bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of historical medical conditions or comorbidities with potential role in clinical decision making related to suitability of immuno-oncologic plus IV antiangiogenic therapy in newly diagnosed first-line unresectable hepatocellular carcinoma in the United States.
Authors: Schuler Tammy , Passos Chaves Leonardo , Kamble Shital , Bland Emily , Feinberg Bruce A.
Published: January 2023

511

Background: Treatment landscape in advanced/unresectable hepatocellular carcinoma (uHCC) has been rapidly changing. In June 2020, the first immuno-oncologic (I/O) + IV anti-angiogenic regimen for uHCC was approved as first line (1L) treatment in the US. As with any new therapy, it is key to understand the prevalence of medical conditions listed in patient medical history/comorbidities that could potentially influence physician choice of 1L therapy in uHCC patients. Methods: We conducted a retrospective chart review study using Cardinal Health's Oncology Provider Extended Network (OPEN). US medical oncologists identified newly diagnosed adult uHCC patients initiating 1L systemic therapy from June 2020 to April 2022. Based on the warnings and precautions section of the US FDA labels, medical conditions reported as part of patient medical history or comorbidities [including gastrointestinal (GI) bleeding risk, chronic kidney disease, autoimmune disorders, thromboembolic events] were identified from patient medical records. Less suitable was defined as the occurrence of ≥ 1 medical condition/comorbidity reported in the medical record. All patient data were deidentified. Proportions of patients with the above medical conditions or with physician-reported record of an esophagogastroduodenoscopy (EGD) procedure to assess risk of bleeding were calculated. Results: In the cohort of 433 uHCC patients initiating 1L systemic therapy, majority were male 287 (66%), Caucasian 244 (56%) with average age of 64 years. At 1L initiation, majority of the patients were 333 BCLC Stage C (77%) and 316 (73%) had ECOG performance status of 0 or 1. Approximately 160 (37%) were Child-Pugh B, 99 (23%) had non-alcoholic steatohepatitis (NASH), 176 (41%) had Hep-C etiology (among those tested), and 294 (68%) had liver cirrhosis. Prior to therapy initiation, 254 (59%) received EGD within 3 months. In the overall cohort, 221 (51%) patients were reported to have at least one condition listed as medical history/comorbidity that could make them less suitable to receive I/O + IV anti-angiogenic regimen. Upper/lower GI bleeding risk and chronic kidney disease were reported in 164 (38%) and 64 (15%) patients, respectively. History of thromboembolic events and autoimmune disorders were reported in 50 (12%) and 22 (5%) of patients, respectively. Conclusions: A significant proportion of the newly diagnosed uHCC patients were found to have at least one condition listed as medical history/comorbidity that would make them potentially less suitable for I/O + IV anti-angiogenic regimen. Our findings reinforce the importance of medical history and co-morbidity assessment in uHCC patients prior to therapy selection to optimize benefit-risk ratio for each patient.
Clinical and prognostic utility of ALBI versus Child-Pugh score in a Mexican population with hepatocellular carcinoma.
Authors: Diaz Romero Maria del Consuelo , Zilli Hernandez Stefan , Calderillo Ruiz German , Camacho Sanchez Ana Zyanya Xcaret , Carbajal Berenice , Herrera Marytere , Ruiz-Garcia Erika , Miyagui-Adame Sayako Mariana
Published: January 2023

517

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The assessment of liver function is crucial in determining the prognosis of patients. Aim: To compare the utility of the ALBI and CHILD-PUGH scores in predicting the prognosis and treatment of patients with hepatocellular carcinoma at the National Cancer Institute, Mexico. Methods: Retrospective, observational study. Included patients diagnosed with HCC and treated at the National Cancer Institute 2008-2021. Statistical analysis included: X2 and t-test, Kaplan Meier, Log Rank, and Cox Regression. Statistical significance was assessed when p was bilaterally <0.05. Results: A total of 315 patients diagnosed with HCC were included, mostly male (61%) with a median age of 67 years, mostly in the advanced stages of the disease (90%). Regarding liver functionality scores, of the patients who were scored in CHILD-PUGH-A5 (n=124), 53% were in ALBI G1, while 47% scored ALBI G2. Regarding the CHILD-PUGH-A6 group (n=92) only 71% of patients scored ALBI G2, and among CHILD-PUGH-B7 score (n=55) patients, only 13% scored in the ALBI G3 group (p<0.001). In survival analysis, CHILD-PUGH-A5 patients had a median OS of 40 months, while CHILD-PUGH-A6 patients showed a median OS of 11 months (p<0.001). Patients with a CHILD-PUGH-B7 score showed a median OS of 10 months compared to patients with a CHILD-PUGH-B8 score who showed a median OS of 4 months (p=0.93). Among ALBI score, G1 patients did not reach median OS, while the median OS of patients with G2 and G3 was 13 and 4 months respectively (p<0.001). At Univariate analysis, histology (HR:1.22; p=0.021), bilirubin (HR:1.12; p<0.001), albumin (HR:0.33; p<0.001), CHILD-PUGH (HR:1.27; p<0.001), ALBI (HR:2.91; p<0.001), ECOG (HR:1.82; p<0.001), surgery (HR:2.24; p=0.029) and systemic treatment (HR:2.57; p<0.001) showed statistical differences. While only albumin (HR: 0.45; p=0.027), ECOG (HR: 1.49; p=0.006), systemic treatment (HR: 1.78; p=0.026) and ALBI score (HR: 1.71; p=0.032) remained predictors of OS. Conclusions: The study demonstrates that ALBI score presents a better prognostic and liver function stratification than CHILD-PUGH score in Mexican population.
Real-world dosing of regorafenib in patients with unresectable hepatocellular carcinoma (uHCC): Final analysis of the prospective, observational REFINE study.
Authors: Finn Richard S. , Merle Philippe , Ikeda Masafumi , Klümpen Heinz-Josef , Masi Gianluca , Granito Alessandro , Lim Ho Yeong , Kudo Masatoshi , Qin Shukui , Gerolami René , Huang Yi-Hsiang , Kim Do Young , Pinter Matthias , Kato Naoya , Kurosaki Masayuki , Numata Kazushi , Khan Javeed , Ozgurdal Kirhan , Kim Yoon Jun
Published: January 2023

518

Background: Final results from the real-world REFINE study confirmed the safety and effectiveness of regorafenib (REG) in a broad population of patients (pts) with uHCC that was consistent with the results from RESORCE, in which REG prolonged overall survival (OS) vs placebo in pts with uHCC who progressed on prior sorafenib. Here we evaluate baseline characteristics and outcomes according to the initial REG dose. Methods: REFINE (NCT03289273), an international, prospective, multicenter study, enrolled pts with uHCC for whom a decision to treat with REG was made by the treating physician prior to enrollment according to the local health authority approved label (160 mg/day, 3 weeks on/1 week off). The primary objective was safety (NCI-CTCAE v4.03); secondary endpoints included OS and progression-free survival (PFS). Results: Of 1005 pts eligible for analysis, 47%, 11%, 40%, and 3% initiated REG at 160 mg, 120 mg, 80 mg, and 40 mg, respectively. A higher proportion of pts from Asia initiated REG at 160 mg (51%) vs non-Asian countries (42%), and 67% were Child–Pugh A in Asia vs 54% in non-Asian countries at study entry. Pts initiating REG at 160 mg were more likely to be Child–Pugh A and albumin–bilirubin (ALBI) grade 1 vs pts initiating REG at <160 mg (Table). A higher proportion of pts (53%) who initiated REG at 160 mg ended prior sorafenib at 800 mg/day. Of the pts intolerant to prior sorafenib (n=91), more pts started REG at 80 mg (49%), followed by 160 mg (32%) and 120 mg (9%). Median duration of REG treatment was similar across initial dose levels (overall 3.7 months). Any-grade TEAEs were reported for 90%, 93%, and 93% of pts initiating REG at 160 mg, 120 mg, and 80 mg, respectively. TEAEs led to dose modifications in 49%, 51%, and 38% and to dose reductions in 34%, 26%, and 17% of pts. Median OS was 15.8 months in pts who initiated REG at 160 mg, 13.3 months at 120 mg, and 11.1 months at 80 mg. Median PFS was similar across doses (overall 3.9 months). Conclusions: In this real-world study, most pts with uHCC initiated REG at 160 mg or 80 mg/day. A higher proportion of pts from Asia initiated REG at the recommended dose, and a higher proportion of pts initiating REG at 160 mg had relatively better liver function at study entry. Safety was generally similar regardless of initial dose, and OS was observed to be longer in pts initiating REG at 160 mg vs lower doses. Clinical trial information: NCT03289273 . [Table: see text]
The real-world prevalence of esophagogastric varices, bleeding, emergency room visits, and hospitalization among patients with advanced hepatocellular carcinoma in the US.
Authors: Parikh Neehar , Yu Shengsheng , Park Noh Jin , Locker Michael , Chopra Ishveen , Yeaw Jason
Published: January 2023

519

Background: Upper gastrointestinal bleeding associated with esophagogastric varices (EGV) is a morbid and potentially deadly complication of advanced hepatocellular carcinoma (aHCC). However, the presence of EGV among the aHCC population receiving esophagogastroduodenoscopy (EGD) in the US is not well understood, nor are the predictors of EGV- or bleeding-related ER or hospitalization (the outcome) among those who are newly initiated on systemic treatment. Methods: A retrospective cohort analysis was conducted utilizing IQVIA’s PharMetrics Plus Health Plans Claims database (January 1, 2016, to July 31, 2021). Patients ≥18 years of age with ≥1 prescription for an aHCC systemic treatment were included; the date of the first prescription was the index date. At least 12 months of continuous enrollment pre-index and 6 months post-index (unless patients were deceased) were required. Patients with pre-index diagnosis codes for renal cell carcinoma, differentiated thyroid carcinoma, colorectal cancer, gastric cancer, non-small cell lung carcinoma, and liver transplant were excluded. Logistic regression was conducted to identify associations between baseline characteristics and the outcome. Results: A total of 904 patients with aHCC were included (mean age: 61.3 years; 75.3% male); 39.4% of patients died within 6 months following the index date. During the pre-index period, 688 (76.1%) patients had portal hypertension-related comorbidity, 327 (36.2%) had EGD, 122 (13.5%) had EGV, and 63 (7.0%) had bleeding. During the observational period, 458 (50.7%) patients received EGD, among whom 209 (45.6%) also had EGV. 141 (15.6%) patients had ≥1 outcome event during the post-index period. In the adjusted analysis, patients with pre-index bleeding and with EGV but no bleeding had 4.5- and 3.1-times higher odds of having post-index outcome, respectively, as compared with those lacking pre-index bleeding and EGV. Moreover, the pre-index presence of portal hypertension-related comorbidities was associated with 3.1 times greater odds of having a post-index outcome. Conclusions: EGV and bleeding events are common in patients with aHCC receiving systemic therapies. The EGV prevalence of 45.6% among those receiving EGD is consistent with prior similar studies outside of the US (Giannini EG, et al. Clin Gastroenterol and Hepatol. 2006; Iavarone M, et al. United European Gastroenterol J. 2016; Hsieh WY, et al. Sci Rep. 2017). The presence of bleeding, EGV, and portal hypertension-related comorbidities prior to treatment initiation were associated with the increased post-treatment risk of EGV- or bleeding-related ER or hospitalization in these patients. To our knowledge, this is the first study to assess and report the presence of EGV among those receiving EGD in a US aHCC population.
Treatment patterns and oncologic outcomes of carcinoma of the ampulla of vater in a reference hospital in a middle income country: A real-world–based study.
Authors: Dip Borunda Abdel Karim , Arteaga Garcia Ricardo Jesus , Barragan Los Santos Javier , Medrano Guzman Rafael , Leal Sosa Alvaro , Pimentel Alfonso
Published: January 2023

524

Background: Gallbladder and other biliary tract tumors account for 0.6 % of all cancers. There is scarce data of Ampullary cancers, but it is known as an extremely rare neoplasia accounting just for 0.2% of gastrointestinal cancers and 7% of periampullary tumors. Most frequent histology is adenocarcinoma being intestinal and pancreatobiliary subtypes conditioning prognosis and treatment. Current approaches include, but not limited to: neo/adyuvant, radiation and palliative therapy. Methods: We conducted a retrospective study in a referral specialized center in Mexico city. We included patients with histologically confirmed ampullary cancer treated between 2008 and 2022, stages I-IV. We evaluated the frequency of surgery, radiation therapy and chemotherapy. Also, we registered, first line, subsequent and maintenance therapy and as for radiation and chemoradiation. Chi square and student T test were used for between group comparisons. Overall survival was performed using the Kaplan Meier method. Results: We included 220 patients with a median age of 60.3 years (range 28-84), female 51.8%. The clinical stage distribution was I 10%, II 16.4%, III 41.3%, IV 32.3%. Performance status 0 (26.5%), 1 (44.5%), 2 (15.6%), 3 (10.4%), 4 (2.8%). Histologic Subtype Adenocarcinoma not otherwise specified 45.7%, Intestinal Adenocarcinoma 27.1%, Pancreatobiliary Adenocarcinoma 16.7%, Mix Intestinal-Pancreatobiliary 6.2%, Signet Ring Cell Adenocarcinoma 2.4%, Neuroendocrine 1.9%. Curative intend surgery in 169 patients was possible in 90%. Initial treatment received was Adjuvant 40.9%, Palliative 27.7%, Neoadjuvant 2.3% and Never Received any kind of treatment in 29.1%. Adjuvant Treatment was given to 94 patients. Among them Gemcitabine and Capecitabine was the election of treatment in 34% and 23.4 respectively. First line Treatment. Patients receiving first line treatment (110 patients) were candidates to Gemcitabine, XELOX, and Gemcitabine-Cisplatin in 30%, 13.6% and 12.7% according to physicians and 56% other line of treatment. Patients who progressed to first line received a second line in 19%. Most frequent second line of treatment was Capecitabine 61.9% and Gemcitabine 23.8%. Of the whole population Median Overall Survival was 30.68 months, Disease Free survival: 30.71 months and 8.0 months for progression free survival in first line. Conclusions: To our knowledge first real world based large volume study reporting treatment patterns and oncologic outcomes of a rare entity.
Influence of clinical and tumor characteristics on survival in patients with hepatocellular carcinoma with bone metastasis.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Fabregas Jesus C. , Ramnaraign Brian Hemendra , Rogers Sherise C. , George Thomas J. , Sahin Ilyas
Published: January 2023

525

Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and the incidence of liver cancer is rapidly rising in the United States. Advanced HCC generally has a dismal prognosis with an expected survival of less than 1 year. Bone metastases from HCC are infrequent with a poorer prognosis. However, the factors influencing their survival are not well-understood. We aimed to study the effects of clinical and tumor characteristics on survival in HCC patients with bone metastasis. Methods: We selected adult patients with HCC who had bone metastasis diagnosed between 2004 and 2019 using the National Cancer Database (NCDB). We described baseline characteristics using percentages. We performed the Kaplan-Meier method to calculate the median overall survival (OS). We included demographics (age at diagnosis, gender, race, insurance status), comorbidity score, and treatment characteristics. Results: Of a total of 3301 HCC patients with bone metastasis, 87.1% were male, and 12.9% were female. Among all, 72.2% were white, 19.3% were black, and 8.5% were others. A total of 59.9% of patients were <65 years. Eighty-six-point four percent of the patients had a total Charlton-Deyo comorbidity score of <3 and 13.6% had it ≥3. Among patients with known tumor grade, 25.4% had well differentiated, 37.8% moderately differentiated, 35.4% poorly differentiated, and 1.2% undifferentiated tumors. In univariate analysis, patients with well-differentiated tumors had better OS compared to poorly differentiated tumors (5.4 mo vs. 3.3 mo, p<0.05). In treatment groups, both single and multi-agent chemotherapy as first-course therapy significantly improved OS compared to patients’ chemotherapy was not administered (6.8 mo vs. 2.1 mo; 8.9 mo vs. 2.1 mo, respectively). We found no mortality difference between age, gender and race groups. Conclusions: In this cohort analysis of NCDB data, we report better OS in treatment receipt, lower tumor grade, and lower comorbidity score in HCC patients with bone metastasis. Previous studies of HCC patients with bone metastasis have been limited by small sample sizes, and lack of nationwide oncology outcomes data. Further large-scale prospective studies are needed.
Report of adverse events of special interest (AESIs) for sintilimab plus a bevacizumab biosimilar (IBI305) in unresectable hepatocellular carcinoma.
Authors: Ren Zhenggang , Xu Jianming , Bai Yuxian , Xu Aibing , Cang Shundong , Du Chengyou , Liu Baorui , Li Qiu , Lu Yinying , Chen Yajin , Shao Guoliang , Guo Yabing , Chen Zhendong , Fan Jia
Published: January 2023

530

Background: In the phase III Orient-32 trial (NCT03794440), sintilimab plus IBI305 demonstrated a meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs. sorafenib (Sor) in patients (pts) with unresectable HCC. Here we report the AESIs for sintilimab and IBI305 in Orient-32. Methods: 571 eligible pts with unresectable HCC were randomly assigned (2:1) to receive either sintilimab plus IBI305 or Sor (400 mg orally twice daily), until disease progression or unacceptable toxicity. The co-primary endpoints were OS and independent radiological review committee (IRRC)-assessed PFS according to RECIST 1.1. AESIs were defined by the sponsor and reported without judgement of causality. Analyses explored the incidence and severity of AESIs as well as correlation between AESIs and efficacy. Results: The safety set included 402 pts in the sintilimab plus IBI305 group and 184 pts in the Sor group. At the data cutoff on Dec 30th, 2021, the median follow-up time was 26.7 months. Any AESIs (≥1%) for sintilimab plus IBI305 group and Sor group occurred in 77.9% pts and 53.3% pts, respectively. The incidence of treatment-related grade 3-4 AESI for sintilimab+IBI305 was 31.3% and treatment-related serious AESI was 13.9%. The most common any AESIs were proteinuria (61.7% ), hypertension (41.8%), hemorrhage (15.4%) and hyperthyroidism (14.2%) (Table). In the characteristics of baseline, ages can be a predictor of the onset of proteinuria, hypertension and hyperthyroidism. In addition, the occurrence of of proteinuria and hypertension can be a predictor for a better survival. Conclusions: AESIs for sintilimab and IBI305 were tolerable and manageable in Orient-32 trial. Further, the incidence and severity of AESIs were consistent with the known safety profiles of the individual agents. Clinical trial information: NCT03794440 . [Table: see text]
Triplets versus doublets in the treatment of right-sided metastatic colorectal cancer in real-world setting: A propensity-score weighting analysis.
Authors: Gil Mariana , Peixoto Renata D'Alpino , Passarini Thais , Mathias Maria Cecilia , Moraes Eduardo Dias de , Canedo Jorge Alexandre , Pereira Sabrina , Amorim Larissa , Prolla Gabriel , Freitas Laura , Costa e Silva Matheus , Ferreira Carlos G. M. , Ferrari Bruno Lemos , Garicochea Bernardo , Dienstmann Rodrigo , Gil Roberto Almeida , Jácome Alexandre A.
Published: January 2023

55

Background: Right-sided metastatic colorectal cancer (mCRC) has a worse prognosis and the best first-line treatment is still uncertain. The aim of this study was to analyze progression-free survival (PFS) and overall survival (OS) comparing triplet versus doublet backbone chemotherapy in first-line setting for right-sided mCRC. Methods: Retrospective study evaluating 510 patients with mCRC who were treated in a private institution in Brazil from January 2011 to December 2019. Information of 118 patients with right-sided primary tumor was analyzed in this study. Demographic and clinical data were retrieved from electronic medical records. PFS and OS were calculated in months (m) using propensity-score weighting analysis (PSWA) due to expected disparity between the number of patients treated with triplet and doublet regimens. Variables used to balance patient groups were age; metastasectomy; primary tumor resection; bevacizumab use; BRAF and RAS mutation status. Results: The median follow-up was 31 months. Our population was mostly composed of elderly (64%) and female (52%) patients. First-line treatment with triplet backbone chemotherapy was done in 16 patients (14%). Primary tumor resection was done in 14% of the cases, 55% underwent metastasectomy, and 57% received anti-VEGF treatment. BRAF mutation was found in 9% of the patients and RAS mutation in 46%. After PSWA we found a significant better median PFS among patients treated with triplet regimen: 12.7m versus 8.9m compared to those receiving doublet backbone chemotherapy, with a hazard ratio of 0.64 (CI 95%: 0.42 – 0.97); p-value: 0.037. No significant difference was found in OS (29.8m versus 45.5m) between triplet and doublet therapy groups, respectively. Conclusions: In our study we found a significantly better PFS with triplet backbone chemotherapy in first-line setting for right-sided mCRC, encouraging the use of this regimen in treatment-naive selected patients. However, no difference in OS was found, probably due to subsequent treatments. PSWA is an acceptable and needed tool to enable retrospective real world studies involving treatments with expected uneven distribution. More studies are needed to answer the best strategy to target right-sided mCRC, which remains a challenge for oncologists, with unmet needs.
Outcomes by antibiotic use in participants with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study.
Authors: He Aiwu Ruth , Tan Benjamin R. , Suksombooncharoen Thatthan , Takahashi Hidenori , Chen Ming-Huang , Ostwal Vikas S , Oh Sang Cheul , Sezer Emel , Potemski Piotr , Rau Kun-Ming , Sirachainan Ekaphop , Li Junhe , Blanc Jean-Frédéric , Cohen Gordon , Żotkiewicz Magdalena , Rokutanda Nana , Oh Do-Youn
Published: January 2023

550

Background: TOPAZ-1 (NCT03875235) is a double-blind, Phase 3 study of durvalumab (D), an immune checkpoint inhibitor (ICI), + gemcitabine and cisplatin (GC) in participants (pts) with advanced biliary tract cancer (BTC). D + GC improved overall survival (OS) in pts with advanced BTC versus placebo (PBO) + GC (Oh et al. NEJM Evid 2022). Use of antibiotics during ICI treatment has been correlated with poorer OS and progression-free survival (PFS; Jiang et al. Front Oncol 2022). Methods: Pts were randomized 1:1 to receive D (1500 mg) or PBO on Day 1 every 3 weeks (Q3W), + G (1000 mg/m2) and C (25 mg/m2) on Days 1 and 8 Q3W, for ≤8 cycles, followed by D or PBO monotherapy Q4W. This exploratory subgroup analysis of TOPAZ-1 assessed OS and PFS by systemic antibiotic use during the study (≥1 dose 14 days before first D/PBO dose to 14 days after last D/PBO dose). Hazard ratios (HRs) were estimated using an unstratified Cox proportional hazards model, adjusting for disease status (initially unresectable or recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer). Data cut-off at primary analysis was Aug 11, 2021. Results: The number (%) of pts using antibiotics during the study (D + GC, 167/341 [49.0%]; PBO + GC, 167/344 [48.5%]) was similar between treatment arms. In the D + GC arm, median OS (95% CI) was similar regardless of antibiotics use: 12.6 (9.7–14.8) months in pts with antibiotics use vs 13.0 (10.8–14.7) months in pts without (Table). In the PBO + GC arm, median OS (95% CI) was 10.3 (8.7–12.5) in pts with antibiotics use vs 12.1 (11.0–13.8) in pts without. OS HRs (95% CI) in D + GC vs PBO + GC were 0.78 (0.59–1.02) in pts with antibiotics and 0.81 (0.62–1.07) in pts without. Median PFS (95% CI) was 7.3 (6.5–7.7) months in pts with antibiotics use vs 7.2 (5.9–7.4) months in pts without in the D + GC arm and 5.7 (5.4–6.6) months vs 6.1 (5.6–7.3) months, respectively, in the PBO + GC arm (Table). PFS HRs (95% CI) were 0.70 (0.55–0.89) in pts with antibiotics use and 0.82 (0.65–1.03) in pts without. Conclusions: In the TOPAZ-1 study of D in BTC, no meaningful difference was found in OS or PFS for participants who received antibiotics during the study period compared with those who did not, and results were consistent with the primary analysis. These results support that people receiving D may be treated with antibiotics when clinically indicated. Clinical trial information: NCT03875235 . [Table: see text]
Efficacy and safety of envafolimab plus lenvatinib combined with TACE in unresectable hepatocellular carcinoma: An open-label, single-arm, phase 2 study—The CISLD-12 study.
Authors: Liang Tingbo , Chen Yiwen , Huang Xin , Hu Wendi , Li Xiang , Sun Junhui , Shen Yan , Zhang Min , Wu Jian , Gao Shunliang , Yu Jun , Que Risheng , Zhang Yun , Yang Fuchun , Xia Weiliang , Zhang Aibin , Tang Xiaofeng , Bai Xueli
Published: January 2023

558

Background: Transarterial chemoembolization (TACE) is one of the standard treatments for patients with intermediate-stage hepatocellular carcinoma (HCC). The combination of immune checkpoint inhibitors (ICIs) and lenvatinib has shown to be an effective regimen in patients with unresectable HCC (uHCC). In this study, we aim to investigate the efficacy and safety of combination of Envafolimab (a novel, single-domain PD-L1 antibody) with Lenvatinib plus TACE in uHCC patients. Methods: This is a prospective, open-label, single-arm, phase 2 study. Adults with confirmed uHCC with BCLC stage B or C, Eastern Cooperative Oncology Group performance status 0 or 1, Child–Pugh scored ≤7 and no previous systemic treatment for HCC are eligible. Patients will receive Lenvatinib once daily plus Envafolimab every 3 weeks plus TACE. TACE will be conducted repeatedly every 6 weeks on demand according to investigators’ consideration, mainly based on the proportion of viable tumors. Imaging evaluation will be conducted every 6 weeks. The primary endpoint is objective response rate (ORR). Disease control rate (DCR), duration of response (DoR), progression free survival (PFS), overall survival (OS) and safety are evaluated as secondary endpoints (NCT05213221). Results: forty patients were consecutively enrolled from March, 2022 to September 2022. The median age was 54.5 years. At present, thirty-six patients were included for efficacy analysis, and forty for safety evaluation. Number of patients with BCLC stage B and C was 17(47.2%) and 19 (52.8%), respectively. 13 (36.1%) patients presented with portal vein tumor thrombus (PVTT) and 2 (5.6%) patient presented with hepatic vein tumor thrombus (HVTT). The ORR was 36.1% and 80.6%, and DCR was 77.8% and 83.3%, based on RECIST v1.1 and modified RECIST respectively. 11 patients reached the standard of conversion to resectable HCC and received radical resection. The most common TRAEs were elevated AST (75%), elevated ALT (65%) and leukopenia (42.5%). No treatment-related deaths occurred. The survival data are not mature at present. Conclusions: Envafolimab plus Lenvatinib combined with TACE is a promising and tolerable therapeutic regimen for patients with BCLC B/C unresectable HCC. Clinical trial information: NCT05213221 .
Nab-paclitaxel plus anti–PD-1 antibody as second-line treatment for advanced biliary tract cancer: An investigator-initiated phase 2 study (NapaSinti trial).
Authors: Li Xiaofen , Zhou Nan , Yang Yu , Gou Hongfeng
Published: January 2023

564

Background: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. Gemcitabine + cisplatin ±durvalumab is the standard first-line treatment for advanced BTC. But in second-line setting, there is no satisfactory regimen for most patients without specific genetic mutations. This prospective, single-arm, phase 2 study is conducted to investigate the efficacy and safety of second-line nab-paclitaxel combined with sintilimab in advanced BTC patients. Methods: Eligible patients are histologically confirmed local advanced or metastatic adenocarcinoma or cholangiocellular carcinoma in biliary tract; aged from 18 to 75 years; with a performance status and adequate organ function; with documented disease progression after prior gemcitabine or fluorouracil-based systemic chemotherapy; not received taxol drugs or immune checkpoint inhibitors treatment. Enrolled patients will receive nab-paclitaxel 125mg/m2 on day 1, 8 plus sintilimab 200mg on day 1, administered intravenously every three weeks. The primary end point is objective response rate (ORR). The secondary end points are progression free survival (PFS), overall survival (OS) and adverse reactions. Next-generation sequencing (NGS) is voluntary before treatment. Results: Up to September 2022, 24 BTC patients have been enrolled, including 22 patients available for efficacy evaluation. The ORR is 27.3% (6/22), including 1 complete response (CR) and 5 partial response (PR). Disease control rate is 63.6% (14/22). And median PFS is 5.63 months (95% CI: 1.92-9.35 months). Median OS from enrollment to death of any cause is 12.60 months (95%CI: 7.84-17.36 months). The frequent grade 3 drug-related adverse events are leukopenia (16.7%), anemia (12.5%), neutropenia (8.3%), peripheral neuropathy (8.3%). There is no grade 4 drug-related adverse event occurred. One patient has experienced grade 3 immunological colitis. 11 participants have received NGS testing, with 9 ones are available for efficacy evaluation. Among the 9 participants, 5 patients harbor TP53 mutation [2 evaluated as PR, 2 SD (stable disease) and 1 PD (progressive disease)]; 3 patients harbor genetic mutations associated with DNA damage response pathway (2 evaluated as PR and 1 PD); and 1 patient is in status of microsatellite instability-high (MSI-H) evaluated as PR. Conclusions: The preliminary results of NapaSinti trial propose a brand new and effective regimen as second-line treatment for advanced biliary tract cancer. NGS may become a hopeful tool for efficacy prediction. Clinical trial information: ChiCTR2100052118 .
Efficacy of pembrolizumab as first-line therapy in patients with mismatch repair–deficient metastatic colorectal cancer in relation to the metastatic site.
Authors: Saberzadeh Ardestani Bahar , Jones Jeremy Clifton , Hubbard Joleen M. , McWilliams Robert R. , Halfdanarson Thorvardur Ragnar , Shi Qian , Sonbol Bassam Bassam , Ticku Jonathan , Jin Zhaohui , Sinicrope Frank A.
Published: January 2023

57

Background: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) show frequent and durable responses to programmed cell death -1 (PD-1) blockade. While the majority of these tumors are sporadics and observed in elderly patients, first-line data are limited to the KEYNOTE-177 study. Here, we report a consecutive series of elderly patients with dMMR mCRC treated with pembrolizumab in routine clinical practice that includes analysis of clinical outcome based on metastatic site. Methods: Patients with dMMR mCRC received first-line pembrolizumab (200 mg every 3 weeks) (N = 41) at Mayo Clinic and Mayo Clinic Health System (2015-2022). Clinicopathological features including metastatic site and molecular data ( BRAFV600E, KRAS) were analyzed in relationship to tumor response rate (RECIST version 1.1). Furthermore, these variables were also analyzed in relationship to patient progression-free survival (PFS) using Kaplan-Meier methodology and multivariable stepwise Cox regression. Results: Among patients with dMMR mCRC, 29/41 (70.7%) were female, 30 (78.9%) harbored BRAFV600E, and 32 (80%) were sporadic. Median age at start of treatment was 80.6 years (IQR of 75.9, 85.9) and median number of treatment cycles was 9 (IQR: 4, 20). At a median follow-up of 23 months (range, 3.0 to 88.5), patient median PFS was 21.3 months (95% CI: 6.4, 38.5). An overall response was observed in 48.8% (20 of 41) of patients including 13 (31.7%) complete (CR) and 7 (17.1%) partial responses (PR). The median duration of response was 42.2 months (95%CI: 8.6, NR). Patients with metastases that included liver had significantly poorer PFS compared to those with non-liver metastases (HRadj 3.40 (95%CI: 1.27-9.13); Padj= 0. 01). In this regard, responses (CR, PR) to pembrolizumab were observed in 3 (21.4%) patients with liver metastasis compared to 17 (62.9%) of those with non-liver metastases. Treatment-related grade 3 or 4 adverse events were observed in 9 (22.0%) patients of whom two discontinued therapy, and there was one treatment-related death. Conclusions: First-line therapy with pembrolizumab for dMMR mCRC significantly prolonged survival in an elderly patient population with manageable toxicity in routine clinical practice. Moreover, the survival benefit of pembrolizumab was significantly attenuated in patients with liver vs non-liver metastases.
ORIENT-32: Updated characterization of response to sintilimab plus bevacizumab biosimilar (IBI305) vs sorafenib for unresectable hepatocellular carcinoma.
Authors: Ren Zhenggang , Xu Jianming , Bai Yuxian , Xu Aibing , Cang Shundong , Du Chengyou , Liu Baorui , Li Qiu , Lu Yinying , Chen Yajin , Shao Guoliang , Guo Yabing , Chen Zhendong , Fan Jia
Published: January 2023

570

Background: ORIENT-32 trial (NCT03794440) assessed sintilimab (anti-PD-1 antibody) plus a bevacizumab biosimilar (anti-VEGF antibody) versus sorafenib (Sor) as first-line treatment for unresectable HCC and demonstrated a significant improvement in both overall survival and progression-free survival. Here we report the updated results of objective response rate (ORR), time to response (TTR), duration of response (DoR) and depth of response (DpR). Methods: 571 eligible patients (pts) with unresectable HCC were enrolled and randomized (2:1) to receive sintilimab (200 mg IV Q3W) plus IBI305 (15 mg/kg IV Q3W) or Sor (400 mg orally, BID) until disease progression or unacceptable toxicity. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)and HCC-modified RECIST (mRECIST). ORR, TTR, DoR, and DpR were analyzed. The DpR was defined as the minimum percentage of (1) sum of longest diameter (SLD) change and (2) longest diameter (LD) change described as mean (standard deviation, SD). Results: At the data cutoff on Dec 30th, 2021, the median follow-up time was 26.7 months. The ORR in sintilimab plus IBI305 and Sor group was 21.0% (77/367) vs 4.7 (8/169) per RECIST 1.1 and 25.1% (92/367) vs 7.7% (13/169) per mRECIST. The median TTR in sintilimab plus IBI305 group was 2.8 (2.4–3.3) months per RECIST 1.1 and 2.6 (1.6–2.9) months per mRECIST. The median DoR in sintilimab plus IBI305gourp was 20.3 (12.3-NE) months per RECIST 1.1. The minimum percentage of SLD change was larger in the sintilimab plus IBI305 arm than in the Sor arm: (−13.4% (35.8) vs 3.2%(26.5) per RECIST 1.1). Similarly, the LD change in the largest liver lesion also favored sintilimab plus IBI305 arm (−27.6% (31.6) vs −11.5% (20.9)), including larger tumors (≥7 cm; −21.2% (30.4) vs −9.9% (23.7)) all per RECIST 1.1. Conclusions: Sintilimab plus IBI305 showed a significant improvement in ORR, TTR, DOR and DpR vs Sor in unresectable HCC. Clinical trial information: NCT03794440 .
Efficacy and safety of TACE combined with anlotinib compared with TACE alone among patients with intermediate or advanced hepatocellular carcinoma (HCC): A randomized, controlled, phase II clinical study.
Authors: Zeng Hui , Shao Guoliang
Published: January 2023

581

Background: Anlotinib hydrochloride is an oral multi targeted tyrosine kinase inhibitor, mainly targeting VEGFR1-3, FGFR 1-4 and PDGFR α/β. Transcatheter arterial chemoembolization (TACE) is the preferred choice for the treatment of intermediate or advanced HCC. Previous studies have proved that antiangiogenic drugs combined with TACE have synergistic effects. The purpose of this study was to explore the efficacy and safety of TACE combined with anlotinib in the treatment of intermediate or advanced liver cancer compared with TACE alone. Methods: This single-center, randomized controlled, phase II study involved 38 HCC patients with BCLC staging B or C and ECOG PS ≤ 1. Enrolled pts were treated with TACE plus anlotinib (12mg, qd, d1-d14, q3w) and TACE alone until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS), the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Both PFS and tumor response were assessed by investigator per RECIST v1.1. Results: At the cutoff date of April 2022, 18 pts received TACE combined anlotinib and 20 pts received TACE alone. The median PFS was 11.04 months (95%CI, 7.17-14.92) in combination group and 6.87 months (95%CI, 5.58-8.16) in TACE group (HR 0.46, 95% CI 0.23 to 0.92, P=0.022). The median OS has not been reached yet. ORR was 27.8% (95%CI, 9.7%-53.5%) and 30% (95%CI, 11.9%-54.3%) and DCR was 94.4% (95%CI 72.7%-99.9%) and 100% (95%CI 83.2%-100%), respectively, with no statistical difference.The median times of TACE are 2 and 3 respectively.The treatment-related adverse events (TRAEs) of any grade occurred in 15 patients (83.3%) and 19 patients (95%). The most common TRAEs were HFSR (61.1%), hypertension (27.8%), thrombocytopenia (11.1%) in combination group and vomiting (35%), upper abdominal liver pain (35%), upper abdomen pain (30%), low fever (10%), fatigue (10%) in TACE group.Grade ≥ 3 TRAEs occurred in 2 pts (11.1%) in combination group and 1pts (5%) in TACE group. Conclusions: Anlotinib combined with TACE is a safe and effective regimen in the treatment ofpatients with intermediate or advanced-stage hepatocellular carcinoma (HCC). This study still needs longer follow-up to evaluate its efficacy more comprehensively. Clinical trial information: NCT04066543 .
Efficacy and safety of anlotinib with PD-1 inhibitors in the treatment of advanced hepatocellular carcinoma: A real-world study.
Authors: Chen Kehe , Huang Xianshi , Yu Lei , Lu Jianxun , Huang Fei , Wang Zhiguang , Wei Yan , Hou Encun , Luo Min , Huang Shiqing , Hu Hongbo , Ou Mei
Published: January 2023

583

Background: The IMbrave 150 study opened the door of immuno-oncology (IO) combined with targeted therapy in patients (pts) with hepatocellular carcinoma (HCC). At present, some other combination of IO and tyrosine kinase inhibitors (TKIs) had been proved as efficient regimens in China and there are many ongoing studies on this approach with preliminarily considerable efficacy. Furthermore, the efficacy of this combination still needs to be explored in real-world patients. The aim of this study is to explore the efficacy and safety of anlotinib plus PD-1 inhibitors in the treatment of HCC in real-world. Methods: This is a multi-center, prospective real-world study in pts (N=200) diagnosed as advanced HCC, who evaluated by physician would get benefits from anlotinib alone or in combination with PD-1 inhibitors. The enrolled patients received treatment according to physicians. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigators according to RECIST version 1.1. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of data cutoff date of Aug, 2022, a total of 119 patients were enrolled with a median age of 55 years (range 29-83). Among them 78% ECOG PS 0-1, 21% ECOG PS 2 and 1% ECOG PS 4. 75 pts received anlotinib plus PD-1 inhibitors as first-line treatment, 17 pts as second-line treatment and 7 pts as third-line and above. 76 patients were eligible for response evaluation. The ORR as best response was 11.8% (95%CI: 5.6%, 21.3%). The DCR was 73.7% (95%CI: 62.3%, 83.1%). The preliminarily results indicated that the median OS was 12.5 months (95%CI: 9.7, 15.4), the median PFS was 8.1 months (95%CI: 5.9, 10.3). Any grade treatment-related adverse events (TRAEs) observed in 50% of pts. The most common TRAEs were hypoalbuminemia (18.6%), hypertension (11.4%), decreased white blood cell count (11.4%) and decreased platelet count (10%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 inhibitors exhibited potential efficacy and manageable adverse events in the treatment of advanced HCC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521 .
The oncologic implications of tumor multiplicity in intrahepatic cholangiocarcinoma: Its prognostic value might be underestimated.
Authors: Yoon So Jeong , Oh Subin , Jeon Hyun Jeong , Jeong Hye Jeong , Lim Soo Yeun , Shin Sang Hyun , Heo Jin Seok , Han In Woong
Published: January 2023

611

Background: In the latest staging system of the American Joint Committee on Cancer (AJCC) for intrahepatic cholangiocarcinoma (IHCCC), solitary tumor with vascular invasion and multiple tumors are grouped together as T2. However, recent studies have reported that multifocal IHCCC have worse prognosis than a single lesion. This study aimed to investigate risk factors of IHCCC and to explore the prognostic significance of multiplicity identified by surgical resection. Methods: A total of 277 patients underwent surgery for IHCCC from 2010 to 2019 and the clinicopathological data were retrospectively reviewed. Risk factor analysis was performed to identify variables associated with survival of resected IHCCC. Survival outcomes were compared between patients with solitary tumors and those with multiple tumors. Results: In multivariable analysis, presence of preoperative symptoms, tumor size, lymph node ratio, multiplicity, and tumor differentiation were risk factors for survival. Among 82 patients with T2, overall survival was significantly better in patients with solitary tumors (sT2) than in those with multiple tumors (mT2) (p = 0.017). Survival was compared among patients with stage II-sT2, stage II-mT2, and stage III. Stage II-sT2 group showed prolonged survival than those with stage II-mT2 or stage III. Survival of stage II-mT2 patients was not statistically different from that of stage III patients. Conclusions: Tumor multiplicity was an independent risk factor for overall survival of IHCCC after surgical resection. Patients with multiple tumors showed poorer survival than patients with a single tumor. The oncologic significance of multiplicity in IHCCC should be reappraised and be reflected in the next update of staging system.[Table: see text]
Three-dimensional radiotherapy dose prediction in patients with liver and pancreas cancer treated with the Viewray system.
Authors: Kim Dong-Yun , Jang Bum-Sup , Kim Eunji , Kim Jae Sik , Chie Eui Kyu
Published: January 2023

612

Background: The radiotherapy (RT) planning process for patients with gastrointestinal tract cancers is regarded as a time-consuming and complicated task due to proximity of multiple organs at risk (OARs). Dose prediction model based on deep learning might be a solution to increase efficiency by reducing the time required to find the optimal plan. Dose distribution model was developed using a three-dimensional (3D) U-Net deep learning. Methods: Altogether RT plan of patients with liver cancer (N=40) and pancreatic cancer (N=26) were acquired from the MRIdian (Viewray Technologies, Oakwood Village, OH) treatment planning system from 2016 to 2018. Magnetic resonance (MR) images for RT, planning dose, and contoured RT structures were retrospectively collected. The 3D U-Net was employed, and transfer-learning was performed on the training set (N=60, 91.3%). The initial learning rate was 0.1, decreasing by 10% every 5 epochs, for a total of 200 epochs. A developed model was evaluated by the testing set (N=5, 7.7%). The difference between ground truth and predicted dose was compared by calculating normalized minimum, maximum, and mean doses of the planning target volume (PTV) and OARs. Results: Root-mean-square error (RMSE) of voxels between ground truth and predictive dose was 3.04 (range 2.29-3.79). Percentage of mean dose difference and standard deviation between clinical and prediction models were 1.75 ± 2.84%, 0.08 ± 0.11%, 0.13 ± 0.08%, 0.05 ± 0.03%, 0.07 ± 0.05% for PTV, duodenum, liver, kidney, and stomach, respectively. And the percentage of max dose difference between the two were 0.91 ± 0.01%, 0.34 ± 0.43%, 0.63 ± 0.39%, 0.25 ± 0.18%, 0.33 ± 0.30%, respectively. Overall, the predicted normalized target DVH metrics were within 2% of the ground truth plans. Conclusions: We developed a deep learning model for dose prediction in liver and pancreatic cancer using MR images acquired from MRIdian system. Larger-scale training and validation are required to prove the efficacy of the dose prediction model by the 3D U-Net.
Liver-directed therapy of neuroendocrine liver metastases.
Authors: Meloche-Dumas Léamarie , Mercier Frédéric , Barabash Tori , Law Calvin , Singh Simron , Myrehaug Sten , Chan Wing , Hallet Julie
Published: January 2023

647

Background: While there have been major advances in the care of neuroendocrine tumors (NETs), there is still no widely adopted therapeutic sequencing in metastatic NETs. The roles and benefits of locoregional treatments need reassessment, in order to define a modern therapeutic algorithm. We examined contemporary short-term outcomes of liver-directed therapy for metastatic NETs. Methods: We conducted a population-based retrospective cohort study of patients with metastatic NETs (2000-2019) undergoing liver embolization (LE) or liver resection (LR). Outcomes were 30-day major morbidity (Clavien-Dindo grade 3-5) and/or re-admission (composite) and length of hospital stay. Modified Poisson regression accounting for clustering at the hospital level examined factors associated with outcomes in both treatment groups. Results: Overall, 1,224 LEs and 502 LRs were performed for 5,159 patients with metastatic NETs. Median length of hospital stay was 1 day (IQR 1-4) for liver embolization and 7 days (IQR 5-9) for liver resection. 30-day major morbidity and re-admission occurred after 213 LEs (17.4%) including 40 (3.3%) deaths, and 138 LRs (27.5%) including 11 (2.2%) deaths. There were 25 (2%) LEs followed by infectious complications. Factors independently associated with increased risk after LE were prior LE treatment (adjusted relative risk- aRR 0.62; 95%CI 0.44-0.88), rural residence (aRR 0.43; 95%CI 0.20-0.91) and high comorbidity burden (aRR 1.85; 95%CI 1.34-2.54). The only factor independently associated with increased risk after LR was metachronous metastases (RR 0.60; 95%CI 0.37-0.98). Conclusions: In this contemporary cohort, LE was associated with mortality similar to that of LR. Prior LE, rural residence, comorbidities, and metachronous metastatic diagnosis were associated with higher risk of major morbidity and re-admission. This information is important when discussing the use of and choice of liver-directed therapies in the multi-disciplinary management of metastatic NETs. Further characterization of long-term outcomes and patient-reported outcomes will further support decision-making, counselling, and patient preparation.