bluuebunny/crossref_metadata_2025 huggingface dataset:
Subsequent anticancer medication following first-line lenvatinib: A posthoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma.
Authors: Alsina Angel , Kudo Masatoshi , Vogel Arndt , Cheng Ann-Lii , Tak Won Young , Ryoo Baek-Yeol , Evans T.R. Jeffry , López-López Carlos , Daniele Bruno , Misir Soamnauth , Ren Min , Izumi Namiki , Qin Shukui , Finn Richard S.
Published: January 2019

371

Background: Lenvatinib (LEN) was shown to be noninferior to sorafenib (SOR) for overall survival (OS) in REFLECT (median OS [mOS], 13.6 vs 12.3 months [mo]; HR 0.92; 95% CI 0.79–1.06). LEN was superior vs SOR for secondary endpoints including objective response rate (ORR) per mRECIST: 24.1% vs 9.2% by investigator and 40.6% vs 12.4% by independent review (Kudo M et al. Lancet 2018). We report a posthoc responder analysis of patients (pts) who received first-line LEN in REFLECT and subsequent anticancer medication during survival follow up. Methods: In REFLECT, pts with unresectable hepatocellular carcinoma were randomized 1:1 to receive first-line LEN or SOR. Objective response was defined as complete or partial response by mRECIST per investigator. Pts with disease progression and who discontinued treatment were followed for survival every 12 weeks; subsequent anticancer medication during survival follow up were recorded until time of death. Data cutoff: Nov 13, 2016. mOS was calculated using Kaplan-Meier estimates with 2-sided 95% CIs. Results: In REFLECT, one third of the overall study population (156/478 pts randomized to LEN and 184/476 to SOR) received subsequent anticancer medication, most commonly SOR (25% in LEN arm). ECOG performance status and laboratory assessments, including liver function tests, were comparable between arms prior to subsequent treatments. Among these pts, mOS was 21 vs 17 mo and ORR was 27.6% vs 8.7% for LEN vs SOR arms, respectively. In a subset analysis of LEN responders who received any subsequent anticancer medication (n = 43), mOS was 26 mo (95% CI 18.5–34.6). For SOR responders who received any subsequent anticancer medication (n = 16), mOS was 22 mo (95% CI, 14.6–NE). For LEN responders who subsequently received SOR (n = 35), mOS was 26 mo (95% CI 18.2–34.6). Conclusions: In REFLECT, one third of pts randomized to first-line LEN received subsequent anticancer medication, including SOR, with a mOS of 21 mo. In this exploratory, posthoc analysis of pts who responded to LEN and received any subsequent anticancer medication or SOR, mOS was 26 mo. Clinical trial information: NCT01761266.
Comparison of adjuvant chemotherapy, chemoradiation, and chemotherapy followed by chemoradiation for resected stage I-II pancreatic cancer.
Authors: Ma Sung Jun , Hermann Gregory , Prezzano Kavitha M , Serra Lucas M , Iovoli Austin J , Singh Anurag K
Published: January 2019

372

Background: Prior National Cancer Database (NCDB) studies have demonstrated an overall survival (OS) benefit for adjuvant concurrent chemoradiation (CRT) compared to chemotherapy alone. Given the more recent adoption of postoperative chemotherapy followed by concurrent chemoradiation (C+CRT), this NCDB analysis evaluates the clinical outcomes of C+CRT compared to CRT alone or adjuvant chemotherapy alone (C) for resected pancreatic cancer. Methods: The NCDB was queried for primary stage I-II, cT1-3N0-1M0, resected pancreatic adenocarcinoma treated with adjuvant C, CRT, or C+CRT (2004-2015). Patients treated with C+CRT were compared with those treated with C (cohort C) or with CRT (cohort CRT). The primary endpoint was overall survival (OS). Baseline patient, tumor, and treatment characteristics were examined. Kaplan-Meier analysis, multivariable Cox proportional hazards method, forest plot, and propensity score matching were used. Results: Among 5667 patients (n = 3031 for C, n = 1307 for CRT, n = 1329 for C+CRT), median follow-up was 34.7 months, 45.2 months, and 39.7 months for the C, CRT, and C+CRT cohorts, respectively. In the multivariable analysis for all patients, C (HR 1.31, p < 0.001) and CRT (HR 1.24, p < 0.001) were associated with worse mortality compared to C+CRT. Treatment interactions were seen among pathologically node positive disease. C+CRT was favored in 1-3 (HR 0.74, p < 0.001) and 4+ (HR 0.75, p < 0.001) positive lymph node disease when compared to C or CRT alone, but none of the treatment options were significantly favored in node negative disease (HR 0.96, p = 0.67). Using 1:1 propensity score matching, 2152 patients for cohort C and 1774 patients for cohort CRT were matched. C+CRT remained significant for improved OS for both cohort C (median OS 23.3 vs 20.0 months, p < 0.001) and cohort CRT (median OS 23.4 vs 20.8 months, p < 0.001). Conclusions: This NCDB study using propensity score matched analysis demonstrates an OS benefit for C+CRT compared to C or CRT alone following surgical resection of pancreatic cancer. Most of this benefit is in patients with positive lymph nodes.
Duodenal neuroendocrine tumors: Somewhere between the pancreas and small bowel?
Authors: Gamboa Adriana Carolina , Liu Yuan , Zaidi Mohammad Yahya , Lee Rachel M , Russell Maria C. , Cardona Kenneth , Maithel Shishir K.
Published: January 2019

377

Background: While small sub-2 cm pancreatic neuroendocrine tumors (NETs) are often observed given their indolent behavior, small bowel NETs are routinely resected with a regional lymphadenectomy regardless of size given their malignant potential. Considering this variability, our aim was to define the natural history of duodenal (D-NETs) and determine the role of resection. Secondary aim was to define clinicopathologic factors associated with overall survival (OS) in pts who undergo resection. Methods: All pts in the National Cancer Database (2004-14) diagnosed with non-metastatic, non-functional D-NETs were included. Local resection (LR) was defined as local excision, polypectomy, or excisional biopsy. Anatomic resection (AR) was defined as removal with radical surgery. Tumor size was divided into three categories (< 1 cm, 1-2 cm, ≥ 2 cm). Propensity score weighting analysis was used to create balanced cohorts between resection and no-resection pts; this was maintained in all three size categories. Primary endpoint was OS. Results: Among 5,502 pts, median age was 65 yrs; 52% were male. Median f/u was 51 mos. Median tumor size was 0.8 cm. Resection was performed in 72% (n = 3954) of which 61% were LR and 39% were AR. At least one lymph node (LN) was retrieved in 25% of pts, of which 44% had LN metastasis. 74% had negative margins. Resection and no-resection cohorts were propensity score weighted for age, gender, race, Charlson-Deyo score, and tumor grade, all of which were independently associated with OS on MV Cox regression analysis, thus creating balanced cohorts. Resection was associated with improved median OS compared to no-resection (MNR vs 94 mos, p < 0.01); this persisted for all three size categories (< 1 cm: MNR vs 194 mos; 1-2 cm: MNR vs 56 mos; > 2 cm: MNR vs 90 mos; all p < 0.01). Subset analysis of each size cohort who underwent resection showed that neither type of resection, LN retrieval, LN positivity, or margin status was associated with OS (all p > 0.05). Conclusions: All pts with non-metastatic non-functional D-NETs should be considered for resection regardless of tumor size. Given their lack of prognostic value, the type of resection and extent of LN retrieval should be tailored to the patient’s clinical picture and safety profile.
Second-line chemotherapy in advanced biliary tract cancer: Who may benefit?
Authors: Salati Massimiliano , Caputo Francesco , Marcheselli Luigi , Rimini Margherita , Spallanzani Andrea , Gelsomino Fabio , Andrikou Kalliopi , Zironi Sandra , Di Emidio Katia , Clo' Vera , Luppi Gabriele , Cascinu Stefano
Published: January 2019

381

Background: No established second-line treatment (2L) is available for patients (pts) with advanced biliary tract cancer (ABC) failing gemcitabine/platinum first-line chemotherapy (CT). However, 20-40% of pts are offered 2L CT in daily practice. We evaluated the impact of clinical and biochemical parameters on survival of ABC in order to identify factors aiding in 2L treatment selection. Methods: Medical records of consecutive ABC pts treated with 2L CT between 2005 and 2018 at the Modena Cancer Centre were reviewed. Log-rank test and multiple Cox proportional hazard regression were performed to assess the prognostic significance of covariates on OS. A prognostic score was developed from the multivariate model. Results: A total of 98 pts were identified and included in the analysis. Median (m) age was 63 years, 52% of pts were female, 75% had ECOG PS of 1-2. 72% of pts received first-line gemcitabine/platinum combination. In the 2L setting, 70% of pts received a doublet and the most common regimen was FOLFIRI (26%), followed by FOLFOX (20%) and fluoropyrimidine monotherapy (19%). Disease control rate was 39%, with 7% of objective responses. mOS and mPFS were 7.2 months and 3.5 months, respectively. At both univariate and multivariate analysis ECOG PS > 0 ( P= 0.002), peritoneum involvement ( P< 0.001), LDH > 430 UI/L ( P< 0.001), albumin < 3.5 g/dL ( P= 0.001), gamma-GT > 100 UI/L ( P= 0.001), PFS to first-line < 6 months ( P= 0.025), Na+ < 140 mEq/L ( P= 0.010), absolute lymphocyte count < 1000/uL ( P= 0.030) were significantly associated with shorter OS. By assigning to each of the 8 variables weight = 1, three different risk groups were identified: low-risk group (0-2 factors), intermediate-risk group (3-4 factors) and high-risk group (5-8 factors). mOS was 18, 9.4, and 2.9 months in the low-, intermediate-, and high-risk group, respectively ( P< 0.001). Conclusions: Our 2L study confirms the prognostic value of ECOG PS, PFS to first-line and peritoneal carcinomatosis, identifies novel biochemical prognosticators and proposes a readily-available and inexpensive score to risk stratify patients both in daily practice and clinical trials.
Efficacy and tolerability of sorafenib in unresectable/advanced hepatocellular carcinoma patients: Real-life experience in a Hong Kong tertiary liver cancer institute.
Authors: Yau Thomas Cheung , Tang Vikki , Leung Roland Ching-Yu , Kwok Gin Wai , Chiu Joanne Wing-Yan , Cheung Tan To
Published: January 2019

382

Background: To evaluate the pattern and outcomes of sorafenib use in unresectable/advanced HCC in a real life setting in a tertiary Hong Kong liver cancer centre. Methods: A retrospective review of unresectable or advanced HCC patients treated with sorafenib at Queen Mary Hospital, Hong Kong from 2010-2015 was conducted. The objectives were to evaluate the sorafenib efficacy in overall treated population as well as different subgroups; and also reviewed the tolerability of sorafenib, especially its impact on liver function. Results: During the study period, 504 consecutive cases were identified and 493 cases with sufficient clinical data were analyzed. Consistent with Asia-Pacific etiologies, 79.3% patients had chronic hepatitis B. Sorafenib was mainly used in patients with high tumor burden (75.1% BCLC-C, 68.6% MVI or/and EHS). Two-third patients (68.2%) were pretreated, mostly with loco-regional therapies . While 70.2% patients had good baseline PS 0, one-quarter (26.6%) had Child-Pugh B/C cirrhosis state. The overall survival (OS) was 8.15 months, with no difference between HBV and non-HBV subgroups. Patients had Child-Pugh A(CP-A) had significantly better OS compared with those at CP-B/C (11.1m vs 3.29m vs 3.34m). About 36.1% patients received subsequent therapies. Safety profile was essentially consistent with literature with hand-foot-skin reaction (HFSR) being the most common AE (30.7% all-grade). Interestingly, the onset of HFSR was associated with significantly better OS (median: 14.59 vs 5.59 months, p <0.001). Notably, there was no significant change in the on-treatment levels of liver function in terms of bilirubin and plasma albumin level. Conclusions: Our study confirms the efficacy and safety in using sorafenib to treat unresectable or advanced HCC patients in the real life setting. Our results are s comparable with those reported in literature. In addition, we found that 1) similar efficacy in treating HCC regardless of HBV status, 2) positive association of OS with HFSR onset, and 3) no compromised liver function during sorafenib therapy.
Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC).
Authors: Ioka Tatsuya , Ueno Makoto , Oh Do-Youn , Fujiwara Yutaka , Chen Jen-Shi , Doki Yuichiro , Mizuno Nobumasa , Park Keunchil , Asagi Akinori , Hayama Manabu , Nii Masahiro , Komuro Keiko , Sugimoto Mariko , Vlahovic Gordana , Ikeda Masafumi
Published: January 2019

387

Background: This Phase 1 study (NCT01938612) evaluated D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) in Asian pts, in whom optimal dosing of D and T is undetermined. No dose-limiting toxicities were observed, and durable responses were seen in a dose escalation phase evaluating various D doses and regimens in Japanese pts (Iguchi, ASCO 2015). The study was subsequently expanded to larger cohorts of Asian pts with advanced solid tumors including BTC. Methods: Two regimens were selected for the expansion phase: D monotherapy (10 mg/kg q2w) and D+T (D 20 mg/kg + T 1.0 mg/kg q4w). One cohort of pts with advanced BTC was enrolled to receive D monotherapy followed by a separate cohort that received D+T with additional pts enrolled if efficacy was observed. Safety, response, and survival endpoints were based on investigator assessment. Results: Pts were enrolled to D (N = 42) or D+T (N = 65). Median age was 64 years for the D cohort and 62 years for the D+T cohort, the majority were male, and ECOG PS was 0 or 1: 64% and 36% for pts in the D cohort and 49% and 51% for pts in the D+T cohort, respectively. Median number of prior chemotherapy regimens was 2 for both cohorts. Treatment-related adverse events (trAE) of any grade occurred in 64% and 82% of pts in the D and D+T cohorts. Grade ≥ 3 trAEs occurred in 19% and 23% of pts in the D and D+T cohorts. trAEs led to discontinuation in 2 pts in the D cohort and 5 pts in the D+T cohort. A death due to trAE (drug-induced liver injury) was reported in the D+T cohort, none in the D cohort. In the D cohort, 2 pts had a partial response (PR) and 7 pts had a PR in the D+T cohort; disease control rate at 12 weeks was 16.7% and 32.2%, respectively. Median duration of response for the D cohort was 9.7 months and 8.5 months for the D+T cohort. Median overall survival was 8.1 (95% CI, 5.6-10.1) months and 10.1 (95% CI, 6.2-11.4) months for the D and D+T cohorts, respectively. Conclusions: Both D monotherapy and D+T combination therapy were tolerable for Asian pts with BTC, and no unexpected toxicities were observed with either regimen. Promising clinical benefit was observed with both D and D+T therapy. This study provides valuable information regarding these therapeutic regimens for future studies in pts with BTC. Clinical trial information: NCT01938612.
Incidence of gastroesophageal junction cancer continues to rise: Analysis of Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Bartel Michael , Brahmbhatt Bhaumik , Bhurwal Abhishek
Published: January 2019

40

Background: Gastroesophageal junction (GEJ) cancer can be endoscopically resected and/or ablated in its early tumor stage. Despite significant effort to address the epidemiology and populations at risk for distal esoaphgeal cancer, very limited effort has been undertaken to assess such in GEJ cancer. Methods: A SEER database analysis was performed for the study period 1973 – 2013. Inclusion criteria were GEJ cancer (microscopically confirmed primary site of malignancy with ICD-O-3 histology of adenocarcinoma). Data was stratified by years 1973-82, 1983-92, 1993-2002 and 2003-2012, patient age, gender, and race. A Kaplan-Meier curve for the 5-year survival analysis of GEJ cancer was calculation. Further, GEJ cancer data was compared with the epidemiology of distal esophageal cancer (ICD-10). Results: 32,073 patients with GEJ cancer were included in the SEER database between 1973 and 2015 (female 19%, Caucasian race 88.7%). The incidence of GEJ cancer increased significantly over the four decades between 1973 and 2013, 15.7%, 25.3%, 26.9% and 32% (p = 0.001). The rising prevalence was particularly accounted in the patient age cohorts 65-74 years and 75+ years and in white male patients followed by black male patients. The 5-year survival analysis showed a median survival during the four analyzed decades of 8, 10, 11, and 14 months, respectively (Log rank test p < 0.001). During the last decades (1993-2002 and 2003-2012) GEJ cancer and distal esophageal cancer had comparable incidences. Conclusions: GEJ cancer incidence is rising over the last four decades and is in fact comparable with the incidence of distal esophageal cancer. This is particularly true for white male patients and patients older than 65 years. Given that early GEJ cancer is endoscopically treatable, more effort is warranted to address its risk factors and to identify populations at risk who could benefit from early cancer detection programs.
Treatment sequencing in MPC, insights from a 3˚ care center.
Authors: Barrera Ivan , Ranger Jill , Roofigari Nooshin , Dalfen Richard , Batist Gerald , Kavan Petr
Published: January 2019

400

Background: Since 2011, options for treatment of metastatic pancreatic cancer (mPC) have improved with the use of nab-paclitaxel plus gemcitabine (n-PGEM) or FOLFIRINOX (FFX) as first line treatments (1LTx). In 2016, Nanoliposomal irinotecan plus 5FU (nal-IRI-5FU) demonstrated efficacy in 2LTx. Yet, optimal sequential Tx has not been established. Methods: We evaluated oncologist-selected Tx algorithms and resultant progression free & overall survival (PFS, OS) for pts with mPC from 2010 and 2018 at the Jewish General Hospital, Montreal, QC. This retrospective study included 203 pts with mPC (33 to 89 years, 54% male). Results: 1LTx included 66 pts on FFX, 60 pts on n-PGEM, and 66 pts on single-agent GEM. The remaining pts received Capecitabine (CAP) or another Tx (N = 11). Mean PFS in FFX, n-PGEM, and GEM groups was 5.07, 5.52, and 4.10 months, respectively (progression was 1˚ or 2˚ disease progression or a change of Tx due to adverse events or intolerance). Only the FFX and GEM groups were significant when compared (p = 0.049). Only 43.8% of pts (N = 89/203) advanced to 2LTx most receiving GEM (N = 27), n-PGEM (N = 21), or FFX (N = 11), PFS 3.87, 7.04, and 2.30 months, respectively. FFX and n-PGEM groups were significant when compared (p=0.011). CAP and nal-IRI-5FU were 2LTx options for 25.8% (N=23/89) and 7.9% (N = 7/89) of pts, respectively. For 30 pts in 3LTx, Txs included: nal-IRI-5FU (N = 8), clinical trials (CT) (N = 7), GEM (N = 5), FFX (N = 4), n-PGEM (N = 2), CAP (N = 2) and Irinotecan (IRI) (N = 2). Only 7 pts received 4LTx: GEM (N = 3), CAP (N = 2), CT (N = 1), and IRI (N = 1). Median OS from start of 1LTx for pts in FFX (N = 60), n-PGEM (N = 41), and GEM (N = 60) groups was 11.42, 9.50, and 6.23 months, respectively. (Excluding pts on ongoing tx and other censored data points). GEM tx was a significant prognostic factor for shorter OS, GEM verus FFX, HR 1.673 (1.165 to 2.402, p = 0.0053), GEM versus n-PGEM, HR 1.511 (1.012 to 2.258, p = 0.0437). No difference in survival was seen between FFX and n-PGEM groups, HR 0.903 (95% CI 0.605-1.349, p = 0.6196). Conclusions: Though FFX and n-PGEM are considered mainstays of 1LTx, GEM was chosen by physicians in ~1/3 of cases despite reduced PFS. Pts on FFX or n-PGEM had better OS compared to GEM alone, as expected. Further investigation into Tx sequencing in this and larger cohorts, is needed.
Outcomes of stereotactic body radiotherapy for unresectable hepatocellular carcinoma.
Authors: Zhao Yizhou , Dunne Emma , Ma Roy , Liu Mitchell , Beaton Laura , Yeung Rosanna , Lund Chad R. , Schellenberg Devin
Published: January 2019

401

Background: Stereotactic body radiotherapy (SBRT) is an emerging curative treatment for hepatocellular carcinoma (HCC). We report toxicity and efficacy of all patients treated in British Columbia, one of the largest series to date. Methods: From 2011 to Jan 2018, 99 patients underwent SBRT to 128 HCCs. Fiducials were placed and 4D CT (78.4%) and respiratory gating (19.6%) were used for motion management. Local control (LC), progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier. Cox regression identified outcome predictors. Results: Median Child-Pugh Score (CPS) was A5 (65% A5, 18% A6, 12% B7, 5% B8, 1% B9) and median Albumin-Bilirubin (ALBI) score was -2.55, grade 2 (48% gr1, 45% gr2, 6% gr3). Most (87.7%) had either Hepatitis B or C and 73.7% had prior HCC treatment, with 47.5% going on to further HCC treatment post SBRT and 42.4% deceased at the time of analysis. The median tumor size was 2.8 cm (range 0.8 – 11). The median prescribed biologically effective dose (BED10) was 112.5 Gy, with 45 Gy in 3 fractions (BED10112.5 Gy) in 56.9% of cases and 45 Gy in 5 fractions (BED10 85.5 Gy) in 30.4%. Median follow-up was 18.5 months (range 2.2 – 73.5). At 3 months, 12 (11.8%) patients had a rise in CPS of ≥ 2, and 26 (25.5%) patients had increased ALBI grade (median change in score of +0.16). Excluding laboratory findings, 14 (14.1%) patients developed CTCAE V5 grade 3 / 4 toxicities (ascites n = 12, hepatic failure n = 4, hepatic pain n = 1, nausea n = 1, GI bleed n = 1). The 1-, 2- and 3-year LC were 94.3%, 86.6% and 80.2%. The median PFS was 14.8 months, respectively 53.7%, 39.5% and 23.8% at 1, 2 and 3 years. The median OS was 41.1 months, respectively 80.3%, 63.5% and 55.2% at 1, 2 and 3 years. Univariate factors predicting improved LC were mean dose (Dmean) ≥ BED10 100 Gy to GTV (p < 0.01) and PTV (p = 0.03). Predictors of improved OS were prescription dose ≥ BED10 100 Gy (p = 0.02), GTV Dmean ≥ BED10 100 Gy (p < 0.01), lower CPS (p = 0.04) and lower ALBI score pre-SBRT (p < 0.01), smaller tumor size (p < 0.01), no liver directed therapy post-SBRT (p < 0.01), younger age (p = 0.03) and favorable ECOG (p = 0.01). Conclusions: SBRT achieves excellent LC, with low rates of toxicity and can be included with or without other therapies in HCC treatment.
Prognostic factors and disease course in patients enrolled onto clinical trials of second-line therapy for hepatocellular carcinoma.
Authors: Personeni Nicola , Pressiani Tiziana , D'Alessio Antonio , Prete Maria Giuseppina , Bozzarelli Silvia , Smiroldo Valeria , Simonelli Matteo , Giordano Laura , Santoro Armando , Rimassa Lorenza
Published: January 2019

406

Background: Prognostic factors of survival and disease course in patients with hepatocellular carcinoma (HCC) and preserved liver reserves, enrolled onto clinical trials of second-line treatments after sorafenib, are unclear. Methods: This single-center database analysis included all patients with Child-Pugh A score and ECOG performance status (PS) 0 - 1 participating between 2012 and 2017 in clinical trials of second-line systemic treatments for advanced HCC. Patients received first-line sorafenib and experienced either disease progression (PD) to sorafenib or were sorafenib-intolerant. Their clinicopathologic characteristics were correlated with overall survival (OS, calculated from the first day of second-line treatment to death or last visit available), and post-treatment survival (PTS, calculated from the date of end-of-treatment to death or last follow-up). Results: Ninety-nine patients (21 sorafenib-intolerant, 78 progressors) were enrolled onto trials of checkpoint inhibitors (CPI, 23 patients), tyrosine kinase inhibitors (TKI, 44 patients) versus best supportive care (BSC, 24 patients), open-label TKI (8 patients). Overall, median OS was 9.4 months (9.6, 9.8, and 8.0 months for CPI, TKI and BSC, respectively; p = 0.493). Median time-to-treatment failure was 3.5, 4.4, 3.7 months for CPI, TKI and BSC, respectively (p = 0.561). In multivariable analyses, worse OS was linked to high neutrophil/lymphocyte ratio (Hazard Ratio, HR = 1.13; p = 0.005) and macrovascular invasion [(MVI), HR = 2.59; p < 0.001]. Second-line treatment discontinuation due to liver failure independently conferred worse PTS than adverse events (HR = 2.32; p = 0.111) or PD (HR = 3.44; p = 0.002), as did ECOG PS > 1 at EOT (HR = 3.05; p = 0.002). Death rate within 30 days of end-of-treatment was 4.2% on placebo versus 10.5% on IO versus 22.9% on TKI. Conclusions: In this homogeneous cohort of compensated HCC patients pre-treated with sorafenib, MVI and NLR at start of second-line clinical trial are prognostic factors of OS. Besides ECOG PS and liver failure, further predictors of subsequent PTS to inform treatment options beyond second-line were not identified.
The association of mutant allele frequency of TP53 with response of chemotherapy in advanced gastric cancer patients.
Authors: Zhang Shu
Published: January 2019

42

Background: The tumor suppressor gene TP53 is one of the most commonly altered genes in advanced gastric cancer (AGC). However, the predictive role of mutant allele frequency (AF) of TP53 on response of chemotherapy in AGC patients remains unclear. This study aims to explore the predictive value of mutant allele frequency of TP53 on efficacy of chemotherapy in AGC. Methods: We obtained a new biopsy using gastroscope and collected blood samples at baseline and at time of 3 cycles of chemotherapy (2 weeks each cycle) in 8 patients with AGC, and the circulating tumor DNA (ctDNA) and tumor tissue DNA were analyzed using next generation sequencing (NGS). The efficacy was evaluated at time of 3 cycles of chemotherapy by CT imaging according to the RECIST’s standard. Results: We selected 8 patients with advanced gastric adenocarcinoma confirmed pathologically, including 5 female, 3 male. Their Median age is 53 (32-78) years old. The sequencing depths of tissue samples and blood samples were greater than 1000x and 10000x, respectively. Of 8 patients, except for one patient with no mutation of TP53, 7 AGC patients had the mutations in the different sites of TP53 gene. The results showed that 5 patients had partial response (PR), and 2 patients revealed stable disease (SD) after chemotherapy. Five patients with PR showed more than 10% of mutant AF of TP53, but two patients with SD had less than 3% of the mutant AF. Of 5 AGC patients with PR, two patients showed that the mutant AF of TP53 had become from 77.0%, 20.20% to negative in the blood samples, three patients exhibited the decrease of mutant AF of TP53 from 36.99%, 21.61% and 10.04% to 15.77%, 0.40% and 0.69%, respectively. In two patients with SD, one patient revealed that the mutant AF of TP53 had decreased from 2.20% to negative, another one from 1.91% to 1.11%, respectively. Conclusions: Our results suggested that the decrease of mutant allele frequency of TP53 in blood sample can predict response to chemotherapy in patients with advanced gastric cancer. The AGC patients with more than 10% of mutant AF of TP53 maybe have a good outcome for chemotherapy but needs to be further explored.
Alpha fetoprotein (AFP) response and efficacy outcomes in the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC).
Authors: Kelley Robin Kate , Rimassa Lorenza , Ryoo Baek-Yeol , Park Joong-Won , Blanc Jean-Frédéric , Chan Stephen Lam , Dadduzio Vincenzo , Yau Thomas Cheung , Sen Suvajit , Markby David W. , Kaldate Rajesh , El-Khoueiry Anthony B. , Cheng Ann-Lii , Meyer Tim , Abou-Alfa Ghassan K.
Published: January 2019

423

Background: AFP response, defined as a decrease in serum levels of the tumor marker AFP after therapy, may be associated with improved survival of patients (pts) with HCC treated with locoregional or systemic therapy, and high baseline AFP levels may be associated with poor prognosis. In the phase III CELESTIAL trial (NCT01908426), C, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) versus P in pts with previously treated advanced HCC. Here we evaluate clinical outcomes with C in CELESTIAL based on AFP response or progression on treatment. Methods: 707 pts were randomized 2:1 to receive C (60 mg daily) or P. Eligible patients had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤ 1. Pts received prior sorafenib and ≤ 2 lines of prior systemic therapy for HCC. Serum AFP levels were measured centrally at baseline and every 8 weeks thereafter. Outcomes were evaluated for pts with baseline AFP ≥ 20 ng/mL based on AFP response ( ≥ 20% decrease from baseline) or progression ( ≥ 20% increase from baseline) at Week 8. This definition of AFP response has been used in previous studies but requires further validation in large prospective studies. Results: Overall, 331 pts (70%) in the C arm and 160 (68%) in the P arm had baseline AFP ≥ 20 ng/mL; among these pts, 236 (71%) and 111 (69%), respectively, were evaluable for AFP response at week 8. Among evaluable pts, 117 pts (50%) in the C arm vs 14 (13%) in the P arm had an AFP response, and 72 (31%) vs 75 (68%) had AFP progression. Median OS with C was 16.1 mo for pts with an AFP response versus 9.1 mo for pts without a response (HR 0.61, 95% CI 0.45-0.84), and median PFS with C was 7.3 mo versus 4.0 mo (HR 0.55, 95% CI 0.41-0.74). For pts with AFP progression, median OS with C was 8.1 mo, and median PFS with C was 3.6 mo. Hazard ratios for OS and PFS with C also favored AFP responders over non-responders when analyzed using best response through week 24. Conclusions: The AFP response rate was higher with C versus P, and AFP response was associated with longer OS and PFS with C for pts with previously treated advanced HCC. On-treatment AFP changes warrant further evaluation as a biomarker of response. Clinical trial information: NCT01908426.
Carcinoids of the ampulla: Long-term follow-up after endoscopic resection.
Authors: Baison George Nyasha , Sahar Nadav , Bonds Morgan M , Rekman Janelle F , Rocha Flavio G. , Irani Shayan
Published: January 2019

430

Background: Neuroendocrine tumors (NET) or carcinoids of the ampulla are exceedingly rare in comparison to duodenal NET. Surgical management is widely accepted as the treatment of choice, but for patients that refuse surgery or are poor operative candidates, endoscopic resection may be option. We present a consecutive case series at a tertiary care center describing our experience with endoscopic resection of ampullary NET. Methods: This is a restrospective review with a long-term follow-up of patients with ampullary NET that were endoscopically resected. Outcomes were analyzed based on the histopathologic classification system proposed by the World Health Organization in 2000. Results: Twelve patients (9 male, 3 female), ranging in age from 41 to 86 (mean 59) underwent endoscopic ampullectomy for ampullary NET, with a mean follow-up time of 5 years. Patients had refused surgery or were poor surgical candidates. All, but one incidentally found case, were symptomatic on presentation, with gastrointestinal bleeding being the main symptom. No patients had a hormonal syndrome. The mean size of the lesions was 21 mm (6 mm to 35 cm). Six (50%) patients had a well-differentiated, benign lesion, 6 (50%) patients had a well-differentiated NET with unknown malignant potential (gangliocytic paragangliomas). Eight (67%) were completely excised during the initial endoscopy with 4 requiring re-excision. Only 2 patients developed recurrence, after 2.5 and 10 years and this necessitated a pancreaticoduodenectomy. Five patients had complications (2 for bleeding and 3 for post-ERCP pancreatitis), with zero deaths. Conclusions: Unlike duodenal carcinoids, ampullary NET are rare. Pancreaticoduodenectomy can be offered to fit patients except for gangliocytic paragangliomas that do not require an aggressive operation. However, for those that refuse surgery or are poor candidates, endoscopic ampullectomy can be an option with acceptable short and long-term outcomes.
Treatment of hepatocellular carcinoma (HCC) after sorafenib (S) over the last 10 years.
Authors: Fung Andrea S. , Lee-Ying Richard M. , Meyers Daniel E. , Sim Hao-Wen , Knox Jennifer J. , Zaborska Valeriya O. , Davies Janine Marie , Ko Yoo-Joung , Batuyong Eugene , Cheung Winson Y. , Samawi Haider , Tam Vincent C.
Published: January 2019

438

Background: Until recently there were no standard treatments for HCC patients after S. This study characterizes subsequent treatments (STx) received by HCC patients over the past 10 years and assesses their impact on survival. Methods: HCC patients treated with S between 01/2008 – 06/2017 in British Columbia, Alberta, and two cancer centers in Toronto, Ontario, Canada (Princess Margaret and Sunnybrook Cancer Centre) were included. Clinical, pathologic, laboratory, treatment, and outcome data were collected. The Kaplan-Meier method was used to assess overall survival (OS) based on STx, and stratified according to a better prognostic group (BPG), defined as ECOG 0-1 and CP-A, and worse prognostic group (WPG), defined as ECOG≥2 or CP-B/C. Results: A total of 730 patients were identified. 177 (24.2%) received STx (table). Patients who received STx had longer median OS (mOS) than those who had no further treatment (12.1 vs. 3.3 months; p < 0.001). For patients treated with localized, systemic, or palliative radiation treatment, mOS was 16.8, 10.5 and 8.6 months, respectively (p < 0.001). After S, there were 206 (30.7%) patients in the BPG and 464 (69.3%) in the WPG. BPG patients were more likely to receive STx compared to WPG patients (60.5% vs. 39.5%, p < 0.001). BPG patients who received STx had better mOS than those who did not (15.9 vs. 7.0 months; p < 0.001). WPG patients also had better mOS if they received STx compared to those who did not (6.0 vs. 2.6 months; p < 0.001). Conclusions: Only a small proportion of HCC patients received subsequent treatment after sorafenib. This is likely due to poor performance status, liver dysfunction, or lack of treatment options. Patients who received subsequent treatment had improved mOS, regardless of whether they were in the better or worse prognostic group. [Table: see text]
Undertreatment of noncurative pancreatic adenocarcinoma?: A population-based analysis of patterns of care.
Authors: Mavros Michail , Davis Laura , Mahar Alyson L. , Beyfuss Kaitlyn , Earle Craig , Liu Ying , Coburn Natalie , Hallet Julie I.
Published: January 2019

439

Background: Noncurative pancreatic adenocarcinoma (PA) portends a guarded prognosis. Advancements in systemic therapy have improved this outlook. It is unknown whether patients get access to these therapies. We sought to define patterns of access to care and therapy for noncurative PA. Methods: We conducted a population-based analysis of nonresected PA over 2005-2016 by linking administrative healthcare datasets. Primary outcome was nonreceipt of cancer-directed therapy (radiation/chemotherapy; NRCDT). The first contact and overall consultations with specialized care (surgery, medical, or radiation oncology) were examined. Multivariate models examined factors associated with NRCDT. Results: Of 10,881 patients surviving a mean of 3.3 months (IQR: 1.2-8.5), 62% had NRCDT. More of patients of older age (65% of 71-80 years old, 89% of ≥81 years old), high comorbidity burden (68%), and lower socioeconomic status (69%), had NRCDT. Distance from residence to nearest cancer centre did not differ based on NRCDT. 35% of all patients did not see medical oncology, including 56% of NRCDT patients; 17% had no consultation with specialists. First contact with specialized care was surgery for 55% of all patients, and 50% with NRCDT. Most patients saw palliative care (81%) at median 27 days (IQR: 9-75) after diagnosis. Older age (OR 0.42 [0.37-0.48], and OR 0.14 [0.12-0.16] for 71-80 and ≥81 years old respectively), lowest income quintile (OR 0.62 [0.54-0.71]) and rurality (OR 0.63 [0.56-0.71]) were independently associated with lower odds of seeing medical oncology. First contact with oncology was independently associated with higher odds of receiving therapy (OR 1.48 [1.34-1.62]), compared to surgery. Conclusions: The majority of patients with noncurative PA did not receive cancer-directed therapy. Of those, more than half did not see medical oncology. While some patients may not be eligible to therapy, we identified disparities in receipt of cancer-directed therapy that indicate potential gaps in assessment for therapy and undertreatment, especially for vulnerable populations. This information is important to optimize access to and delivery of evidence-based care, and improve PA outcomes.
Dosing modifications to increase tolerability of gemcitabine and nab-paclitaxel in treatment of pancreatic cancer in the elderly.
Authors: Martin Jasmine L , Sidhu Simran , Benhayoun Nabil , Dedonno Michael , Brenner Warren S.
Published: January 2019

441

Background: Gemcitabine and nab-paclitaxel has been reported to prolong survival in patients with metastatic pancreatic cancer. This drug combination was studied in such patients in the MPACT trial with an average age of enrolled patients being 63. Pancreatic cancer, however, is a disease of the aging with a median age at diagnosis of 70. Reductions in dosing by 20% or more in one or both components and has been shown to improve the tolerability of this regimen, thereby increasing treatment exposure. Our study aims to examine the efficacy and tolerability of this drug combination in an elderly population and how this is affected by schedule and dosing modifications. Methods: A retrospective chart review was performed of 83 patients over the age of 70 with a median age of 79 who received this drug combination as first-line treatment for pancreatic adenocarcinoma at a single institution. Overall survival and progression-free survival were assessed as well as schedule modification, dose reduction, and rates of adverse events. Results: For patients with metastatic or non-metastatic disease, the mean overall survival and progression-free survival were found to be 10.57 months and 6.63 months, respectively. When only patients with metastatic disease are analyzed, these values were found to be 9.26 months and 6.05 months, respectively, which are similar to those observed in the MPACT trial. The most common adverse events of grade 3 or greater were fatigue in 34.9% of patients and hematologic adverse events including neutropenia in 27.7% and leukopenia in 25.3% of patients. Dose reductions were commonly used to mitigate adverse events. Reductions in either one or both drugs by at least 20% occurred in 84.3% of patients. Conclusions: Gemcitabine and nab-paclitaxel in treatment of pancreatic cancer is well tolerated in an elderly population with similar rates of adverse effects when compared with previous studies, though this population experienced a significantly higher rate of fatigue. Dose reductions were used frequently in this population to improve tolerability, which may have contributed to the observed increase in overall survival in this population.
Combined radiotherapy and transarterial chemoembolization as a first-line treatment for hepatocellular carcinoma with macroscopic vascular invasion.
Authors: Yoon Sang MIN , Joo Ji Hyeon , Jung Jinhong , Kim Yeon Joo , Park Jin-hong , Kim Jong Hoon
Published: January 2019

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Background: To evaluate the long-term clinical outcome of respiratory-gatedconformal radiotherapy in combination withtransarterial chemoembolization (TACE)asafirst-line treatment foradvanced hepatocellular carcinoma (HCC) with macroscopic vascular invasion (MVI). Methods: This was a retrospective analysis of patientswho were diagnosed with HCC showing MVI who received TACE plus radiotherapy as their initial treatment between 2010 and 2015. Inclusion criteria were Child-Pugh A or B hepatic function and Eastern Cooperative Oncology Group performance score 0–2. None of the patients had a previous history of radiotherapy to the liver or extrahepatic metastasis. Results: A total of 467 patients were included in the study. Patients were between 34 and 87 years of age, and 89.3% were male. The median maximum tumor diameter was 9.8 cm and 297 patients (63.6%) had Child-Pugh A hepatic function. Two hundred and eighty (60%) patients had multiple tumors; 45% of tumors showed bilobar involvement. Unilateral portal vein invasion was observed in 206 (44.1%) patients and main/bilateral portal veinor multiple vascular invasion were observed in 261 (55.9%) patients. The median overall survival was 12.5 months, with one- and two-year survival rates of 52% and 28%, respectively. Larger tumor size, multiple tumors, infiltrative tumor type, Child-Pugh class B, and alpha-fetoprotein ≥ 200 ng/ml were independent predictors of overall survival. Grade ≥ 3 hepatic and gastrointestinal toxicities were observed in 3 (0.6%) and 5 (1.1%) patients, respectively. Conclusions: Radiotherapy combined with TACE as an initial treatment was a safe and effective modality for advanced HCC patients with MVIand could be considered as first-line therapy in patients with liver-confined HCC showing MVI.
A randomized phase III trial of S-1/oxaliplatin (SOX) versus UFT/leucovorin as adjuvant chemotherapy for high-risk stage III colon cancer: The ACTS-CC 02 trial.
Authors: Takahashi Takao , Sunami Eiji , Kusumoto Tetsuya , Ota Mitsuyoshi , Sakamoto Yoshiyuki , Tomita Naohiro , Maeda Atsuyuki , Tejima Jin , Okabe Michio , Tanaka Chihiro , Yamauchi Junichiro , Itabashi Michio , Kotake Kenjiro , Takahashi Keiichi , Baba Hideo , Boku Narikazu , Aiba Keisuke , Ishiguro Megumi , Morita Satoshi , Sugihara Kenichi ,   ACTS-CC 02 Study Group
Published: January 2019

484

Background: The ACTS-CC 02 trial was designed to verify the superiority of postoperative adjuvant chemotherapy with S-1/oxaliplatin (SOX) over UFT/leucovorin (LV), one of the standard oral fluoropyrimidine regimens in Japan, in terms of disease-free survival (DFS) in patients (pts) with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). The results of the safety analysis have been reported previously (Clin Colorectal Cancer, 2018). We now present the 3-year DFS results as the primary endpoint. Methods: Pts who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300–600 mg/day of UFT according to body surface area [BSA] and 75 mg/day of LV on days 1-28, every 35 days, 5 courses) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80–120 mg/day of S-1 according to BSA on days 1-14, every 21 days, 8 courses). The primary endpoint was DFS. Results: From April 2010 through October 2014, a total of 966 pts were enrolled at 260 institutions. The full analysis set, excluding pts who withdrew informed consent before protocol treatment, comprised 478 and 477 pts in the UFT/LV group and SOX group, respectively. The median age was 65.0 years. The ECOG PS was 0 in 94.0%, and the disease stage was IIIA/IIIB/IIIC in 1.3%/50.2%/48.6%. The 3-year DFS rate was 60.6% in the UFT/LV group and 62.7% in the SOX group (HR: 0.90; 95% CI: 0.74-1.09; p = 0.28); the superiority of SOX was not demonstrated. In stage IIIB, the 3-year DFS rate was 69.3% and 68.5% in the UFT/LV group and SOX group, respectively (HR: 1.01; 95% CI: 0.74-1.37; p = 0.95). In Stage IIIC, the 3-year DFS rate was 50.6% and 55.8% in the UFT/LV group and SOX group, respectively (HR: 0.82, 95% CI: 0.63-1.06; p = 0.12). Notably, in the N2b subgroup, the 3-year DFS rate was 46.0% and 54.7% in the UFT/LV group and SOX group, respectively (HR: 0.76, 95% CI: 0.55-1.05; p = 0.10). Conclusions: SOX was not shown to be superior to UFT/LV in pts with high-risk stage III colon cancer. However, the oxaliplatin-based regimen was suggested to be more effective in advanced disease, such as stage IIIC and N2b. Clinical trial information: JapicCTI-101073.
Recent trends in age at diagnosis of colon cancer in the United States, 2004-2015, a National Cancer Database study.
Authors: Goodgame Boone Wilder , Virostko Jack , Capasso Anna , Yankeelov Thomas
Published: January 2019

490

Background: The incidence of colorectal cancer (CRC) in adults younger than age 50 has been increasing in the US since 1970. The US Preventive Services Task Force recommends screening for CRC beginning at age 50, while the American Cancer Society recently revised its guidelines to advise screening at age 45. We analyzed the National Cancer Database (NCDB) from 2004 through 2015 to determine whether the proportion of patients diagnosed younger than 50 has changed during this time. Methods: This was a retrospective study of NCDB data, which includes more than 70 percent of newly diagnosed cancer cases in the US. We examined the proportion of patients diagnosed prior to age 50 as our primary endpoint. We used the Cochran–Armitage test for trend to assess changes in the proportion of cases diagnosed at age < 50 years old as a function of year of diagnosis. Results: We identified 152,749 patients diagnosed under age 50 and 1,033,014 patients diagnosed at age 50 or greater. Over the study period, the proportion of the total number of patients diagnosed with colorectal cancer under age 50 increased (14.3% in 2015 vs. 11.5% in 2004, p < 0.0001). Younger adults with CRC presented with more advanced disease, with 49.9% stage III or IV disease, as compared to 40.0% in those diagnosed over age 50. Both men and women had a rising proportion of cases diagnosed younger than 50 (p < 0.0001) over time. In men, only non-Hispanic whites had an increase in diagnosis at ages less than 50 (p < 0.0001), while in women, all racial and ethnic subgroups had an increase in younger diagnoses over time (p < 0.01). All income quartiles (p < 0.001) demonstrated a proportional increase in younger adults over time, with the highest income quartile having the highest proportion of younger cases. The proportion of younger-onset CRC rose in urban areas (p < 0.001), but did not rise in rural areas. Conclusions: The proportion of persons diagnosed with CRC under age 50 in the US has continued to increase over the past decade. Younger adults presented with more advanced disease, suggesting that screening could improve outcomes.
Novel radiomics signature predicts lymph node metastasis in T1 colorectal carcinoma.
Authors: Ma Yanlei , Zhang Sheng , Li Xinxiang , Niu Tianye
Published: January 2019

506

Background: This study evaluates the predictive performance of radiomic features in metastasis of T1 colorectal carcinoma (CRC) to lymph nodes. Methods: A total of 10 200 CRC patients from our clinical cancer center included in this analysis. 225 eligible cases diagnosed with T1 CRC were included and divided into two groups: computed tomography (CT) image group (n = 82) and magnetic resonance image (MRI) group (n = 143) based on the preoperative image data available. A total of 548 radiomic features were extracted from each case and analyzed, and then a panel of radiomic features associated with lymph node metastases (LNM) were selected using Mann-Whitney U test. Combining these selected radiomic features and clinical data, the predictive performance for LNM was calculated using receiver operating characteristic (ROC) curves. Results: The prediction accuracy for LNM of T1 CRC could be improved to 0.88 by area under the receiver operating characteristic curve (AUC) through integration of one radiomic feature and three clinical indicators in CT group. In the group of contrast enhanced T1-weighted MRI (T1w-MRI), combination of two radiomic features and three clinical parameters present an AUC value of 0.85. In the group of T2-weighted MRI (T2w-MRI), combination of four radiomic features and five clinical characteristics identified T1 tumors with LNM with an AUC value of 0.87. Conclusions: The current study present a good predictive performance of combination of radiomic features with clinic characteristic in identifying T1 CRC with LNM, which may provide an important opportunity for us to make clinical treatment decision-making for T1 CRC patients.