 2 trial. Methods: The updated PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated data from 10 clinical studies with 9510 measurable C concentrations from 2023 subjects, including 489 pts with advanced HCC. Eligible pts with HCC were Child-Pugh class A. Evaluated covariates included age, gender, race, body weight, cancer type, and liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG). Results: Overall, 70% of pts had normal hepatic function by NCI-ODWG criteria; 28% had mild, 1% had moderate, and <1% had severe hepatic dysfunction. A 2-compartment model with first-order elimination and dual first- and zero-order absorption processes adequately described the data. As in the previous model, the MTC population was the only cancer type to have a notable difference in C PK, with ~90% increase in apparent clearance (CL/F) versus HV and pts with other cancers including HCC. For a White male, CL/F was estimated as 2.48 L/hr and apparent volume of the central compartment (Vc/F) as 212 L. Inter-individual variability was ~46% for CL/F and ~67% for Vc/F. Other demographic covariates were predicted to have a small to moderate impact on C CL/F. Liver dysfunction, per NCI-ODWG criteria, had no discernable effect on C CL/F. Conclusions: C exposure at an equivalent daily dose is predicted to be similar in pts with several cancer types including advanced HCC with mild liver dysfunction.
Single-shot celiac plexus radiosurgery in pancreatic cancer: Palliative and functional outcomes—Final results of a prospective clinical trial.
Authors: Lawrence Yaacov Richard , Shmueli Einat Shacham , Hammer Liat , Morag Ofir , Ben-Ayun Maoz , Margalit Ofer , Halpern Naama , Yarom Nirit , Boursi Ben , Jacobson Galia , Symon Zvi , Shefer Kinneret , Yanovsky Inessa , Golan Talia , Hausner David
Published: January 2019

309

Background: Pancreatic cancer is characterized by severe epigastric/lower back pain caused by infiltration of the celiac plexus. The celiac plexus is a network of nociceptive nerves, located along the abdominal aorta. Contemporary approaches (opioids, celiac plexus chemical neurolysis, systemic chemotherapy) are often inadequate. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate pain. Here we report results for pancreatic cancer patients treated with a single fraction of radiation. Methods: We conducted a single-institution single-arm prospective clinical trial. Eligible cancer patients had celiac-pain > 4/10 on Numerical Rating Scale (NRS) and completed treatment per protocol with at least one post-treatment visit. The celiac plexus was irradiated from D12 to L2. Radiation was given as a single-fraction 25 Gy. The primary endpoint was NRS pain 3 weeks post-treatment. Secondary endpoints were toxicity, pain at 6w, analgesic use, and pain interference with daily activities as evaluated by the ‘The Brief Pain Inventory’. Analgesia was not restricted. Total daily dose of opioids was measured in morphine milligram equivalents (MME). Results: Seventeen patients were evaluable, 65% female, median age 68 yr (range 51-79), three had undergone pancreatic resection, nine had liver metastases, median ECOG = 1. Sixteen patients reported 3-week outcomes, and 10 reported 6-week outcomes. At time of treatment subjects were a median of 8.2 months from diagnosis, and had received a median of one systemic treatment (range 0-3). Toxicity was limited to grade 1. Median baseline pain was 6/10 (IQR 5-7), was reduced to 2.3/10 (IQR 0.9-3.6) (p < 0.0005) at 3 w, and to 2.5/10 (IQR 0-3.1) at 6 w post-treatment, for both p < 0.001. Median opioid consumption numerically decreased (baseline 52.9 MME, 3 w 43.9 MME, 6 w 37.5 MME, NS). ‘BPI pain interference’ improved significantly: median baseline score 7.1 dropped to 1.1 at 3 weeks and 0 at 6 weeks (p < 0.01 for both time points). Conclusions: Celiac plexus radiosurgery alleviates pain, and improves quality of life among patients with pancreatic cancer. A follow-up international trial is accruing. Clinical trial information: NCT02356406.
Ramucirumab (RAM) as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline α-fetoprotein (AFP): An analysis of AFP kinetics in the phase III REACH-2 study.
Authors: Finn Richard S. , Kudo Masatoshi , Kang Yoon-Koo , Yen Chia-Jui , Galle Peter R. , Llovet Josep , Assenat Eric , Brandi Giovanni , Lim Ho Yeong , Pracht Marc , Rau Kun Ming , Merle Philippe , Motomura Kenta , Ohno Izumi , Daniele Bruno , Shin Dongbok , Gerken Guido , Abada Paolo , Hsu Yanzhi , Zhu Andrew X.
Published: January 2019

326

Background: REACH-2 (NCT02435433) demonstrated a significant survival benefit with RAM vs placebo in the second-line treatment of patients with advanced HCC and AFP ≥ 400 ng/mL. This analysis investigated changes in AFP during treatment, as well as potential relationships with survival or progression. Methods: Patients were randomized (2:1) to RAM 8 mg/kg IV or placebo Q2W plus best supportive care until disease progression or unacceptable toxicity. Serum AFP levels were measured at baseline and every 3 cycles. Percent change in AFP from baseline was analyzed at each time point up to Cycle 12 with descriptive statistics and Wilcoxon rank sum test between treatment arms. AFP response was defined as ≥ 20% decrease from baseline. The association between AFP progression and radiographic progression in each time interval was assessed by odds ratio [OR] and Fisher’s exact test. Time to AFP progression and time to radiographic progression (TTP) were evaluated by the Kaplan-Meier method and compared between treatment arms using a stratified log-rank test. AFP progression was defined as ≥ 20% increase from baseline. Hazard ratio (HR) was generated using a stratified Cox regression model. Results: AFP response was significantly higher with RAM compared with placebo (42.1% vs 10.5%, p < 0.0001). Overall survival (OS) was longer in patients with AFP response (13.5 months) than in patients without (6.7 months), irrespective of treatment (HR 0.470, p < 0.0001). The median percent increase in AFP level from baseline was smaller in the patient population treated with RAM (0.4%, 6.1%, 15.4%, 10.8%) than with placebo (45.7%, 98.5%, 122.2%, 91.3%) at Cycles 3, 6, 9 and 12, respectively. Time to AFP progression (HR 0.422, p < 0.0001) and TTP (HR 0.427, p < 0.0001) favored a RAM benefit; subsequent analyses demonstrated a strong association between AFP progression and radiographic progression at 6 weeks (OR 2.44, p < 0.0084) and at 12 weeks (OR 1.89, p = 0.0430). Conclusions: Changes in AFP levels were associated with TTP and OS. RAM prolonged time to AFP progression and radiographic TTP, and slowed the rate of AFP increase during treatment. Clinical trial information: NCT02435433.
Checkmate-040: Nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status.
Authors: Kudo Masatoshi , Matilla Ana , Santoro Armando , Melero Ignacio , Gracian Antonio Cubillo , Acosta-Rivera Mirelis , Choo Su Pin , El-Khoueiry Anthony B. , Kuromatsu Ryoko , El-Rayes Bassel F. , Numata Kazushi , Itoh Yoshito , Di Costanzo Francesco , Crysler Oxana V. , Reig Maria , Shen Yun , Neely Jaclyn , Dela Cruz Christine Marie , Baccan Carlos , Sangro Bruno
Published: January 2019

327

Background: Pts with aHCC and CPB liver status are often excluded from clinical trials of novel therapies due to their poor prognosis (Greten British J Cancer 2005). Historical overall survival (OS) for these pts when treated with sorafenib (SOR) has ranged ≈3–5 mo in retrospective or descriptive studies (Abou-Alfa Gastrointest Cancer Res 2011; Da Fonseca Mol Clin Oncol 2015; Pressiani Ann Oncol 2013; Chiu Cancer 2012); thus, novel treatment options are needed for these pts. The PD-1 inhibitor NIVO is approved in the US, Canada, and elsewhere, most recently Australia, for SOR-treated pts with aHCC based on results from CheckMate-040 (NCT01658878) (El-Khoueiry Lancet 2017). Here we report data from the CPB cohort of CheckMate-040, the first prospective study of immunotherapy in this pt group. Methods: Pts with CPB (B7–B8) aHCC who were SOR-naïve (n = 25) or -experienced (n = 24) received NIVO 240 mg IV for 30 min Q2W until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) (investigator assessed [INV], RECIST v1.1) and duration of response (DOR). Safety was assessed in all treated pts using NCI CTCAE v4.0. Results: Of 49 analyzed pts, 28 (57.1%) had vascular invasion or extrahepatic spread. During a follow-up range of 6–18 mo, INV ORR was 10.2% with 5 pts responding; disease control rate (DCR) was 55.1%. Median (m) time to response was 2.7 mo and mDOR was 9.9 mo; 2 pts had ongoing responses at data cutoff. The mOS was 7.6 mo (mOS follow-up was 7.4 mo); mOS in SOR-naïve and -treated pts was 9.8 and 7.3 mo, respectively. Treatment-related adverse events (TRAEs) were reported in 25 (51%) pts; 4 (8.2%) pts had select hepatic TRAEs. TRAEs led to discontinuation in 2 pts (4.1%). NIVO safety profile in these pts appeared comparable to cohorts of pts with CPA aHCC. Comparison data for pts with CPA aHCC and extended follow-up for pts with CPB aHCC will be presented. Conclusions: Encouraging DCR and durable responses were observed in pts with CPB aHCC treated with NIVO. AEs were manageable and did not lead to higher discontinuation compared with pts with CPA aHCC. NIVO showed promising efficacy and tolerability compared with historical data, supporting further investigation. Clinical trial information: NCT01658878.
Safety and efficacy of high-intensity focused ultrasound in pancreatic cancer.
Authors: Kim Jin Il , Cheung DaeYoung
Published: January 2019

339

Background: The aim of this study was to evaluate safety and efficacy of high-intensity focused ultrasound (HIFU) for advanced pancreatic cancer. Methods: Patients with pancreatic cancer TNM stage III or IV were included. Magnetic resonance imaging was performed 2 weeks before and after the HIFU. The ablating tumor volume was calculated by ratio of the non-perfused necrotic area of the planned area on contrast-enhanced T1-weighted image on post-HIFU magnetic resonance imaging. The ablation results were stratified into 4 ranges: 100% to 90% unenhanced area of targeting area, 90% to 50%, within 50%, and no change. Results: High-intensity focused ultrasound treatment was performed without severe adverse event in 52 patients, 53 times (male/female = 28/24; mean age, 62.7 ± 12.1; TNM stage 3/stage 4 = 21/31). Average size of the pancreatic cancer lesion was 4.5 ± 1.6 cm (1.4 - 9.5 cm). After HIFU treatment, ablating tumor volume was as follows: 90% to 100% in 41 lesions, 90% to 50% in 11, and within 50% in 3. Overall median survival (S1) from initial pancreatic cancer diagnosis was 13.1 months. Overall survival (S2) rates at 6, 12, and 18 months from HIFU were 53.1%, 31.6%, and 23.5%, respectively, with a median survival of 7.4 months. Conclusions: High-intensity focused ultrasound is safe and effective, which induced excellent local tumor control in most patients with advanced pancreatic cancer.
Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tumors: A randomized double-blinded placebo-controlled phase II trial.
Authors: Demols Anne , Borbath Ivan , Van Den Eynde Marc , Houbiers Ghislain , Peeters Marc , Maréchal Raphael , Delaunoit Thierry , Goeminne Jean Charles. , Laurent Stéphanie , Holbrechts Stephane , Paesmans Marianne , Van Laethem Jean L.
Published: January 2019

345

Background: A high clinical unmet need remains in treating advanced or metastatic biliary tract cancers (BTC) after failure of gemcitabine and platinum-based chemotherapy, with no standard of care. Regorafenib is potent oral multi-kinase inhibitor of kinases involved in tumor angiogenesis, oncogenesis and tumor microenvironment. It has demonstrated efficacy and acceptable safety in some GI tumors that have progressed on standard therapies. Methods: REACHIN (NCT02162914) is a multicenter double-blinded placebo-controlled randomized phase II study to evaluate the safety and efficacy of regorafenib (REG) in patients with locally advanced (non resectable) and metastatic histologically proven BTC, progressing after gemcitabine-platinum. 66 patients were randomized (1:1) to receive BSC plus REG160 mg od, 3 weeks on/ one week off (cycle = 4 weeks) or BSC + placebo (P) until progression or unacceptable toxicity. Sample size calculation was based on the logrank test, assuming a one-sided significance of 10%, 80% power, and an improvement in median PFS of 50% (6 to 12 weeks in the REG group). Primary endpoint is PFS. Secondary endpoints are response rate and OS. Results: Between May 2014 and February 2018, 68 (33 REG, 35 P) patients have been included (2 patients died before starting treatment and were replaced). Of 66 patients treated (26 F/ 40 M), tumors were intra-hepatic and hilar (n = 48), extra-hepatic (n = 10) and gallbladder (n = 8). One patient remains on REG treatment. Median PFS for REG is 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI : 1.2-2.0) for P with a HR of 0.48 (95% CI : 0.29-0.80), p = 0.004. Rates of PR+SD are 23/33 (70%) for REG and 11/33 (33%) for P (p = 0,002). Median treatment duration is 10,9 weeks for REG vs 6,3 weeks for P (p = 0,004). Dose reductions were applied in 14/33 patients in REG and in 5/33 patients in P. There is no unexpected/new safety signal. Median OS is 5.3 months for REG and 5.1 months for P (p = 0.21). Conclusions: Regorafenib significantly increases median PFS and tumor control in patients with previously treated metastatic/ unresectable biliary tract cancer. Clinical trial information: NCT02162914.
Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma.
Authors: Yau Thomas Cheung , Tang Vikki , Leung Roland Ching-Yu , Kwok Gin Wai , Lee Ann-Shing , Law Ada , Chiu Joanne , Li Bryan , Cheung Tan To
Published: January 2019

365

Background: We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced hepatocellular cancer (HCC) in a multicenter, open-label and randomized setting. Methods: Patients not suitable for surgery or various loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone continuously in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, overall tumor response rate, overall survival (OS) and progression-free survival (PFS). Results: Forty-six patients were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority of the patients were male (72%). 40 patients (87%) were hepatitis B carrier, and 42 patients (91%) had Child-Pugh A liver function. Thirty patients (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis,one patient in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p=0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p=0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 patients (9%) and no patients achieved partial response in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p=0.50). Incidence of treatment-related adverse events (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p=0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP. Clinical trial information: NCT02716766.
A phase II study of ipilimumab and nivolumab with radiation in metastatic pancreatic adenocarcinoma.
Authors: Parikh Aparna , Wo Jennifer Yon-Li , Ryan David P. , Clark Jeffrey W. , Nipp Ryan David , Blaszkowsky Lawrence Scott , Weekes Colin D. , Van Seventer Emily , Ly Leilana , Foreman Bronwen , Corcoran Ryan Bruce , Hong Theodore S.
Published: January 2019

391

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer. Immunotherapy (IO) has shown minimal activity. In preclinical models, radiation (XRT) increases likelihood of response to IO via an abscopal effect where local tx (treatment) of a tumor leads to an antitumor response distantly, with synergy between XRT and dual checkpoint blockade. In this study, we assessed CTLA-4 and PD-1 blockade with XRT as a strategy to stimulate an immune response for patients (pts) with PDAC. Methods: In this open-label, single arm phase-2 study, we enrolled 25 metastatic PDAC pts in an exploratory cohort. Eligible pts had histologically-confirmed PDAC, ECOG PS 0-1, and progression on at least 1 line of tx. Tx consisted of Ipilimumab (1 mg/kg every 6 wks), Nivolumab (240 mg every 2 wks) and 3 fractions of 8 Gy of XRT at cycle 2. Tx continued until PD, discontinuation or withdrawal. Endpoints include Disease Control Rate (DCR), ORR, PFS, OS and safety. Radiological evaluations were every 3 months. Response was defined as disease control outside of the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone and 2 weeks after XRT. Intention to treat analysis includes all pts receiving at least one dose of study tx. Results: 22 pts were enrolled and evaluable from 6/2017-6/2018, median age 60 years (32-75), 73% male and 100% MSS. DCR was 27% and ORR was 14% with 1 pt having a complete response. All responses were out of the radiation field. Median PFS was 76 days in the entire cohort; 163 days for pts with disease control vs 62.5 days for pts with PD or who came off study prior to initial imaging. 7 pts did not receive XRT due to clinical progression. Treatment-related adverse events (AEs) were reported in 12/22 pts (54.5%). 8/22 pts (36.4%) experienced grade ≥ 3 toxicities. Elevated lipase, lymphopenia, fatigue, hyperglycemia, mucositis and hepatitis were the most common AEs. 1/22 (4.5%) pt had a grade 5 AE possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with XRT is feasible and demonstrates promising activity in pts with metastatic PDAC. We will report the updated efficacy and safety data as well as outcomes from the correlative serial biopsies upon completion. Clinical trial information: NCT03104439.
Impact of adjuvant hepatic arterial chemoinfusion using high-dose 5-fluorouracil with systemic gemcitabine for pancreatic cancer: A propensity score–matched analysis.
Authors: Nakamura Kota , Sho Masayuki , Akahori Takahiro , Nagai Minako , Nakagawa Kenji , Takagi Tadataka , Ikeda Naoya , Tanaka Toshihiro , Nishiofuku Hideyuki , Kichikawa Kimihiko
Published: January 2019

402

Background: The aim of this retrospective study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) using high-dose 5-fluorouracil with systemic gemcitabine on prognosis of resected pancreatic cancer. Methods: Between January 2006 and April 2016, 298 patients underwent elective pancreatic resection for resectable or borderline resectable pancreatic cancer at Nara Medical University Hospital. Patients who received adjuvant HAI plus systemic gemcitabine after surgery (HAI group) were compared with those who received systemic chemotherapy alone (control group). Patients were propensity score matched for age, sex, ASA score, CA19-9, NCCN resectability status, neoadjuvant treatment, surgical procedure, portal vein invasion, T stage, N stage, and margin status. Results: 224 patients with resectable or borderline resectable pancreatic cancer were enrolled in this study. 151 patients in the HAI group and 73 patients in the control group were included. Propensity score matching analysis was used to identify 63 well-balanced patients in each group for overall survival comparison. The estimate overall survival (OS) for patients treated with HAI was longer than patients without HAI in both the whole cohort (median OS, 54 vs. 24 months, respectively; P < 0.001) or matched cohort (median OS, 58 vs. 26 months, respectively; P = 0.003). The liver was only recurrence site in which significant decrease was observed in the HAI group compared to the control group ( P = 0.031). In the multivariate analysis, adjuvant chemotherapy without HAI were independently associated with worse outcome in the whole cohort. A total of 127 patients in the HAI group (84%) had completed the planned dose of HAI. The remaining 24 patients stopped treatment before the end of the planned cycle due to catheter-associated complications in 9 (6.0%) and development of liver abscess in 2 (1.3%). No treatment-related deaths occurred. Conclusions: The efficacy of hepatic arterial chemoinfusion as adjuvant treatment for resectable pancreatic cancer should be revisited.
The need for improvement in the management of fatigue, depression and pain in pancreatic cancer.
Authors: Westermann Amy , Matrisian Lynn McCormick , Rahib Lola
Published: January 2019

429

Background: Pancreatic cancer (PC) and its treatment(s) results in symptom and side effect burden and can impact patient’s overall quality of life (QOL). Methods: Patient reported information on management of side effects and symptoms were collected using PanCAN’s Patient Registry (01/2016 – 07/2018). Results: Patient reported information on side effects, pain and depression is detailed in the table. Side effects: 94% reported fatigue and 8% reported taking anti-fatigue medication. 72% reported nausea or vomiting during treatment and 83% reported taking anti-nausea medication. Pain: Of the 90% of patients who reported pain related to PC, 27% did not take pain medication, 47% visited the ER and 32% were hospitalized due to pain. Depression: Of the 83% of users reported feeling depressed during PC, 46% were diagnosed with depression, 37% prescribed anti-depressant, and 48% did not see a therapist. Conclusions: Nausea was reported as most managed. Fatigue, pain and depression were generally unmanaged. ER visits and hospitalizations due to pain were frequently reported. An improvement in the management of these side effects and symptoms is needed as it can affect patient’s ability to tolerate treatment, improve overall QOL, and may lower overall healthcare costs. [Table: see text]
Phase II study of ibrutinib in advanced carcinoid and pancreatic neuroendocrine tumors.
Authors: Al-Toubah Taymeyah E. , Valone Tiffany , Schell Michael J. , Strosberg Jonathan R.
Published: January 2019

434

Background: Ibrutinib is an orally administered, inhibitor of Bruton’s tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited with neuroendocrine tumors (NETs) where they remodel the stroma and stimulate angiogenesis, driving macroscopic tumor expansion. Ibrutinib inhibits mast cell degranulation, and has been associated with regression of a mouse insulinoma model. Methods: A prospective, phase II trial evaluated patients with advanced GI/lung NETs and pNETs who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. Primary endpoint was objective response rate. Results: 20 patients were enrolled on protocol from November 2015 – December 2017 (15 carcinoid and five pNETs). No patients experienced objective response. Median PFS was 3.1 months. A total of 43 drug related AEs were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs and one patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment. Conclusions: Ibrutinib does not show significant evidence of activity when compared to other agents (e.g. Everolimus) in well-differentiated gastroenteropancreatic and lung NETs. Clinical trial information: 02575300.
Adjuvant HIPEC in patients with colon cancer at high risk of peritoneal metastases: Primary outcome of the COLOPEC multicenter randomized trial.
Authors: Klaver Charlotte Emma Louise , Wisselink Daniel D , Punt Cornelis J. A. , Snaebjornsson Petur , Crezee Johannes , Aalbers Arend , Bemelman Willem A , Brandt Alexandra , Bremers Andre , Burger Jacobus W.A. , van Grevenstein Wilhelmina M.U. , Hemmer Patrick H.J. , de Hingh Ignace H.J.T. , Kok Niels , Tuynman Jurriaan , Wiezer Marinus J. , de Wilt Johannes H. W. , Dijkgraaf Marcel G , Tanis Pieter J. ,   Dutch Colorectal Cancer Group
Published: January 2019

482

Background: Patients with T4 or perforated colon cancer are at high risk (~25%) of peritoneal metastases (PM). Sensitivity of imaging modalities for PM is limited and the majority of patients is diagnosed in a palliative setting. This provides a rationale for adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). In this study, the effectiveness of adjuvant HIPEC in reducing the risk of PM was determined. Methods: In this multicenter trial, patients with T4 (either cT4 or pT4, N0-2, M0) or perforated colon cancer, who underwent curative resection were randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy or to adjuvant systemic chemotherapy alone (1:1). Adjuvant HIPEC with oxaliplatin was performed simultaneously (9%) or within five-eight weeks (91%) after the primary tumor resection. Patients without evidence of recurrent disease at 18 months based on CT imaging underwent diagnostic laparoscopy in both arms. The primary endpoint was PM free survival (PMFS) at 18 months using Kaplan Meier analysis. Results: Between April 2015 and January 2017, 204 patients were randomized: 102 in the control arm (0 drop-outs), 102 in the experimental arm (two drop-outs). Surgical exploration at the start of the HIPEC procedure at five-eight weeks postoperatively revealed metastases in 11 patients (PM in 9/11) in the experimental arm, and adjuvant HIPEC was not applied. Adjuvant systemic chemotherapy was administered in 89/100 eligible patients after median 6 weeks (IQR 5-7) in the control arm and in 84/89 after 10 weeks (IQR 9-12) in the experimental arm. PM rate after completion of 18 months follow-up was 22/102 and 18/100, respectively. In the ITT analysis no difference in 18 months PMFS was observed: 77% (control) versus 81% (experimental), HR 0.836 (0.489-1.428)). Also, no differences were observed in 18 months DFS (HR 1.016 (0.646-1.598)) and OS (HR 1.139 (0.532-2.439)). One patient developed encapsulating peritoneal sclerosis after HIPEC. Conclusions: Adjuvant HIPEC with oxaliplatin for patients with T4 or perforated colon cancer does not result in improved 18 months PMFS. Long-term results have to be awaited to assess the role of HIPEC in the adjuvant setting. Clinical trial information: NCT02231086.
Molecular comparison of primary colorectal cancer (pCRC) with peritoneal metastases (PM).
Authors: Stein Matthew K , Williard Forrest W , Tsao Miriam , Deschner Benjamin , Dickson Paxton Vandiver , Glazer Evan Scott , Martin Michael Gary , Deneve Jeremiah Lee
Published: January 2019

498

Background: PM from CRC are associated with poor outcomes; however, molecular differences are not defined. Methods: We compared tumor profiles of pCRC and PM patients (pts) from Caris Life Sciences. Testing included next-generation sequencing (NGS) of 592 genes, immunohistochemistry (IHC), copy number variants (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were termed pathogenic (PATH) or variants of undetermined significance (VUS). TMB in mutations/Mb (MMB) was compared. Results: 617 pCRC and 348 PM pts had similar gender (55% male) and age (median 59). 232 pCRC were left-sided (LS), 189 right-sided (RS), 147 rectum (R) and 49 not otherwise specified (NOS); PM were 45 RS, 29 LS, 22 R and 252 NOS. For pts with IHC testing, expression was increased in PM in TOPO1 (62% v. 52%, p < 0.01), ERCC1 (27% v. 18%, p < 0.01) and MLH1 (96% v. 92%, p < 0.05) and decreased in PD-1 (36% v. 65%, p < 0.01), TOP2A (76% v. 100%, p < 0.01) and PTEN (64% v. 72%, p < 0.05). By sidedness, LS PM were more frequently TOP01 and PD-L1 and less commonly MGMT positive compared to pCRC. PTEN IHC was higher in R pCRC than PM. 7 CNVs were increased in PM ( ADGR2A2, CCND1, ELL, FGF3, FGF4, JAK3 and PDGFRB) and FLT3 CNVs were decreased. MYC CNVs were more common in RS PM compared to pCRC. No difference was seen in PM and pCRC PATHs in KRAS, BRAF, SMAD2, SMAD4, PTEN. PM had more PATHs in GNAS (8% v. 1%, p < 0.01) while pCRC PATHs were increased in APC (76% v. 48%, p < 0.01), TP53 (72% v. 53%, p < 0.01), ARID1A (29% v. 12%, p < 0.05), PIK3CA (22% v. 15%, p < 0.05) and FBXW7 (13% v. 7%, p < 0.01). LS PM had increased FLCN PATHs (12% v. 2%, p < 0.01); R PM had more PATHs in KMT2D (20% v. 1%, p < 0.01) and RNF43 (13% vs. 3%, p < 0.05). VUS were increased in 39/592 (7%) genes for PM compared to pCRC. No MSI or fusion difference was seen. 53% pCRC (median = 8) pts had TMB ≥8 MMB compared to 43% PMs (median = 7; p = 0.03); no TMB difference was seen for LS, RS or R subgroups. Conclusions: Compared to pCRC, PM had more PATHs in GNAS and less in classic CRC markers APC and TP53. While TMB was generally lower in PM, differences in IHC expression, CNV and VUSs may serve as biomarkers for PM requiring further study.
Patient and disease characteristics of colorectal cancer in a cohort of young patients.
Authors: Hanayneh Wissam , George Thomas J. , Read Thomas , Tan Sanda , Iqbal Atif , Allegra Carmen Joseph , Parekh Hiral D.
Published: January 2019

513

Background: Despite effective screening for colorectal cancer (CRC), the incidence has been steadily rising in younger patients; the etiology for this phenomenon remains elusive. Methods: CRC patients diagnosed at < 50 years of age (UF institutional registry 2000-2017) constituted the IRB approved study cohort. Results: Young CRC patients (n = 286) comprised 16% of total CRC patients (n = 1806) treated at our institution. (See table for demographics and tumor characteristics.) The median age at diagnosis was 45 years (range 17-50) with two-thirds diagnosed at age 40-50 (n-212, 74%) and 182 patients (63.6%) had a history of tobacco and/or alcohol use. The majority of patients (73.1%) had a left-sided tumor and 35% (n = 99) had stage 4 disease at presentation. The median time to diagnosis from onset of first symptoms was 90 days. DNA mismatch repair gene deficiencies (dMMR) and/or microsatellite instability (MSI) was tested in 172 patients (60.1%); 18 (10.5%) had MSI-H or dMMR tumors and 11 of those had confirmed Lynch syndrome through. Next generation sequencing (NGS, n = 71) or mutational analysis (n =79) was performed on 52.4%; most common mutation was KRAS (40.7%, n = 61) followed by TP53 (7.33%; n = 11) and PIK3CA (5.33%; n = 8). BRAF V600E was seen in five patients and another two had BRAF variant. Conclusions: Our results reveal that the majority of younger CRC were 40-50 years age group with a female preponderance. Advanced disease at diagnosis and longer median time to diagnosis should prompt educational efforts regarding appropriate screening and timely diagnostic investigation in this patient cohort. [Table: see text]
Outcomes by tumor location in patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG): Final analysis from the prospective, observational CORRELATE study.
Authors: Ducreux Michel , Petersen Lone Nørgård , Öhler Leopold , Bergamo Francesca , Metges Jean-Philippe , de Groot Jan Willem , Wang Chao-Yuan , García-Paredes Beatriz , Dochy Emmanuelle , Fiala-Buskies Sabine , Cervantes Andres , O'Connor Juan Manuel , Falcone Alfredo ,   CORRELATE Investigators
Published: January 2019

539

Background: The anatomical location of the primary tumor has been associated with different prognosis and outcomes in mCRC. REG significantly improved overall survival (OS) versus placebo in patients with mCRC who progressed on standard therapies in phase 3 trials. We report the final results of outcomes in patients with mCRC with left-sided (L) or right-sided (R) primary tumors who were treated with REG in the real-world CORRELATE study. Methods: CORRELATE (NCT02042144) was a prospective, observational study designed to characterize the safety and effectiveness of REG in patients previously treated with approved therapies and for whom the decision to treat with REG was made by the treating physician according to the local health authority label. Patients with tumor location unknown or tumors in both regions were excluded (n = 62). OS was analyzed using the Kaplan–Meier method. Results: Overall, 975 patients were included in the analysis: L = 768 (79%) and R = 207 (21%). Most patients were ECOG PS 0–1 (L: 86%; R: 87%). Median time from initial diagnosis and from diagnosis of metastatic disease to REG treatment was slightly longer in L versus R tumors (34 vs 30 months and 27 vs 23 months, respectively). A higher proportion of patients with L versus R tumors, respectively, had prior radiotherapy (34% vs 15%) and a lower proportion had a partial colectomy (44% vs 75%). Both groups received a median of three prior regimens. REG treatment duration was similar in the two groups (median duration: L 2.6 months vs R 2.3 months), as was median progression-free survival (95% CI): 2.8 months (2.6, 2.9) for L tumors versus 2.7 months (2.5, 3.1) for R tumors. Median OS (95% CI) was 7.4 months (6.7, 8.0) for L tumors versus 8.2 months (6.6, 9.3) for R tumors; one-year OS rates were 32% versus 34%, respectively. Conclusions: Results from this observational study suggest that OS is similar in patients with L and R tumors treated with REG. Clinical trial information: NCT02042144.
Occurrence of irreversible sinusoidal obstruction syndrome during adjuvant chemotherapy for colorectal cancer using oxaliplatin: A multi-center study.
Authors: Yamada Takeshi , Koda Keiji , Yoshida Hiroshi , Tanakaya Kohji , Ishibashi Keiichiro , Yoshimatsu Kazuhiko , Kosugi Chihiro , Tanaka Soichi , Hara Keisuke , Tsubaki Masahiro , Nakajima Hideo , Oya Masatoshi , Ishida Hideyuki
Published: January 2019

546

Background: Oxaliplatin reduces the recurrence rate after curative surgery for stage III colorectal cancer. However, it can cause hepatic sinusoidal obstruction syndrome (SOS), an adverse effect that creates morbidity after liver resection for recurrence. SOS has conventionally been diagnosed by liver biopsy, which is invasive. We have reported that a 10% increase in splenic volume (SV) indicates SOS (J Surg Oncol 2017). In this multi-center study, we measured SV to evaluate SOS caused by adjuvant chemotherapy. Methods: This multi-center study included the participants of the FACOS study, which included patients with Stage III colon cancer. Participants received 12 cycles of mFOLFOX6 or eight cycles of XELOX as adjuvant chemotherapy. We used multi-detector raw CT to measure SV three times; before surgery, on completion of adjuvant chemotherapy, and 1-year after completing adjuvant chemotherapy. CT images were taken in 5-mm slices. SV was calculated by using a volume calculator SYNAPSE VINCENT v3.0(Fujifilm, Japan). Results: The FACOS study included 130 patients, 16.9% of whom discontinued treatment. The mean relative dose intensity (RDI) of oxaliplatin was 80.3%. Grade 3 neutropenia, thrombocytopenia, and neuropathy were observed in 28.5%, 6.2%, and 4.6% of patients, respectively. The 3 year DFS was 82.2%. We analyzed data of 75 patients (57.7%) for whom the three CT studies were available. SV on completing chemotherapy (median 181 cm3) and SV 1-year after completing chemotherapy (141 cm3) were significantly higher than that before surgery (128 cm3) (P < 0.001). SV increased by more than 10% after chemotherapy in 72% and was still increased 1 year after chemotherapy in 51% of patients. Conclusions: In our previous single center study, SV had increased in 84% on completing chemotherapy and was still increased in 47% 1 year after completing chemotherapy. Adjuvant chemotherapy without oxaliplatin induced SV increases in only 20% of patients on completing chemotherapy. Thus, these results are reproducible and show the potential of oxaliplatin to induce SOS. Oxaliplatin frequently induces SOS and this SOS persists for over 1 year in half of affected patients. Clinical trial information: UMIN000005427.
Circulating tumor derived cell-free DNA (ctDNA) to predict recurrence of metastatic colorectal cancer (mCRC) following curative intent surgery or radiation: Interim results.
Authors: Esquivel Mikaela , Chee Bryant , Shih Brandon , Zhang Li , Corvera Carlos U. , Hirose Kenzo , Nakakura Eric K. , Van Loon Katherine , Raymond Victoria M. , Dix Daniel , Odegaard Justin , Atreya Chloe Evelyn
Published: January 2019

552

Background: Over half of patients (pts) with oligometastatic CRC treated with definitive surgery or radiotherapy experience cancer recurrence. Early detection of ctDNA could identify high risk pts for additional intervention to eliminate micrometastatic disease. Here we report interim results of a prospective study aiming to determine ctDNA detection rates using a sensitive multigene assay and to correlate post-procedure ctDNA detection with radiographic mCRC recurrence. Methods: Pts with mCRC intending to undergo a curative intent procedure were prospectively recruited at a single site. ctDNA was collected pre-procedure, 3 weeks (wks) post-procedure, and at multiple follow-up timepoints. ctDNA detection utilizing a multi-gene sequencing panel (Guardant Health) included somatic variant and epigenetic assessments. A novel variant classifier was applied to differentiate tumor derived versus non-tumor derived alterations. A Simon’s two-stage design with planned interim analysis to assess 3wk post-procedure ctDNA detection rate was employed. Results: Of 25 pts enrolled, 21 (84%) had evaluable paired pre- and post-procedure samples. In these 21 pts, the 3 wks post-procedure sample was collected after surgery (N = 20) or radiation (N = 1) to address liver (N = 17), lung (N = 3), or ovarian (N = 1) metastases ± colon resection (N = 6). ctDNA was detected (+) in 15/21 (71%) pre- and 11/21 (52%) post-procedure samples. ctDNA was (+) in 8/12 (67%) pre- and 8/17 (47%) post-procedure samples with carcinoembryonic antigen < 5 ng/ml. Conclusions: In this interim analysis of pts with mCRC undergoing curative intent procedures, the post-procedure ctDNA detection rate was 52%. The similarity between the observed post-procedure ctDNA detection and expected recurrence rate suggests promise for recurrence prediction using this approach. Given post-procedure ctDNA was (+) in > 3 pts, the study will continue to enroll, and pts are being followed for future correlation of ctDNA with radiographic recurrence. [Table: see text]
Using circulating tumor DNA (ctDNA) to predict surgical outcome and postoperative recurrence following neoadjuvant chemoradiation (CRT) for borderline resectable/locally advanced rectal cancer (LARC).
Authors: McDuff Susan G.R. , Hardiman Karin , Parikh Aparna Raj , Ulintz Peter , Hazar-Rethinam Mehlika , Zheng Hui , Van Seventer Emily , Fetter Isobel , Nadres Brandon , Ryan David P. , Weekes Colin D. , Clark Jeffrey W. , Cusack James C. , Goyal Lipika , Zhu Andrew X. , Wo Jennifer Yon-Li , Blaszkowsky Lawrence Scott , Allen Jill N. , Corcoran Ryan Bruce , Hong Theodore S.
Published: January 2019

562

Background: This study was designed to assess the capability of perioperative ctDNA analysis to predict surgical outcome and recurrence following neoadjuvant CRT for LARC. Methods: Thirty-one patients (pts) with newly diagnosed LARC ( n = 29) or locally recurrent (non-metastatic) rectal cancer ( n= 3) were treated between 7/2013 - 7/2017. Pts received long-course neoadjuvant CRT prior to surgical resection: 50.4 Gy/28 fractions. Serum ctDNA was typically measured at baseline, weekly during CRT, pre-operatively, and post-operatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital PCR was used to detect mutation fraction in ctDNA. Results: The median age of the cohort was 53 years (IQR 46.5-65.3 y). The overall R0-node negative (R0-NN) resection rate was 66.7%. The rate of R0-NN resection was significantly higher among pts with undetectable preoperative ctDNA ( n = 17, 88%) compared to pts with a detectable preoperative ctDNA ( n = 10, 30%, Fisher’s exact p = 0.036). The overall pathologic complete response (pCR) rate was 18.5%. The pCR rate among pts with undetectable preoperative ctDNA was 23.5% vs 10% among pts with detectable preoperative ctDNA ( ns). For patients with a positive assay at baseline and weekly draws available, those who went on to have an R0NN resection were observed to exhibit ctDNA clearance by the second week of chemoradiation. Recurrence free survival (RFS) was calculated for the subset ( n= 22) who were able to undergo surgery and had post-operative ctDNA available. Pts with detectable postoperative ctDNA experienced poorer RFS than those with undetectable ctDNA, HR 8.0, p < 0.001. Conclusions: Undetectable preoperative ctDNA is associated with R0-NN surgical outcome, and detectable postoperative ctDNA is associated with worse RFS in a cohort of pts treated with neoadjuvant CRT for LARC. Validation is ongoing in a larger cohort of 39 pts.
CD276-positive circulating endothelial cells in advanced colorectal cancer.
Authors: Gootjes Elske C. , Kraan Jaco , Buffart Tineke , Verhoef Cornelis , Verheul Henk M.W. , Sleijfer Stefan ,   ORCHESTRA Study Group
Published: January 2019

572

Background: The value of circulating endothelial cells (CECs) as predictive biomarker in metastatic colorectal cancer (mCRC) may be improved by using tumor-derived CECs. CD276 can discriminate between tumor derived and normal CECs. We evaluated whether CD276+CEC is a clinically relevant biomarker with 100% sensitivity to predict response to first line palliative combination systemic therapy with fluoropyrimidine and oxaliplatin in patients with mCRC. Methods: Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial. At baseline and at first evaluation (after 4 cycles of 5-FU/LV or 3 cycles capecitabine with oxaliplatin ± bevacizumab), CECs were measured by flowcytometry with a previously validated panel (CD34+CD45-CD146+DNA+; and additional CD276+ for tumor derived CECs). A clinically relevant cut-off value of (CD276+) CECs was determined as 100% sensitivity (and 80% specificity in 95% CI) identifying patients with progressive disease within 6 months. Results: There were 182 baseline samples, from which 133 follow up samples were available for analysis. CEC and CD276+CEC counts significantly increased during treatment from 48 to 90 CEC/4 ml (p = 0.00) and from 14 to 33 CD276+CEC/4 ml (p = 0.00) at baseline and at first evaluation, respectively. In patients treated with bevacizumab, CEC counts were lower after three cycles compared to patients treated with chemotherapy alone 75.5 vs 131 CEC/4ml (p = 0.04), 28 vs 41 CD276+CEC/4 ml (p = 0.08). Baseline values nor changes in CEC and CD276+CEC counts were predictive for poor response (progressive disease within 6 months, AUC 0.53 for CEC and AUC 0.52 for CD276+CEC). Conclusions: Despite numerical changes during therapy, CEC and CD276+CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC. (NCT01792934.)