bluuebunny/crossref_metadata_2025 huggingface dataset:
The interdisciplinary team: Education as a means to exemplify and optimize patient outcomes in gastric/GEJ cancers through collaborative discussions.
Authors: Parikh Kinjal , Cameron Davecia Ragoonath , Peters Pamela M.
Published: January 2021

248

Background: Care of patients with gastric/GEJ cancer involves multimodality treatment including various systemic and supportive approaches and collaboration of interdisciplinary team members. Optimizing care requires not only adherence to the latest evidence-based and guideline-driven recommendations but also the management of underlying comorbidities or treatment-induced conditions. This complex interplay of factors in treatment planning requires timely education for oncologists and nurses/NPs in both clinically driven topics and interdisciplinary collaboration. Methods: A series of 2 CME/CE-certified activities were launched to educate oncologists and nurses/NPs on the changing paradigms in gastric cancer as well as the interdisciplinary collaboration needed to optimize patient eligibility for treatment. Effectiveness was analyzed using 3 multiple-choice questions measuring knowledge and competence and 1 confidence question were presented as pre-/post- repeated pairs for each of the activities. Oncologists and nurses/NPs who completed both the pre- and post-CME questions were included in the analysis and McNemar’s tests were conducted to assess statistical significance of the results with p < .05 being considered significant. The CME activities launched in 2/2020 with data collected and reported as of 9/2020. Results: 8034 learners participated in the activities including 1163 oncologists and 3665 nurses/NPs. Analyses from the activities found improvement in knowledge, competence, and confidence. Data from oncologists (n = 94-302) and nurses/NPs (n = 169-510) are reported. Statistically significant changes were seen for oncologists in: Knowledge regarding the impact of nutrition and anemia can have on quality-of-life (QOL) and further treatments (50% pre, 72% post; p < .001); Competence related to implementing strategies to address nutrition and anemia to improve quality-of-life and to advance treatment (45% pre, 72% post; p < .001); Confidence regarding their ability to work together as an integrated, interdisciplinary team to enhance quality of life and treatment outcomes through a holistic treatment approach (68% pre, 83% post; p < .001). And for nurses/NPs in: Knowledge regarding the impact that nutrition and anemia can have on QOL and further treatments (34% pre, 50% post; p < .01). Conclusions: This online, interactive, expert-led, CME/CE-certified educational activity resulted in gains in oncologist and nurse/NP knowledge, competence, and confidence surrounding advanced gastric/GEJ cancer management and team collaboration. As patients with gastric cancer continue to present with poor performance status and require not only systemic interventions but also amelioration of underlying conditions, education remains essential for optimal outcomes to members of the interdisciplinary team.
Prognostic impact of chemoradiation-related lymphopenia in patients with gastric and gastroesophageal cancer.
Authors: Kim Daniel W , Lee Grace , Hong Theodore S. , Li Guichao , Roeland Eric , Keane Florence , Eyler Christine Elissa , Drapek Lorraine C. , Ryan David P. , Allen Jill N. , Berger David L. , Parikh Aparna Raj , Mullen John , Klempner Samuel J , Clark Jeffrey William , Wo Jennifer Y
Published: January 2021

249

Background: Limited data exists on how chemoradiation (CRT)-induced lymphopenia affects survival outcomes in patients with gastric and gastroesophageal junction (GEJ) cancer. We evaluated the association between severe lymphopenia and its association with survival in gastric and GEJ cancer patients treated with CRT. We hypothesized that severe lymphopenia would be a poor prognostic factor. Methods: We performed a retrospective analysis of 154 patients with stage 1-3 gastric or GEJ cancer who underwent CRT at our institution. Patients underwent photon-based radiation therapy (RT) with a median dose of 50.4 Gy (IQR 45.0-50.4 Gy) over 28 fractions and concurrent chemotherapy (CTX) with carboplatin/paclitaxel, 5-fluorouracil based regimen, or capecitabine. 49% received CTX prior to RT. 84% underwent surgical resection, 57% pre-CRT and 26% post-CRT. Absolute lymphocyte count (ALC) at baseline and at 2 months since initiating RT were analyzed. Severe lymphopenia, defined as Grade 3 or worse lymphopenia (ALC < 0.5 k/μl), was analyzed for any association with overall survival (OS). Results: Median time of follow up was 48 months. Median age was 65. 77% were male and 86% were Caucasian. ECOG PS was 0 or 1 in 90% and 2 in 10%. Tumor location was stomach in 38% and GEJ in 62%. Timing of CRT was preoperative among 68% and postoperative among 32%. The median ALC at baseline for the entire cohort was 1.6 k/ul (range 0.3-7.0 k/ul). At 2 months post-CRT, 49 (32%) patients had severe lymphopenia. Patients with severe lymphopenia post-CRT had a slightly lower baseline TLC compared to patients without severe lymphopenia (median TLC 1.4 k/ul vs. 1.6 k/ul; p = 0.005). There were no differences in disease and treatment characteristics between the two groups. On the multivariable Cox model, severe lymphopenia post-CRT was significantly associated with increased risk of death (HR = 3.99 [95% CI 1.55-10.28], p = 0.004). ECOG PS 2 (HR = 34.97 [95% CI 2.08-587.73], p = 0.014) and postoperative CRT (HR = 5.55 [95% CI 1.29-23.86], p = 0.021) also predicted worse OS. The 4-year OS among patients with severe lymphopenia was 41% vs. 61% among patients with vs. without severe lymphopenia (log-rank test p = 0.041). Conclusions: Severe lymphopenia significantly correlated with poorer OS in patients with gastric or GEJ cancer treated with CRT. CRT-induced lymphopenia may be an important prognostic factor for survival in this patient population. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating CRT-induced lymphopenia.
IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
Authors: Finn Richard S. , Qin Shukui , Ikeda Masafumi , Galle Peter R. , Ducreux Michel , Kim Tae-You , Lim Ho Yeong , Kudo Masatoshi , Breder Valeriy Vladimirovich , Merle Philippe , Kaseb Ahmed Omar , Li Daneng , Verret Wendy , Shao Hui , Liu Juan , Li Lindong , Zhu Andrew X. , Cheng Ann-Lii
Published: January 2021

267

Background: Atezo + bev has been approved globally for pts with unresectable HCC who have not received prior systemic therapy, based on results from IMbrave150 (NCT03434379). At a median of 8.6 mo follow-up, both coprimary endpoints were met, with statistically significant and clinically meaningful improvements observed with atezo + bev vs sor for OS (HR, 0.58 [95% CI, 0.42, 0.79]; P<0.001) and independently-assessed progression-free survival (PFS; per RECIST 1.1; HR, 0.59 [95% CI, 0.47, 0.76]; P<0.001) (Finn, et al. N Engl J Med 2020). Here, we report an updated OS analysis for IMbrave150. Methods: The global, multicenter, randomized, open-label, Phase III study IMbrave150 enrolled 501 systemic treatment–naive pts with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. This post hoc, descriptive OS analysis was conducted with 12 mo of additional follow up from the primary analysis. Results: 501 pts were enrolled, including 336 to atezo + bev and 165 to sor. At the clinical cut-off date of Aug 31, 2020, median follow-up was 15.6 mo and 280 OS events were observed. Median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (HR, 0.66 [95% CI, 0.52, 0.85]; P=0.0009). Survival at 18 mo was 52% with atezo + bev and 40% with sor. Survival benefit with atezo + bev over sor was generally consistent across subgroups and with the primary analysis. The updated objective response rate (ORR; 29.8% per RECIST 1.1) with atezo + bev was in line with the primary analysis, with more pts achieving complete response (CR; 7.7%) than previously reported. Additional response data are in Table. Safety was aligned with the primary analysis, with no new signals identified. Conclusions: IMbrave150 showed consistent clinically meaningful treatment benefit and safety with 12 mo of additional follow-up. The combination provides the longest survival seen in a front-line Phase III study in advanced HCC, confirming atezo + bev as a standard of care for previously untreated, unresectable HCC. Clinical trial information: NCT03434379. [Table: see text]
When will it be better? Lenvatinib combined with TACE for unresectable hepatocellular carcinoma: A retrospective analysis of real-world evidence in China.
Authors: Zhang Lan , Wang Yanhong , Ge Ningling , Gan Yu-Hong , Ren ZhengGang , Chen Yi
Published: January 2021

281

Background: TACE and lenvatinib has each shown to prolong overall survival in patients with unresectable HCC, combination of which may also improve clinical outcomes and have been widely used in the real world accordingly. However, the optimal timing of adding on lenvatinb to TACE remains unclear. We are aiming to evaluate the efficacy and safety between two combination strategies. Methods: From Nov 2018 to Jun 2020, 79 consecutive patients had received a combination treatment of lenvatinib and TACE. Patients followed up for more than 2 months were included in this analysis. They were classified as early-combination group(add on lenvatinib before or after the first TACE ) and late-combination group(add on lenvatinib after at least two procedures of TACE ). Tumor response and progression-free survival (PFS,time from the first day of prescribing lenvatinib to progression or death) were assessed according to RECIST1.1 criteria. Liver function were also evaluated at baseline and every 2 months later. AEs were recorded during the combination treatment period according to CTCAE 5.0. Results: A total of 48 u-HCC patients was finally enrolled. Median follow-up in all patients was 9.3(5.3-14.3)months. Patients’ baseline characteristics were similar in two groups. For early-combination group(n=22)and late-combination group(n=26), the mean age was 65±9.7 and 61±11.6years(p=0.2);BCLC stage C HCC was 59% and 54%(p=0.89);and Child-Pugh A proportion was 81.8% and 77%(p=0.73) respectively. The objective response rate(ORR) was 22.9% in total 48 cases. There was no significant difference in response rate (18.2% vs 26.9%, P=0.51) or disease control rate (90.9% vs 92.3%, P=1.00). Median PFS was significantly longer in the early-combination group than that in late-combination group (14.5 vs 8.9 months; p=0.048). The safety profile was similar between two groups. Grade 3/4 adverse events were 3 (13.6%) and 2 cases(7.7%) respectively (P=0.65). Conclusions: This is to date the first real-world data of the combination timing of lenvatinib with TACE in u-HCC patients. Early-combination strategy may be a better option for the u-HCC patients with a longer mPFS.
Treatment patterns and outcomes of hepatocellular carcinoma (HCC) patients (pts) in the CancerLinQ Research Database (CLQ).
Authors: Kabadi Shaum , Luo Linlin , Moren Andrew (Scott) , Baria Katherine
Published: January 2021

283

Background: Treatment and management of pts with HCC is complicated by the presence of underlying chronic liver disease. Clinical trials with unresectable HCC pts are generally limited to Child-Pugh A or pts with good performance status. Therefore there is limited data for less fit HCC pts, particularly those treated in the community practice setting. Methods: The study design was a retrospective cohort study using the US-based CancerLinQ Discovery Database (CLQ). CLQ was launched by the American Society of Clinical Oncology in 2016 and consists of longitudinal, demographically, and geographically diverse data aggregated from oncology practice Electronic Health Record databases. Eligible pts were ≥18 years at time of HCC diagnosis, had a diagnosis of stage IV HCC within the record, and had ≥2 clinical encounters on separate dates during follow-up after the date of diagnosis. The study period and patient identification period was Jan 1997–Aug 2019; follow up continued through May 2020. Patient demographics, clinical characteristics, and general treatment characteristics were summarized using descriptive statistics. Results: 460 pts were eligible for analysis. Of these, 141 pts (31%) had a Child-Pugh score as reported in medical charts or imputed based on structured and curated data. 76 (54%) pts were Child-Pugh class A, 59 (42%) Child-Pugh class B, and 6 (4%) Child-Pugh class C. The proportion of pts with chronic hepatitis C infection and liver cirrhosis was higher in pts with Child-Pugh classes B and C compared to A. Time from diagnosis to first systemic therapy decreased from a median of 126 days for pts with Child-Pugh class A, to 47 and 16 days for class B and C, respectively. Sorafenib was the most common regimen regardless of line of therapy, followed by PD-1 pathway inhibitors and chemotherapy. Median duration of sorafenib therapy decreased from Child-Pugh class A to C (table). There was a similar decrease in duration of therapy for pts receiving PD-1 pathway inhibitors and chemotherapy when moving from class A to class C. Conclusions: This is the first published retrospective study in HCC using the CLQ. Pts with Child-Pugh class B or C, who are typically excluded from clinical trials, represented 48% of the pts with a Child-Pugh score included in this analysis. Duration of therapy was numerically lower for pts with Child-Pugh class B or C compared to Child-Pugh class A. Further research is needed to describe real-world evidence outside the context of a clinical trial for HCC pts. Funding: AstraZeneca. [Table: see text]

Avg, average; obs, observed; TKI, tyrosine kinase inhibitor
DEDUCTIVE: A study of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma—Phase Ib results.
Authors: Iyer Renuka V. , Li Daneng , Dayyani Farshid , Phan Alexandria T. , Needle Michael N. , Abrams Thomas Adam
Published: January 2021

294

Background: A recent ph3 study combining bevacizumab (VEGF-A Mab) with atezolizumab (PD-L1 inhibitor) has shown significant improvements in OS and PFS demonstrating that a combination of VEGF and PDL1 inhibition can improve patient outcomes over sorafenib. Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The ph1 portion of this study combines T with D to establish the recommended phase II dose (RP2D) and provide preliminary safety and efficacy data. Methods: Major eligibility criteria are adults with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, creatinine clearance > 40 ml/min. Major exclusion criteria are co-infection with HBV and HCV and significant organ dysfunction. The starting dose is the combination of T 1 mg orally for 21 days followed by 7 days off treatment and D 1500 mg intravenously every 28 days. A DLT is generally defined as the occurrence of any Grade ≥3 immune or non-immune adverse event (AE) in Cycle 1 that is at least possibly related to the investigational regimen other than any grade of vitiligo or alopecia or Grade 3 controllable hypertension in cycle 1. The primary objective is to establish the RP2D and the safety and tolerability for this combination in patients with advanced HCC. Patients will be treated until progression of disease, unacceptable side effects, or death. Outcome measures will be AEs per CTCAE v.5 and cross-sectional imaging performed every 8 weeks. Results: Seven patients were enrolled in phase I. Six were male; the median age was 75 (range 40 to 82). One patient had mild elevation of LFTs and did not complete the 21-day course of T and was replaced. No patient experienced a >=grade 3 AE in cycle 1. The most common AEs, each seen in two of seven patients, were anorexia, cough, diarrhea, dysphonia, fatigue, hypertension, and palmar-plantar erythrodysesthesia. Two of seven have achieved a partial response. Conclusions: The combination of T with D in patients with untreated advanced HCC is well tolerated. The RP2D for the combination is T 1 mg orally for 21 days on treatment followed by 7 days off treatment and D 1500 mg intravenously every 28 days. In the phase II portion of the study an additional 30 patients will be treated at the RP2D. Secondary objectives are to assess the objective response rate, progression free survival, and overall survival in this population. Clinical trial information: NCT03970616.
Preliminary results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua
Published: January 2021

314

Background: Hepatocellular carcinoma (HCC) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. In the last decade, sorafenib was the first molecular target drug approved for the treatment of advanced liver cancer. Until recently, the combination of angiogenic inhibitor with anti-PD-1 /L1 monoclonal antibody has represented significant efficacy over sorafenib monotherapy in the first-line regimen of unresectable HCC. Nevertheless, there are still unmet needs in clinical practice due to limited choice of drugs. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, and has been approved for standard treatment of non-small cell lung cancer, small cell lung cancer and soft tissue sarcoma in China. Toripalimab, a humanized IgG4 mAb against PD-1, is the first Chinese-produced PD-1 inhibitor marketed, which has been approved as a second-line treatment for metastasis melanoma. This study aims to evaluate the efficacy and safety of anlotinib plus toripalimab as the first-line treatment for unresectable HCC. Methods: This was a single-arm, multicenter, phase II trial. 30 patients with unresectable HCC, Child-Pugh ≤7 and ECOG PS <2 will be enrolled if they had not been treated with prior treatment. Pts received anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigator according to mRECIST and irRECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR) and safety. Results: By the cutoff date of September 21, 2020, 11 pts were enrolled and of those 8 pts were evaluable. 9 pts (81.8%) experienced treatment related adverse events (TRAEs) and grade 3 TRAEs occurred in 5 pts (45.5%). No grade 4 or above TRAEs occurred. The most common TRAEs were decreased appetite (n =6, 54.5%) and fatigue (n =5, 45.5%).Among 8 evaluable pts, unconfirmed ORR was 25% (95% CI 0.032-0.651) with 1 unconfirmed CR and 1 unconfirmed PR, and DCR was 87.5% (95% CI 0.473-0.997) according to mRECIST. Conclusions: Anlotinib in combination with toripalimab showed tolerant toxicity and preliminary anti-tumor efficacy in first-line regimen for uHCC patients. Furthermore, it is needed to be proved in update results and large scale studies. Clinical trial information: ChiCTR1900028295.
Real-world data on overall survival associated with biweekly versus weekly cetuximab among metastatic colorectal cancer (mCRC) patients in the United States.
Authors: Agg Himani , Han Yimei , Cui Zhanglin Lin
Published: January 2021

33

Background: Cetuximab 250mg/m2 weekly (Q1W) after an initial dose of 400mg/m2 is approved for treatment of K-Ras wild-type mCRC. In real world 29% of patients received cetuximab 500mg/m2 biweekly (Q2W). In this study overall survival (OS) associated with Q2W vs Q1W dosing of cetuximab for mCRC in real world was compared. Methods: This study utilized Flatiron Health electronic health record-derived database to identify adult patients with stage IV or recurrent K-Ras wild-type mCRC who received cetuximab+FOLFIRI/FOLFOX/irinotecan, or cetuximab monotherapy in first, second or third-line therapy from 01/01/2013 to 12/31/2019. Patients were assigned to Q1W or Q2W cohort if they had 70% or more cetuximab infusions with a gap of 4-10 days or 11-18 days from previous infusion. Patients who did not fall into either cohort were excluded from analysis. Propensity score (PS) matching was used to balance cohorts on their baseline demographic, clinical and treatment characteristics. Kaplan-Meier methods and Cox proportional hazards regressions were used to compare OS. Results: Baseline characteristics for Q2W (N = 422) vs Q1W (N = 653) cohorts before PS matching- median age 62 vs 65 years, male 58.5% vs 59.3%, white 68.3% vs 66.5%, stage IV 56.6% vs 58.5%, ECOG PS 0/1 61.6% vs 52.1%, ECOG PS 2+ 9.2% vs 9.5%. After PS matching, baseline characteristics were balanced. Hazard ratios (HRs) comparing OS in PS-matched Q2W vs Q1W cohorts were not significant for overall or line of therapy populations (Table). Conclusions: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study. [Table: see text]
Dissecting novel mechanisms of hepatitis B virus-related hepatocellular carcinoma using meta-analysis of public data.
Authors: Aljabban Jihad , Rohr Michael , Syed Saad A , Cohen Eli , Hashi Naima , Syed Sharjeel , Khorfan Kamal , Boateng Emmanuel , Nemer Mary , Panahiazar Maryam , Hadley Dexter , Jalil Sajid , Mumtaz Khalid , Aljabban Hisham
Published: January 2021

333

Background: Hepatitis B is a cause of hepatocellular carcinoma (HCC) globally, irrespective of viral loads. Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation, and has implications in early diagnosis and treatment. Methods: We employed our Search, Tag, Analyze, Resource (STARGEO) platform to conduct a meta-analysis of public data from NCBI's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples. We present the results from the meta-analysis in Ingenuity Pathway Analysis. Results:Our analysis revealed LXR/RXR activation, LPS-IL-1 mediation inhibition of RXR, and FXR/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene RABL6. The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. Additionally, HOXA10 was a top upstream regulator and was strongly upregulated in our analysis. While described in other cancer, HOXA10 has not been well documented in HBV-related HCC and our causal analysis suggests it mediates pathogenesis through downregulation of tumor suppressors and its protective effect from oxidative stress. Conclusions: This meta-analysis describes possible role of viral regulatory proteins such as RABL6 and HOXA10 in the pathogenesis of HBV -related HCC. Further prospective studies are needed to confirm our findings.
Characterization of hyperprogressive disease in patients with advanced biliary tract cancer treated with anti-PD-1 inhibitor: A multicenter retrospective study.
Authors: Lee Choong-kun , Cheon Jaekyung , Kim Eo Jin , Kim Chang Gon , Kim Sunkyu , Kim Chan , Kang Beodeul , Choi Hye Jin , Yoo Changhoon , Chon Hong Jae
Published: January 2021

339

Background: Immunotherapy, including anti-PD-1 inhibitor, represents a promising breakthrough treatment in poor prognostic cancers such as biliary tract cancer (BTC). However, subset of pts suffer from unexpected acceleration of tumor growth following the initiation of immunotherapy, termed hyperprogressive disease (HPD). We assessed HPD in BTC pts treated with anti-PD-1 inhibitor in association with clinicopathologic features. Methods: This retrospective study included pts with BTC who were treated with pembrolizumab 200mg IV as palliative second or third line treatment in 4 tertiary hospitals in South Korea. Previous proposed tumor dynamic parameters including time to treatment failure (TTF), tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated per RECIST v1.1. Neural network modeling technique was adopted to find clinicopathologic features that can predict HPD. Results: Total of 223 pts with BTC were treated with palliative second or third line pembrolizumab between December 2015 to August 2020. ORR was 11.2% (n=1 for CR, n=24 for PR, n=70 for SD, n=118 for PD, and 10 pts not evaluable). Among patients with best response as PD (n=118), 41 patients (18.4% from total pts) met the criteria for HPD definition (>2-fold increase in both TGK and TGR in the experimental period compared to the reference period). HPD pts had worse prognosis compared to non-HPD pts in terms of TTF (median 1.4 vs 2.7 months, P =<0.0001) and OS (median 3.57 vs 5.27 months, P =0.03). Clinicopathologic features including age, ECOG performance status, primary tumor site, pathology, metastatic organ, previous treatment history (surgery or radiotherapy), pretreatment PD-L1 score, tumor markers, and baseline laboratory results (LDH, albumin, or neutrophil-to-lymphocyte ratio) did not predict HPD (compared to non-HPD pts or PD without HPD pts). By neural network modeling and plotting with hidden vectors, we could define HPD-high-risk cluster (n=37) and HPD-lower-risk cluster (n=80). Higher CA 19-9-to-lymphocyte ratio ( P =0.0004) or higher platelet-to-PD-L1 CPS (combined positivity score) ratio ( P =0.002) predicted HPD-high-risk-cluster. HPD pts (n=41) tend to have progression due to liver (73.2% vs 45.6%, P =0.0026) or peritoneum (53.7% vs 21.4%, P=<0.0001) metastases, compared to non-HPD pts (n=182). Conclusions: This study for the first time describe the clinicopathologic features of HPD among pembrolizumab treated BTC pts. Baseline pathology and laboratory tests may help optimal patient selection for immunotherapy to avoid HPD in BTC pts. Further validation of BTC-specific HPD predictive features and definition (TGK or TGR ratio cut-off) will be presented after comparison with clinicopathologic features among second line 5FU-based chemotherapy treated BTC pts.
Whole-genome sequencing of cholangiocarcinoma to reveal distinct profiles of patients with underlying cirrhosis or inflammatory disorders.
Authors: Holzapfel Nicholas Timothy , Zhang Amy , Denroche Robert Edward , Lam Bernard , Wilson Julie , Fischer Sandra , Notta Faiyaz , Gallinger Steven , Knox Jennifer J. , O'Kane Grainne M.
Published: January 2021

340

Background: Cholangiocarcinoma (CCA) is a lethal malignancy with limited treatment options. Molecular profiling of these tumours has revealed a number of actionable mutations and four clusters have been defined through integrative genomic analysis. We sought to explore whole genome sequencing (WGS) data in 20 patients enriched for CCA arising in the setting of cirrhosis or inflammatory disorders. Methods: A previously established Biliary Tract Cancer (BTC) database at the Princess Margaret Cancer Centre (PMCC)/University Health Network (UHN) was used to identify patients of clinical interest including long-term survivors, those with germ-line mutations, and those with chronic inflammatory disorders. WGS and bioinformatic analyses were performed at the Ontario Institute for Cancer Research. Results: The 20 resected samples included 12 patients (pts) with intrahepatic CCA, 7 perihilar CCA, and 1 distal CCA. 8 pts were alive > 8 years post resection and one patient harboured a germline MLH1 pathogenic variant (MLH1 G67R). 3 pts had documented cirrhosis (hepatitis B n = 2, haemochromatosis n = 1); other inflammatory disorders (n = 4) included ulcerative colitis (UC) without documented PSC (n = 1), PSC alone (n = 1), UC with PSC (n = 1), and ankylosing spondylitis (n = 1). The remaining cases were randomly selected. The predominant COSMIC single base substitution (SBS) mutational signatures were 1, 8 and 5, and the median TMB was 1.75 mutations per MB (0.73-33.23). The pt with an MLH1 mutation exhibited a TMB of 33.23 with predominance of SBS26. Actionable variants were enriched in the 8 pts who are alive and disease free including 2 predicted FGFR fusions and mutations in IDH1 (n = 1), BRAF V600E (n = 1), and BAP1 (n = 1). TP53 mutations (n = 7) were present exclusively in patients with cirrhosis or inflammatory disorders and the median survival in the group was 12 months (3 -21 months). Although SBS signatures were similar in this group, in the two cases of UC, SBS17 (unknown etiology) was evident. SBS17 was also dominant in one case where the TMB was 13 mutations per MB and the patient died within 3 months of diagnosis. A somatic case of homologous recombination deficiency, with no causative genetic alteration identified, was evident in a further patient receiving maintenance rituximab for a coexisting stage 4 mantle cell lymphoma. Conclusions: WGS may provide additional biological information in CCA particularly in patients with underlying inflammatory disorders, where TP53 mutations are prevalent and mutational signatures are distinct.
Association between post-treatment (tx) alpha-fetoprotein (AFP) reduction and outcomes in real-world (rw) U.S. patients (pts) with advanced HCC (aHCC).
Authors: Wang Xiaoliang , Magee Kelly , Gossai Anala , Parrinello Christina M. , Miksad Rebecca A. , Kim Richard D. , Abou-Alfa Ghassan K.
Published: January 2021

341

Background: A decrease in post-tx AFP may be associated with improved outcomes in clinical trials. However, the impact of AFP reduction after initiation of a first-line (1L) tyrosine kinase inhibitor (TKI) therapy on outcomes is unclear among pts with aHCC treated in routine clinical practice. Methods: This analysis utilized data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included pts with aHCC with ≥2 visits between 1/1/2011-7/31/2019 who received 1L TKI. Pts with a baseline serum AFP value (closest to 1L initiation within -30 to +7 days) and a post-tx AFP value (closest to 8 weeks after 1L initiation within ±2 weeks) were included. Post-tx AFP reduction was defined as a ≥20% decrease from baseline AFP, and no reduction as a <20% decrease or any increase. Rw overall survival (rwOS) was defined as time from post-tx AFP measurement to death (censored at last EHR activity). Rw progression-free survival (rwPFS) was based on clinician documentation and defined as the first progression event or death after post-tx AFP measurement (censored at last clinic note date). Adjusted hazard ratios (aHR) for reduction vs no reduction (reference) were estimated using multivariable Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification was assessed by conducting tests for interactions with analyses stratified by HCC risk factors. Results: 441 pts were included in the study. 8% had documented history (hx) of hepatitis B (HBV), 52% hepatitis C (HCV), 47% obesity/diabetes (DM), 42% heavy alcohol use, and 11% no documented risk factor. Median baseline AFP was 210 ng/mL (IQR 237 - 2981) and 150 ng/mL (IQR 17 - 1311) among pts with reduction (N = 150) and no reduction (N = 291). There was a 35% decrease in hazard of death for pts with reduction vs no reduction (median rwOS 10.3 vs 6.7 months; Table). Similarly, a 35% decrease in hazard of rw progression or death was observed for pts with reduction vs no reduction (aHR=0.65; 95% CI: 0.52-0.81; median rwPFS 4.4 vs 2.4 months). Reduction (vs no) was associated with better rwOS among pts with hx of HCV, obesity/DM or alcohol use vs without the respective risk factor, however, no statistically significant interactions were observed (Table). Conclusions: Results show post-tx AFP reduction may be prognostic for rwPFS and rwOS in pts with aHCC treated with 1L TKI. Further research may clarify if prognostic value differs by HCC risk factor profile. [Table: see text]
Factors influencing adjuvant treatment decision making among Chinese patients with hepatocellular carcinoma (HCC): Results of a patient survey.
Authors: Sun Hui-Chuan , Zhu Xiao-Dong , Xu Li , Shen Ying-Hao , Huang Cheng , Zhou Jian , Fan Jia
Published: January 2021

346

Background: This study aimed to understand patient decision-making factors for post-operative adjuvant treatment after resection of hepatocellular carcinoma (HCC) in China. Methods: Patients who had received surgical resection of HCC in the last 2 years at 27 hospitals in China were surveyed using a questionnaire (https://pro.wenjuan.com/t/jUZFU). Feedback was collected by telephone or online. The survey covered three domains: adjuvant treatment decision making, selection of treatment regimen and the influence of recurrence risk on willingness to receive adjuvant treatment. For each domain, participants were asked to identify decision makers and to score decision-making factors from 1 (no influence) to 7 (high influence). All factors with an average score of 6 or 7 points were considered impactful, and those with scores ≤5 were not considered impactful. Descriptive statistics were used to summarize the findings. This study was approved by the ethics committee of Zhongshan hospital and patients provided informed consent. Results: In total, 2,220 valid responses were collected (2,183 patients from Zhongshan Hospital, 37 from 26 other hospitals); 75% of respondents were male, 60% were aged 50-70 years, and 50% had a monthly family income ≤5,000 Chinese Yuan (~$740 USD). Among respondents, 62% had received adjuvant treatment: 56% received systemic therapy (chemotherapy, tyrosine kinase inhibitors, immune therapy and traditional Chinese medicine), 27% transarterial chemoembolization (TACE) plus systemic therapy and 17% TACE alone. The majority of respondents (75%) identified physicians as the decision makers for use of adjuvant therapy and selection of treatment regimen. Of the 38% of respondents who did not receive adjuvant treatment, 90% gave ‘physician recommendation’ as the reason. When patients were the decision makers, factors influencing decisions to use adjuvant treatment and selection of treatment regimen, ranked from most to least influential, were efficacy (for prevention of tumor recurrence), reimbursement status, treatment side effects and cost. Patient willingness to receive adjuvant treatment was influenced by predicted risk of recurrence; among respondents with an estimated 2-year recurrence risk > 10% and > 30%, 40% and 56%, respectively, believed they should receive adjuvant therapy. Conclusions: A majority of patients surveyed received adjuvant therapy, the most common of which were systemic therapy and TACE. Patients who underwent resection had a strong desire to reduce postoperative recurrence by using adjuvant therapy. Physician opinion was identified as the most important factor in treatment decision making, followed by economic factors. When patients were the decision maker, the most influential factors were treatment effectiveness followed by reimbursement status.
Defining optimal selection criteria to improve prognosis and avoid futility in surgical resection of colorectal peritoneal metastases.
Authors: Bijelic Lana , Ramos Isabel , Sabia Domenico , Crusellas Oriol , Martin Montse , Barrios Pedro
Published: January 2021

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Background: Surgical resection of peritoneal metastases of colorectal cancer (CRC PM) may benefit some patients similar to hepatic metastases. This approach remains controversial in part due to inconsistent selection criteria and reported outcomes. The impact of preoperative clinical characteristics and tumor molecular profiles on survival among surgically treated patients is incompletely understood. The aim of this study was to investigate the relationship between possible predictive variables and survival in a large cohort of patients treated on a standardized clinical pathway and to develop a clinically useful patient selection tool. Methods: This retrospective cohort study utilized the database of the Catalonian peritoneal metastases regional program, established in 2006. The program provides treatment for all PM patients within an autonomous region with a population of 7.5 million and includes a single dedicated high volume surgical unit. We included all adult patients with surgically resected CRC PM. The clinical pathway includes the administration of perioperative (neoadjuvant and adjuvant) systemic chemotherapy and has historically included a dose of heated intraoperative intraperitoneal chemotherapy (HIPEC) at the time of surgery. Demographic and clinical data was analyzed with descriptive statistics. Survival and the associated predictors were analyzed with the Cox proportional hazard model with HRs used to create a predictive nomogram. Results: A total of 538 patients (mean age 59) have been treated with surgery and a complete resection (CC0) was achieved in 94% of cases. Planned preoperative systemic chemotherapy was delivered in 95% of cases, consistent with the clinical pathway. Surgical morbidity was low (urgent reoperation 6.1%, postoperative return to the ICU 2.4%, 30-day readmission 4.3%) as was 30-day mortality (0.4%). After a median follow up of 27.5 months, the median overall survival (OS) was 43.1 months. It varied considerably by subgroup: patients with low peritoneal tumor burden had the highest OS (median 49 months) and those with signet ring cell subtype the lowest (median 19 months). Factors independently associated with survival were: N stage at diagnosis, histological subtype, quantified peritoneal tumor burden (PCI score) and presence of visceral involvement. A selection tool and predictive nomogram were designed incorporating the results of the multivariable analysis. Conclusions: A set of clinical variables can be identified that independently influences patient survival after surgical resection of CRC PM that should be used as selection criteria when considering surgery. With optimized patient selection and treatment within a specialized center, excellent survival and low morbidity can be anticipated following surgery for CRC PM.
A clinical score (CS) for patients with well-differentiated neuroendocrine tumors (WD NETs) under consideration for peptide receptor radionuclide therapy (PRRT) with Lu 177-dotatate.
Authors: Das Satya , Du Liping , Schad Aimee , Jain Shikha , Jessop Aaron , Shah Chirayu , Eisner David , Cardin Dana Backlund , Ciombor Kristen Keon , Goff Laura Williams , Bradshaw Marques , Delbeke Dominique , Sandler Martin P. , Berlin Jordan
Published: January 2021

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Background: Despite the benefit of PRRT for patients with WD NETs, questions remain regarding sequencing and optimal patient selection for the treatment. We developed a CS at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with WD NETs receiving PRRT. Methods: Patients with progressive WD NETs (N = 146) under consideration for PRRT with Lu 177-dotatate between 3/1/2016-3/17/2020 at VICC (N = 122) and Rush Medical Center (RMC) (N = 24) were scored. The CS included 5 categories: available non-PRRT treatments for tumor type, prior systemic treatments, patient symptoms, tumor burden in critical organs and peritoneal carcinomatosis presence. All categories were scored from 0-2 except the peritoneal carcinomatosis category which was scored from 0-1; scoring criteria were determined by the VICC NET tumor board. All patients at VICC were prospectively scored, while patients from RMC were scored retrospectively with the investigator blinded to patient outcomes. The primary outcome, progression-free survival (PFS) was estimated by the Kaplan‐Meier method; a Cox proportional‐hazards model adjusting primary tumor site, tumor grade and number of PRRT doses administered (none, 1-2 doses or 3-4 doses) was used to analyze effect of CS. Results: Median patient age was 62.7 while median CS was 5 (range 1-8); the most common primary tumor sites were small intestinal (N = 81) and pancreatic (N = 37). A total of 101 patients and 31 patients received 3-4 doses and no doses of PRRT, respectively. On multivariable analysis, in patients treated with 3-4 doses of PRRT, for each 2-point increase in CS, the estimated hazard ratio (HR) for PFS was 3.26 (95% confidence interval (CI) 2.05-5.19). On multivariable analysis, in patients who received no doses of PRRT, for each 2-point increase in CS, the estimated HR for PFS was 1.37 (95% CI .78-2.41). Conclusions: Among patients treated with 3-4 doses PRRT, those with lower CS had better PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive PRRT, suggesting the predictive utility of the CS for patients with WD NETs receiving PRRT with Lu 177-dotatate. Though the CS needs to be validated, it is the first of its kind reported.
Treatment response and clinical outcomes of well-differentiated high-grade neuroendocrine tumors to 177Lu-DOTATATE.
Authors: Coffman Kelley Lauren , Bodei Lisa , Le Tiffany , Choi Ye , Chou Joanne F. , Capanu Marinela , Dunphy Mark , Fox Josef J. , Grewal Ravinder K , Reddy Ryan , Riedl Christopher , Schöder Heiko , Reidy Diane Lauren , Raj Nitya Prabhakar
Published: January 2021

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Background: 177Lu-DOTATATE is an approved therapy for somatostatin receptor (sstr) positive gastroenteropancreatic neuroendocrine tumors (NETs). There are little data available on response and outcomes for well differentiated (WD) high grade (HG) NETs treated with 177Lu-DOTATATE. Methods: Pts with WD HGNETs treated with 177Lu-DOTATATE at MSK from 2018-2020 were identified. Demographics, response to treatment, and progression-free survival (PFS) were determined. In pts with archival tumor tissue, next-generation sequencing (NGS) was performed through an institutional platform (MSK-IMPACT). Results: 19 pts were identified (mean age 54, 63% female). Site of tumor origin included: pancreas (14/19, 74%), small bowel (2/19, 10.5%), rectal (2/19, 10.5%), lung (1/19, 5%). Average tumor Ki-67 was 34.8 (range 22-56). All tumors were sstr avid on pre-treatment Ga68-DOTATATE PET/CT; none of the patients had sstr negative lesions detected. Median number of prior treatments (systemic and/or liver-directed) was 4 (range 2-7). All pts had progressive disease prior to initiation of 177Lu-DOTATATE. 13 pts (68%) completed all four treatment cycles; treatment was incomplete in 6 pts due to treatment-related toxicities (n = 3) and clinical progression (n = 3). Best response by radiographic report was available in 16 patients (84%):10/16 (63%) with partial response, 1/16 (6%) with stable disease, 5/16 (31%) with disease progression. One pt with stable disease as best response received two additional cycles of 177Lu-DOTATATE at progression. Median PFS (from date of first treatment with 177Lu-DOTATATE until progression/death) was 11.1 months (95% CI 10.6 to NA). Five pts (26%) experienced dose modifying toxicity with 177Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 pts, 47%; G3/4 in 1 pt, 5%), anemia (7 pts, 37%; G3/4 in 2 pts, 10.5%), leukopenia (6 pts, 32%; G3/4 in 0 pts), and AST/ALT elevation (4 pts, 21%; G3/4 in 0 pts). NGS results were available in the tumor tissue of 13 pts (68%). The most commonly observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations were identified. Conclusions: We observed a meaningful disease control rate of 69% during treatment of WD HGNETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of pts received all four treatment cycles with treatment-related toxicities largely bone-marrow related, as expected, based on historical data. As would be expected in sstr avid tumors, the vast majority had alterations in chromatin remodeling genes (MEN1, DAXX) consistent with WD NETs, with no RB1 alterations identified.
Efficacy of ipilimumab and nivolumab in patients with high-grade neuroendocrine neoplasms.
Authors: Al-Toubah Taymeyah E. , Gile Jennifer , Strosberg Jonathan R. , Halfdanarson Thorvardur Ragnar
Published: January 2021

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Background: Dual checkpoint inhibitor therapy with anti-PD-1 and ant-CTLA-4 therapy has shown promising results in patients with high-grade NENs, demonstrating varying response rates of 9 – 44%. More data are needed to evaluate the true response in a real-world cohort of patients. Methods: Retrospective study of all patients with high-grade neuroendocrine neoplasms treated at the Moffitt Cancer Center and Mayo Clinic between 9/2017 and 7/2020 who received combination therapy with ipilimumab and nivolumab. Primary endpoint was objective response rate. Results: 34 patients met eligibility criteria for evaluation. Patients had received an average of 2 lines of therapy prior to treatment with ipilimumab/nivolumab, including at least one cytotoxic chemotherapy regimen. 27 (79.4%) of patients had poorly differentiated NECs and 7 (20.6%) had well-differentiated high grade NETs. The most common primary site (10, 29.4%) was pancreas; other primary sites of disease included unknown primary (n = 9), colon (n = 5), uterus (n = 3), anorectum (n = 2), esophagus (n = 2), cervix (n = 1), stomach (n = 1), and small intestine (n = 1). 5 patients (14.7%) exhibited a best response of PR per RECIST 1.1 criteria, 9 (26.5%) SD, and 17 (50%) PD: 3 patients did not have a follow-up scan and discontinued treatment shortly after initiation due to clinical progression. ORR was 14.7% and DCR was 41.2%. Median PFS was 1 month (95% CI, 0.45 – 1.55); median OS from time of treatment initiation was 5.0 months (95% CI, 3.42 – 6.59) and median OS from diagnosis was 14.0 months (95% CI, 1.49 – 26.51). Median duration on treatment was 1 month (range 0 – 10 months). 26 patients discontinued treatment for progression, 4 patients for toxicity, and 4 remain on treatment at the time of data cut off. 12 patients (35%) experienced grade 3 and 4 treatment-emergent toxicities: liver transaminitis, elevated blood bilirubin, arthralgia, myalgia, peripheral sensory neuropathy, lower extremity edema, confusion, diarrhea, encephalopathy, acute kidney injury, rhabdomyolysis, myocarditis, and colitis. Conclusions: The ipilimumab and nivolumab regimen has modest activity in aggressive and heavily pretreated high-grade NENs who have progressed on prior cytotoxic chemotherapy. Use of this regimen may be considered in patients with particularly aggressive, refractory high-grade NENs.