SupporTive Care At Home Research (STAHR) for patients with advanced cancer: Protocol for a cluster non-randomized controlled trial.

Advancements in the treatment and management of patients with cancer have extended their survival period. To honor such patients' desire to live in their own homes, home-based supportive care programs have become an important medical practice. This study aims to investigate the effects of a multidimensional and integrated home-based supportive care program on patients with advanced cancer. SupporTive Care At Home Research is a cluster non-randomized controlled trial for patients with advanced cancer. This study tests the effects of the home-based supportive care program we developed versus standard oncology care. The home-based supportive care program is based on a specialized home-based medical team approach that includes (1) initial assessment and education for patients and their family caregivers, (2) home visits by nurses, (3) biweekly regular check-ups/evaluation and management, (4) telephone communication via a daytime access line, and (5) monthly multidisciplinary team meetings. The primary outcome measure is unplanned hospitalization within 6 months following enrollment. Healthcare service use; quality of life; pain and symptom control; emotional status; satisfaction with services; end-of-life care; advance planning; family caregivers' quality of life, care burden, and preparedness for caregiving; and medical expenses will be surveyed. We plan to recruit a total of 396 patients with advanced cancer from six institutions. Patients recruited from three institutions will constitute the intervention group, whereas those recruited from the other three institutions will comprise the control group.

Prognostic Impact of Visceral Adipose Tissue Imaging Parameters in Patients with Cholangiocarcinoma after Surgical Resection.

Visceral adiposity is known to be related to poor prognosis in patients with cholangiocarcinoma; however, the prognostic significance of the qualitative features of adipose tissue in cholangiocarcinoma has yet to be well defined. This study investigated the prognostic impact of adipose tissue imaging parameters reflecting the quantity and qualitative characteristics of subcutaneous (SAT) and visceral (VAT) adipose tissue on recurrence-free survival (RFS) and overall survival (OS) in 94 patients undergoing resection of cholangiocarcinoma. The area, mean computed tomography (CT) attenuation, and mean 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake of SAT and VAT on positron emission tomography (PET)/CT for staging work-up were measured, and the relationship of these adipose tissue imaging parameters with clinicopathological factors and survival was assessed. TNM stage, histologic grade, lymphovascular invasion, and the size of cholangiocarcinoma showed positive correlations with adipose tissue imaging parameters. Multivariate survival analysis demonstrated that the visceral-to-subcutaneous adipose tissue area ratio (VSR) (p = 0.024; hazard ratio, 1.718) and mean FDG uptake of VAT (p = 0.033; hazard ratio, 9.781) were significant predictors for RFS, but all of the adipose tissue imaging parameters failed to show statistical significance for predicting OS. In addition to visceral adiposity, FDG uptake of VAT might be a promising prognostic parameter for predicting RFS in patients with cholangiocarcinoma.

Organ-specific responses to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma: A multicentre, retrospective study.

BACKGROUND AND AIMS: Anti-programmed death 1 (PD-1) monotherapy triggers various responses by each organ. In advanced hepatocellular carcinoma (HCC), while extrahepatic lesions demonstrate objective response rates (ORR) of 20%-40%, only 10% of intrahepatic lesions respond. Although first-line atezolizumab/bevacizumab has shown survival benefits in advanced HCC, organ-specific responses remain unexplored. Therefore, we aimed to assess organ-specific responses in patients with advanced HCC receiving atezolizumab/bevacizumab. METHODS: This retrospective, multicenter, observational study included patients who received first-line atezolizumab/bevacizumab for advanced HCC. Patients with Child-Pugh class A, measurable tumour lesions and serial imaging available for response evaluation were eligible. RESULTS: Between May 2020 and June 2021, 131 patients (median age: 62) from three cancer referral institutions were included. Ninety-one had hepatitis B (69.5%), 108 were at Barcelona clinic liver cancer stage C (82.4%), and 78 had extrahepatic metastasis (59.5%). After a median follow-up of 10.1 months, median progression-free survival was 6.8 months (95% confidence interval [CI], 4.6-9.2), median overall survival remained unreached (95% CI, range unavailable) and the ORR was 29.0%. Among 270 individual tumour lesions, the liver was the most commonly involved organ (n = 158). Atezolizumab/bevacizumab induced ORR of 27.8%, 42.2%, 29.1% and 21.0% for liver, lymph nodes, lungs and other sites, respectively. The organ-specific response rate for intrahepatic tumours decreased with increasing size (35.6%: <5 cm, 15.0%: ≥ 5 cm). CONCLUSIONS: Unlike anti-PD-1 monotherapy, atezolizumab/bevacizumab demonstrated favourable responses in intrahepatic lesions, comparable to those in extrahepatic lesions, and may potentially overcome the immune-tolerant hepatic microenvironment in patients with advanced HCC.

Impact of Coronavirus Disease 2019 on Unresectable Hepatocellular Carcinoma Treated with Atezolizumab/Bevacizumab.

(1) Background: The coronavirus disease 2019 (COVID-19) pandemic has proven challenging to the management of patients with cancer, particularly those receiving systemic therapy. This study aimed to evaluate the impact of COVID-19 on patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab/bevacizumab. (2) Methods: Patients with unresectable HCC who started atezolizumab/bevacizumab treatment between June 2020 and December 2021 at a tertiary cancer center in Korea were included (n = 241) and classified according to their COVID-19 status and severity. (3) Results: Thirty-five (14.5%) patients with unresectable HCC were diagnosed with COVID-19 during atezolizumab/bevacizumab treatment; 26 (74.2%) and nine (25.7%) in the low- and high-severity groups, respectively. The high-severity group showed higher neutrophil-to-lymphocyte ratios and lactate dehydrogenase levels. Liver and kidney injuries were observed in 31.4% and 17.1% of total patients, respectively. Liver injury was more prominent in patients with pre-existing liver dysfunction at baseline, who were more prevalent in the high-severity group. Atezolizumab/bevacizumab treatment was delayed by a median of 0 (range, 0-21) day in the low-severity group and 12 (range, 0-35) days in the high-severity group. The high-severity group showed worse post-infection progression-free survival (1.1 vs. 4.8 months, p = 0.017) and overall survival (2.2 months vs. not reached, p = 0.004). (4) Conclusions: Patients with impaired liver function at baseline are more susceptible to high-severity COVID-19, which affects atezolizumab/bevacizumab treatment outcomes.

Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after Atezolizumab/Bevacizumab Failure: A real-world study.

Background: Atezolizumab plus bevacizumab (ATE+BEV) therapy has become the recommended first-line therapy for patients with unresectable hepatocellular carcinoma (HCC) because of favorable treatment responses. However, there is a lack of data on sequential regimens after ATE+BEV treatment failure. We aimed to investigate the clinical outcomes of patients with advanced HCC who received subsequent systemic therapy for disease progression after ATE+BEV. Methods: This multicenter, retrospective study included patients who started second-line systemic treatment with sorafenib or lenvatinib after HCC progressed on ATE+BEV between August 2019 and December 2022. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). Clinical features of the two groups were balanced through propensity score (PS) matching. Results: This study enrolled 126 patients, 40 (31.7%) in the lenvatinib group, and 86 (68.3%) in the sorafenib group. The median age was 63 years, and males were predominant (88.1%). In PS-matched cohorts (36 patients in each group), the objective response rate was similar between the lenvatinib- and sorafenib-treated groups (5.6% vs. 8.3%; p=0.643), but the disease control rate was superior in the lenvatinib group (66.7% vs. 22.2%; p<0.001). Despite the superior progression-free survival (PFS) in the lenvatinib group (3.5 vs. 1.8 months, p=0.001), the overall survival (OS, 10.3 vs. 7.5 months, p=0.353) did not differ between the two PS-matched treatment groups. Conclusion: In second-line therapy for unresectable HCC after ATE+BEV failure, lenvatinib showed better PFS and comparable OS to sorafenib in a real-world setting. Future studies with larger sample sizes and longer follow-ups are needed to optimize second-line treatment.

Opioid use and subsequent delirium risk in patients with advanced cancer in palliative care: a multicenter registry study.

The prevalent use of opioids for pain management in patients with advanced cancer underscores the need for research on their neuropsychiatric impacts, particularly delirium. Therefore, we aimed to investigate the potential association between opioid use and the risk of delirium in patients with advanced cancer admitted to the acute palliative care unit. We conducted a retrospective observational study utilizing a multicenter, patient-based registry cohort by collecting the data from January 1, 2019, to December 31, 2020, in South Korea. All data regarding exposures, outcomes, and covariates were obtained through retrospective chart reviews by a team of specialized medical professionals with expertise in oncology. Full unmatched and 1:1 propensity-score matched cohorts were formed, and stratification analysis was conducted. The primary outcome, delirium, was defined and diagnosed by the DSM-IV. Of the 2,066 patients with advanced cancer, we identified 42.8% (mean [SD] age, 64.4 [13.3] years; 60.8% male) non-opioid users and 57.2% (62.8 [12.5] years; 55.9% male) opioid users, respectively. Opioid use was significantly associated with an increased occurrence of delirium in patients with advanced cancer (OR, 2.02 [95% CI 1.22-3.35]). The risk of delirium in patients with advanced cancer showed increasing trends in a dose-dependent manner. High-dose opioid users showed an increased risk of delirium in patients with advanced cancer compared to non-opioid users (low-dose user: OR, 2.21 [95% CI 1.27-3.84]; high-dose user: OR, 5.75 [95% CI 2.81-11.77]; ratio of OR, 2.60 [95% CI 1.05-6.44]). Patients with old age, male sex, absence of chemotherapy during hospitalization, and non-obese status were more susceptible to increased risk of delirium in patients with cancer. In this multicenter patient-based registry cohort study, we found a significant, dose-dependent association between opioid use and increased risk of delirium in patients with advanced cancer. We also identified specific patient groups more susceptible to delirium. These findings highlight the importance of opioid prescription in these patients with advanced cancer, balancing effective doses for pain management and adverse dose-inducing delirium.

Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial.

Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib-nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67+ proliferating CD8+ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib-nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709 .

Development of a Prediction Model for Delirium in Hospitalized Patients with Advanced Cancer.

Purpose: Delirium is a common neurocognitive disorder in patients with advanced cancer and is associated with poor clinical outcomes. As a potentially reversible phenomenon, early recognition of delirium by identifying the risk factors demands attention. To develop a model to predict the occurrence of delirium in hospitalized patients with advanced cancer. Materials and Methods: This retrospective study included patients with advanced cancer admitted to the oncology ward of four tertiary cancer centers in Korea for supportive cares and excluded those discharged due to death. The primary endpoint was occurrence of delirium. Sociodemographic characteristics, clinical characteristics, laboratory findings, and concomitant medication were investigated for associating variables. The predictive model developed using multivariate logistic regression was internally validated by bootstrapping. Results: From January 2019 to December 2020, 2,152 patients were enrolled. The median age of patients was 64 years, and 58.4% were male. A total of 127 patients (5.9%) developed delirium during hospitalization. In multivariate logistic regression, age, body mass index, hearing impairment, previous delirium history, length of hospitalization, chemotherapy during hospitalization, blood urea nitrogen and calcium levels, and concomitant anti-depressant use were significantly associated with the occurrence of delirium. The predictive model combining all four categorized variables showed the best performance among the developed models (area under the curve 0.831, sensitivity 80.3%, and specificity 72.0%). The calibration plot showed optimal agreement between predicted and actual probabilities through internal validation of the final model. Conclusion: We proposed a successful predictive model for the risk of delirium in hospitalized patients with advanced cancer.

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma.

Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

Atezolizumab plus bevacizumab in patients with child-Pugh B advanced hepatocellular carcinoma.

Background: Atezolizumab plus bevacizumab (Ate/Bev) demonstrated promising efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III IMbrave150 trial. However, patients with Child-Pugh B HCC were excluded in the abovementioned prospective trial. Therefore, we aimed to investigate the efficacy and safety of Ate/Bev in patients with Child-Pugh B HCC. Methods: This multicenter retrospective study included 36 patients with Child-Pugh B advanced HCC who received Ate/Bev at four cancer referral centers between May 2020 and August 2021. Comparative analyses were performed with an independent cohort of patients with Child-Pugh A HCC from the same registry (n = 133). Results: All patients received Ate/Bev as first-line systemic treatment for advanced HCC. The objective response and disease control rates of patients in the Child-Pugh groups B and A were 11.1% and 58.3% and 34.6% and 76.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.0 months [95% confidence interval (CI), 1.7-4.3) and 7.7 months (95% CI, 4.8-10.6) in the Child-Pugh B group, whereas the median PFS and OS were 9.6 months (95% CI, 5.1-14.2) and not reached (95% CI, not available) in the Child-Pugh A group, respectively. Compared to the Child-Pugh A group, grade 3-4 adverse events (AEs) were more common in the Child-Pugh B group (44.4% versus 15.8, p < 0.001), with the most frequent grade 3-4 AEs being gastrointestinal bleeding (n = 6, 16.7%), neutropenia (n = 5, 13.9%), and thrombocytopenia (n = 4, 11.1%). Conclusions: In the Child-Pugh B subgroup of patients with advanced HCC, Ate/Bev treatment showed modest clinical activity. However, due to the increased frequency of serious AEs, careful evaluation of treatment response and AE management is required in this subgroup of patients.

High levels of baseline serum IL-10 are associated with reduced clinical benefit from first-line immune checkpoint inhibitor therapy in advanced renal cell carcinoma.

Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8+ T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.

ARID1A Mutation from Targeted Next-Generation Sequencing Predicts Primary Resistance to Gemcitabine and Cisplatin Chemotherapy in Advanced Biliary Tract Cancer.

PURPOSE: There are clinical unmet needs in predicting therapeutic response and precise strategy for the patient with advanced biliary tract cancer (BTC). We aimed to identify genomic alterations predicting therapeutic response and resistance to gemcitabine and cisplatin (Gem/Cis)-based chemotherapy in advanced BTC. MATERIALS AND METHODS: Genomic analysis of advanced BTC multi-institutional cohorts was performed using targeted panel sequencing. Genomic alterations were analyzed integrating patients' clinicopathologic data, including clinical outcomes of Gem/Cis-based therapy. Significance of genetic alterations was validated using clinical next-generation sequencing (NGS) cohorts from public repositories and drug sensitivity data from cancer cell lines. RESULTS: 193 BTC patients from three cancer centers were analyzed. Most frequent genomic alterations were TP53 (55.5%), KRAS (22.8%), ARID1A (10.4%) alterations, and ERBB2 amplification (9.8%). Among 177 patients with BTC receiving Gem/Cis-based chemotherapy, ARID1A alteration was the only independent predictive molecular marker of primary resistance showing disease progression for 1st-line chemotherapy in the multivariate regression model (odds ratio, 3.12; p=0.046). In addition, ARID1A alteration was significantly correlated with inferior progression-free survival on Gem/Cis-based chemotherapy in the overall patient population (p=0.033) and in patients with extrahepatic cholangiocarcinoma (CCA) (p=0.041). External validation using public repository NGS revealed that ARID1A mutation was a significant predictor for poor survival in BTC patients. Investigation of multi-OMICs drug sensitivity data from cancer cell lines revealed that cisplatin-resistance was exclusively observed in ARID1A mutant bile duct cancer cells. CONCLUSION: Integrative analysis with genomic alterations and clinical outcomes of the first-line Gem/Cis-based chemotherapy in advanced BTC revealed that patients with ARID1Aalterations showed a significant worse clinical outcome, especially in extrahepatic CCA. Well-designed prospective studies are mandatory to validate the predictive role of ARID1Amutation.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma.

Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Outcomes of an Acute Palliative Care Unit at a Comprehensive Cancer Center in Korea.

Background: The acute palliative care unit (APCU) bridges between active cancer treatment and hospice care. However, no study has proven the efficacy of APCU in Korea. Objective: To evaluate the first-year outcomes of the patients admitted to an APCU at a tertiary hospital in Korea. Design: The APCU admitted 205 patients between April 14, 2014, and April 30, 2015. Of these patients, 57 were evaluable for baseline and one-week follow-up Edmonton Symptom Assessment System (ESAS). Results: Of the 57 participants, 56.1% were male, with a median age of 60 years (range, 52.8-69.5 years). All patients had advanced cancer, and 42 out of 57 had terminal illnesses. The median APCU stay was 14 days (range, 10-17 days). The 42 (73.7%) patients were referred to the APCU after anticancer treatment was completed. Ten (17.5%) patients died during their stay, and 20 (35.1%) were discharged home. Among those who completed the ESAS, there were significant improvements in scores in the following symptoms: fatigue, depression, loss of appetite, and shortness of breath. Physical symptoms (pain, fatigue, nausea, drowsiness, appetite, and shortness of breath) and the total ESAS scores were significantly improved (p = 0.002 and p = 0.005, respectively). Each non-medical palliative care program, such as art and music therapy, yoga, foot massage, haircut, and body care, showed no significant differences between the group who received them and those who did not. Conclusion: During the APCU stay, the overall symptoms of inpatients were reduced. A comprehensive and multidisciplinary team approach is essential for patients who need palliative care.

Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma.

BACKGROUND: This study was conducted to evaluate the clinical feasibility of nab-paclitaxel plus gemcitabine-cisplatin triplet chemotherapy in patients with locally advanced cholangiocarcinoma in real-world practice. METHODS: We retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with nab-paclitaxel plus gemcitabine-cisplatin between October 2019 and August 2021 at a single institution. The initial diagnosis of cholangiocarcinoma was histologically confirmed. RESULTS: One hundred twenty-nine patients were included in this study. Among the patients with a measurable lesion (57.4%), the objective response rate and disease control were 60.8% and 91.9%, respectively. Seventy-seven patients (59.7%) were determined as resectable after triplet chemotherapy, but 73 (56.6%) underwent subsequent curative surgery. The major postoperative complication rate was 15.1%, and there were 2 postoperative mortalities (2.7%). There were 6 complete remission cases (8.2%) in the final pathology. The R0 resection was achieved in 67 patients (91.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 67 patients (91.8%). Fifty-two patients (71.2%) had no lymph node metastasis. Patients who underwent surgery after triplet chemotherapy had significantly higher 12-month overall survival (95.9% vs 76.8%; P < .001) than those treated with chemotherapy alone. CONCLUSION: Nab-paclitaxel plus gemcitabine-cisplatin chemotherapy demonstrated a down-staging effect through a high response rate, indicating that this triplet chemotherapy is feasible as induction therapy in patients with locally advanced cholangiocarcinoma.

Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14).

BACKGROUND: HER2 overexpression or amplification, which is present in 15% of all cases of biliary tract cancer, has been identified as a druggable molecular target by genomic profiling. In the phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival benefit compared with active symptom control as second-line therapy for biliary tract cancer. We aimed to evaluate the clinical activity of FOLFOX plus anti-HER2 antibody trastuzumab as a second-line or third-line treatment for HER2-positive biliary tract cancer. METHODS: This study was an investigator-initiated, open-label, non-randomised, single-arm, multi institutional, phase 2 trial in participants aged 19 years or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and in-situ hybridisation positive or ERBB2 gene copy number ≥6·0 by next-generation sequencing) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) who progressed on chemotherapy containing gemcitabine and cisplatin (with one or two previous chemotherapy lines permitted). In cycle one, patients received intravenous trastuzumab-pkrb at 6 mg/kg on day 1, and FOLFOX (consisting of intravenous oxaliplatin [85 mg/m2], intravenous leucovorin [200 mg/m2], and fluorouracil [400 mg/m2 bolus] all on day 1, and fluorouracil [2400 mg/m2 infusion] on days 1-2. In cycle two onwards, participants were administered intravenous trastuzumab-pkrb at 4 mg/kg and FOLFOX, every 2 weeks, until unacceptable toxic effects or disease progression. The primary endpoint of the study was objective response rate based on RECIST version 1.1, assessed in the participants who completed at least one study cycle. The response rate threshold for a positive objective response rate was 25%. This trial is registered with ClinicalTrials.gov (NCT04722133) and is ongoing. FINDINGS: 34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0-16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7-46·3) and the disease control rate was 79·4% (95% CI 62·9-89·9). Median progression-free survival was 5·1 months (95% CI 3·6-6·7); median overall survival was 10·7 (95%CI 7·9-not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time. INTERPRETATION: For HER2-positive biliary tract cancer, second-line or third-line trastuzumab biosimilar plus FOLFOX exhibited promising activity with acceptable toxicity, warranting further investigation. FUNDING: Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National R&D Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.

Mid-upper Arm Circumference as an Indicator of Quality of Life of Patients with Advanced Cancer.

Objective: Mid-upper arm circumference (MUAC) has been used to assess malnutrition and health status across various disease groups. However, it is unclear whether MUAC is associated with quality of life (QOL) of patients with advanced cancer. Our goal was to investigate the relationship between MUAC and QOL in ambulatory out-patients with advanced cancer. Method: This was a cross-sectional study conducted in a tertiary cancer center in South Korea. A total of 200 patients with advanced cancer at oncology clinics of Seoul National University Bundang Hospital from March 2016 to January 2019 were enrolled. Out-patients with advanced cancer whose survival was expected to be less than one year by their oncologists were enrolled. QOL of patients was evaluated using the European Organization for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30). Associations of QOL with MUAC and nutritional parameters were examined with generalized linear models. Results: The most common cancer sites were the lung, colon or rectum, and genitourinary tract. In univariate analyses, significant factors associated with higher summary score of EORTC QLQ-C30 were higher MUAC (≥ 26.5 cm, p < 0.001), higher body mass index (BMI) (≥ 22 kg/m2, p < 0.001), higher serum albumin (≥ 3.7 g/dL, p < 0.01), higher creatinine (≥ 0.8 mg/dL, p = 0.023), and higher uric acid (≥ 5 mg/dL, p < 0.01). In multivariate analysis, higher serum albumin (≥ 3.7 g/dL, p < 0.01) and higher MUAC (≥ 26.5 cm, p = 0.03) were independently associated with better summary score of EORTC QLQ-C-30. Conclusion: MUAC was highly associated with QOL in terms of summary score and overall health status. Thus, MUAC, with its simplicity, can be a useful tool to reflect QOL in patients with advanced cancer.

Predictive biomarkers of survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab treatment.

BACKGROUND: Since atezolizumab plus bevacizumab (ATE+BEV) regimen for patients with unresectable hepatocellular carcinoma (HCC) was released quite recently, real-world data are lacking. We evaluated efficacy, safety, and predictive biomarkers for survival in patients receiving ATE+BEV. METHODS: Between 2020 and 2021, HCC patients receiving ATE+BEV at academic teaching hospitals were recruited. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). RESULTS: Among 121 patients enrolled, the median age was 63 years, with male predominance (82.6%). Complete response, partial response, stable disease, and progressive disease were identified in 2.5%, 26.4%, 54.5%, and 16.6%, respectively. Patients with alpha-fetoprotein and des-gamma-carboxy prothrombin (DCP) response, defined as ≥30% and ≥50% decreases, respectively, at the first response evaluation relative to baseline, and those with neutrophil-to-lymphocyte ratio (NLR) <2.5, had significantly higher objective response rates (42.6% vs. 21.5%, 50.0% vs. 26.2%, and 39.0% vs. 19.4%, respectively; all p < 0.05). During follow-up, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 5.7 months. Multivariable analyses showed that macrovascular invasion (adjusted hazard ratio [aHR] 2.541; p = 0.017), DCP ≥186 mAU/ml (aHR 5.102; p < 0.001), NLR ≥2.5 (aHR 3.584; p = 0.001), and an NLR decrease ≥10% at the first response (aHR 0.305; p = 0.002) were independent predictors of OS, and DCP ≥186 mAU (aHR 2.311; p = 0.002) and NLR ≥2.5 (aHR 1.938; p = 0.012) were independent predictors of PFS. Grade ≥3 treatment-related adverse events (AEs) occurred in 33 (27.3%) patients. CONCLUSION: ATE+BEV showed favorable efficacy and safety. Baseline high DCP and NLR may be useful prognostic predictors for OS and PFS.

High Serum Levels of IL-6 Predict Poor Responses in Patients Treated with Pembrolizumab plus Axitinib for Advanced Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.

A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer.

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4-88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.