Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. METHODS: In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. RESULTS: Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. CONCLUSIONS: The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

Factors of preparedness for loss from cancer among Taiwanese family caregivers.

This cohort study investigated factors associated with 336 Taiwanese family caregivers' emotional and cognitive preparedness for death of a loved one with terminal cancer. Caregivers' death-preparedness states (no-death-preparedness [as reference], cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) were previously identified. Associations of factors with these states were determined by a hierarchical generalized linear model. Financial hardship decreased caregivers' likelihood for the emotional-death-preparedness-only and sufficient-death-preparedness states. Physician prognostic disclosure increased membership in the cognitive-death-preparedness-only and sufficient-death-preparedness states. The better the quality of the patient-caregiver relationship, the higher the odds for the emotional-death-preparedness-only and sufficient-death-preparedness states, whereas the greater the tendency for caregivers to communicate end-of-life issues with their loved one, the lower the odds for emotional-death-preparedness-only state membership. Stronger coping capacity increased membership in the emotional-death-preparedness-only state, but perceived social support was not associated with state membership. Providing effective interventions tailored to at-risk family caregivers' specific needs may facilitate their death preparedness.

Gut microbiota and clinical response to immune checkpoint inhibitor therapy in patients with advanced cancer.

BACKGROUND: There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. METHODS: Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients' clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array. RESULTS: We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters. CONCLUSIONS: The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy.

Factors Associated With Family Surrogate Decisional-Regret Trajectories.

CONTEXT/OBJECTIVES: The scarce research on factors associated with surrogate decisional regret overlooks longitudinal, heterogenous decisional-regret experiences and fractionally examines factors from the three decision-process framework stages: decision antecedents, decision-making process, and decision outcomes. This study aimed to fill these knowledge gaps by focusing on factors modifiable by high-quality end-of-life (EOL) care. METHODS: This observational study used a prior cohort of 377 family surrogates of terminal-cancer patients to examine factors associated with their membership in the four preidentified distinct decisional-regret trajectories: resilient, delayed-recovery, late-emerging, and increasing-prolonged trajectories from EOL-care decision making through the first two bereavement years by multinomial logistic regression modeling using the resilient trajectory as reference. RESULTS: Decision antecedent factors: Financial sufficiency and heavier caregiving burden increased odds for the delayed-recovery trajectory. Spousal loss, higher perceived social support during an EOL-care decision, and more postloss depressive symptoms increased odds for the late-emerging trajectory. More pre- and postloss depressive symptoms increased odds for the increasing-prolonged trajectory. Decision-making process factors: Making an anticancer treatment decision and higher decision conflict increased odds for the delayed-recovery and increasing-prolonged trajectories. Making a life-sustaining-treatment decision increased membership in the three more profound trajectories. Decision outcome factors: Greater surrogate appraisal of quality of dying and death lowered odds for the three more profound trajectories. Patient receipt of anticancer or life-sustaining treatments increased odds for the late-emerging trajectory. CONCLUSION: Surrogate membership in decisional-regret trajectories was associated with decision antecedent, decision-making process, and decision outcome factors. Effective interventions should target identified modifiable factors to address surrogate decisional regret.

Associations Between Surrogates' Decisional Regret Trajectories and Bereavement Outcomes.

BACKGROUND: Family surrogates experience heterogeneous decisional regret and negative long-lasting postdecision impacts. Cross-sectional findings on the associations between decisional regret and surrogates' bereavement outcomes are conflicting and cannot illustrate the directional and dynamic evolution of these associations. In this study, we sought to longitudinally examine the associations between 4 previously identified decisional-regret trajectories and bereavement outcomes among family surrogates of terminally ill patients with cancer. PATIENTS AND METHODS: This prospective, longitudinal, observational study included 377 family surrogates. Decisional regret was measured using the 5-item Decision Regret Scale, and 4 decisional regret trajectories were identified: resilient, delayed-recovery, late-emerging, and increasing-prolonged. Associations between bereavement outcomes (depressive symptoms, prolonged grief symptoms, and physical and mental health-related quality of life [HRQoL]) and decisional-regret trajectories were examined simultaneously by multivariate hierarchical linear modeling using the resilient trajectory as a reference. RESULTS: Surrogates in the delayed-recovery, late-emerging, and increasing-prolonged trajectories experienced significantly higher symptoms of prolonged grief (ß [95% CI], 1.815 [0.782 to 2.848]; 2.312 [0.834 to 3.790]; and 7.806 [2.681 to 12.931], respectively) and poorer physical HRQoL (-1.615 [-2.844 to -0.386]; -1.634 [-3.226 to -0.042]; and -4.749 [-9.380 to -0.118], respectively) compared with those in the resilient trajectory. Membership in the late-emerging and increasing-prolonged trajectories was associated with higher symptoms of depression (ß [95% CI], 2.942 [1.045 to 4.839] and 8.766 [2.864 to 14.668], respectively), whereas only surrogates in the increasing-prolonged decisional-regret trajectory reported significantly worse mental HRQoL (-4.823 [-8.216 to -1.430]) than those in the resilient trajectory. CONCLUSIONS: Surrogates who experienced delayed-recovery, unresolved, or late-emerging decisional regret may carry ceaseless doubt, guilt, or self-blame for patient suffering, leading to profound symptoms of prolonged grief, depressive symptoms, and worse HRQoL over their first 2 bereavement years.

Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer.

Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

Factors associated with cancer patients' distinct death-preparedness states.

BACKGROUND/OBJECTIVE: Facilitating death preparedness is important for improving cancer patients' quality of death and dying. We aimed to identify factors associated with the four death-preparedness states (no-preparedness, cognitive-only, emotional-only, and sufficient-preparedness) focusing on modifiable factors. METHODS: In this cohort study, we identified factors associated with 314 Taiwanese cancer patients' death-preparedness states from time-invariant socio-demographics and lagged time-varying modifiable variables, including disease burden, physician prognostic disclosure, patient-family communication on end-of-life (EOL) issues, and perceived social support using hierarchical generalized linear modeling. RESULTS: Patients who were male, older, without financial hardship to make ends meet, and suffered lower symptom distress were more likely to be in the emotional-only and sufficient-preparedness states than the no-death-preparedness-state. Younger age (adjusted odds ratio [95% confidence interval] = 0.95 [0.91, 0.99] per year increase in age) and greater functional dependency (1.05 [1.00, 1.11]) were associated with being in the cognitive-only state. Physician prognostic disclosure increased the likelihood of being in the cognitive-only (51.51 [14.01, 189.36]) and sufficient-preparedness (47.42 [10.93, 205.79]) states, whereas higher patient-family communication on EOL issues reduced likelihood for the emotional-only state (0.38 [0.21, 0.69]). Higher perceived social support reduced the likelihood of cognitive-only (0.94 [0.91, 0.98]) but increased the chance of emotional-only (1.09 [1.05, 1.14]) state membership. CONCLUSIONS: Death-preparedness states are associated with patients' socio-demographics, disease burden, physician prognostic disclosure, patient-family communication on EOL issues, and perceived social support. Providing accurate prognostic disclosure, adequately managing symptom distress, supporting those with higher functional dependence, promoting empathetic patient-family communication on EOL issues, and enhancing perceived social support may facilitate death preparedness.

Tislelizumab in Patients with Previously Treated Advanced Hepatocellular Carcinoma (RATIONALE-208): A Multicenter, Non-Randomized, Open-Label, Phase 2 Trial.

Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC. Methods: The multiregional phase 2 study RATIONALE-208 examined single-agent tislelizumab (200 mg intravenously every 3 weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by the Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab. Results: Between April 9, 2018, and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% (n = 32/249; 95% confidence interval [CI], 9-18), including five complete and 27 partial responses. The number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8-20]; two or more prior lines, 13% [95% CI, 7-20]). Median duration of response was not reached. The disease control rate was 53%, and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment. Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC.

Decisional-Regret Trajectories From End-of-Life Decision Making Through Bereavement.

CONTEXT: Regret plays a central role in surrogate decision making. Research on decisional regret in family surrogates is scarce and lacks longitudinal studies to illustrate the heterogenous, dynamic evolution of decisional regret. OBJECTIVES: To identify distinct decisional-regret trajectories from end-of-life (EOL) decision making through the first two bereavement years among surrogates of cancer patients. METHODS: A prospective, longitudinal, observational study was conducted on a convenience sample of 377 surrogates of terminally ill cancer patients. Decisional regret was measured by the five-item Decision Regret Scale monthly during the patient's last six months and 1, 3, 6, 13, 18, and 24 months post loss. Decisional-regret trajectories were identified using latent-class growth analysis. RESULTS: Surrogates reported substantially high decisional regret (pre- and postloss mean [SD] as 32.20 [11.47] and 29.90 [12.47], respectively). Four decisional-regret trajectories were identified. The resilient trajectory (prevalence: 25.6%) showed a general low decisional-regret level with mild and transient perturbations around the time of patient death only. Decisional regret for the delayed-recovery trajectory (56.3%) accelerated before the patient's death and decreased slowly throughout bereavement. Surrogates in the late-emerging (10.2%) trajectory reported a low decisional-regret level before loss but their decisional regret increased gradually thereafter. The increasing-prolonged trajectory (6.9%) rapidly increased in decisional-regret levels during EOL decision making, peaked one-month post loss, then declined steadily but without a complete resolution. CONCLUSION: Surrogates heterogeneously suffered decisional regret from EOL decision making through bereavement as evident by four identified distinct decisional-regret trajectories. Early identification and prevention of increasing/prolonged decisional-regret trajectories is warranted.

Transdermal buprenorphine improves overall quality of life and symptom severity in cancer patients with pain.

AIM AND OBJECTIVES: This study explored the effect of transdermal buprenorphine on quality of life and six symptoms in cancer patients with pain. BACKGROUND: Transdermal opioids offer advantages over traditional routes of administration. The impact of transdermal buprenorphine on quality of life for patients with cancer in Asian populations is unknown. DESIGN: This study employed a single-arm observational repeated measures design. Cancer patients with pain were evaluated prior to treatment (baseline). Over a 4-week treatment period, quality of life and symptoms were assessed at 2 and 4 weeks. This study adhered to the recommendations of STROBE guidelines. METHODS: This multi-site study was conducted in six hospitals located across northern, middle and southern Taiwan. Adult cancer patients whose pain was previously stable with opioid analgesics and, based on clinical judgement, were able to convert to transdermal buprenorphine treatment were invited to participate. Quality of life was measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30). RESULTS: Generalised estimating equations showed participants who completed at least one follow-up measurement (N = 80) over 4-weeks had a significant improvement in overall quality of life. Functional status only improved for social functioning. However, symptom severity decreased significantly for nausea/vomiting, pain, insomnia and constipation. CONCLUSIONS: The study provides initial evidence supporting transdermal buprenorphine for providing beneficial effects of improving quality of life and reducing severity of symptoms in Asian patients with cancer. RELEVANCE TO CLINICAL PRACTICE: The findings of this study can inform the clinical practice that the use of transdermal buprenorphine in cancer patients with pain may also reduce the severity of other symptoms and improve overall quality of life. TRIAL REGISTRATION DETAILS: This study was registered in ClinicalTrials.gov. Identifier: NCT04315831.

Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era.

BACKGROUND: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. METHODS: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively. RESULTS: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality (p = 0.003) and a 48% reduction in risk of recurrence (p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3-4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend (p = 0.058) towards worse recurrence-free survival. CONCLUSIONS: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab.

Modifiable factors of depressive-symptom trajectories from caregiving through bereavement.

BACKGROUND/PURPOSE: The purpose of this secondary-analysis study was to identify never-before-examined factors associated with distinct depressive-symptom trajectories among family caregivers from end-of-life caregiving through the first 2 bereavement years. PARTICIPANTS/METHODS: Participants (N=661) were family caregivers who provided end-of-life caregiving for terminally ill cancer patients. Multinomial logistic regressions were conducted to identify modifiable factors associated with caregivers' seven previously identified depressive-symptom trajectories: minimal-impact resilience, recovery, preloss-depressive-only, delayed symptomatic, relief, prolonged symptomatic, and chronically persistent distressed. Drawing from the stress-appraisal-coping model, modifiable time-varying factors associated with distinct depressive-symptom trajectories were examined in three domains: (1) stressors, (2) stress appraisal, and (3) available resources (internal coping capacity and external social support). RESULTS: Profound objective caregiving demands were associated with caregivers' increased likelihood of belonging to more distressing depressive-symptom trajectories than to the minimal-impact-resilience trajectory. But, stronger negative appraisal of end-of-life caregiving increased odds of caregiver membership in preloss-depressive-only and relief trajectories over the recovery, delayed, and prolonged-symptomatic trajectories. Stronger internal coping capacity and perceived social support buffered the tremendous stress of end-of-life caregiving and permanent loss of a relative, as evidenced by higher odds of being in the minimal-impact-resilience and recovery trajectories. CONCLUSION: Family caregivers' distinct depressive-symptom trajectories were linked to their preloss caregiving demands, appraisal of negative caregiving impact, personal coping capacity, and perceived social support. Our results highlight actionable opportunities to improve end-of-life-care quality by boosting family caregivers' coping capacity and enhancing their social support to help them adequately manage daily caregiving loads/burdens thus relieving the emotional toll before patient death and throughout bereavement.

Clinical Utility of Circulating Tumor Cells for Predicting Major Histopathological Response after Neoadjuvant Chemoradiotherapy in Patients with Esophageal Cancer.

BACKGROUND: A "surgery as needed" approach may be offered to patients with esophageal cancer (EC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT). However, the utility of clinical response assessment (CRE) for predicting histopathological response to nCRT remains limited. Circulating tumor cells (CTCs) hold promise as biomarkers of response to nCRT. METHODS: We analyzed the clinical utility of post-nCRT CTCs, alone or in combination with CRE, in the prediction of MaHR. We defined MaHR as either the lack or a limited presence (≤10%) of vital residual tumor cells in the resected esophageal specimen in the absence of nodal involvement. RESULTS: Of the 48 study patients, 27 (56%) achieved MaHR. Patients with MaHR had a significantly lower CTCs count compared with those without (3.61 ± 4.53 versus 6.83 ± 5.22 per mL of blood, respectively; P = 0.027). Using a cutoff for positivity of 5 CTCs per mL of blood, the combination of CTCs and CRE allowed achieving a negative predictive value for MaHR of 93% (95% confidence interval [CI] = 70-99%) along with a false negative rate of 5% (95% CI = 1-33%). CONCLUSION: CTCs count assessed in combination with CRE can potentially help identify patients with EC who achieved MaHR after nCRT.

Associations of surrogates' death-preparedness states with decisional conflict and heightened decisional regret over cancer patients' last 6 months of life.

OBJECTIVE: Preparing family surrogates for patient death and end-of-life (EOL) decision making may reduce surrogate decisional conflict and regret. Preparedness for patient death involves cognitive and emotional preparedness. We assessed the associations of surrogates' death-preparedness states (that integrate both cognitive and emotional preparedness for patient death) with surrogates' decisional conflict and regret. METHODS: Associations of 173 surrogates' death-preparedness states (no, cognitive-only, emotional-only, and sufficient preparedness states) with decisional conflict (measured by the Decision Conflict Scale) and heightened decisional regret (Decision Regret Scale scores >25) were evaluated using hierarchical linear modeling and hierarchical generalized linear modeling, respectively, during a longitudinal observational study at a medical center over cancer patients' last 6 months. RESULTS: Surrogates reported high decisional conflict (mean [standard deviation] = 41.48 [6.05]), and 52.7% of assessments exceeded the threshold for heightened decisional regret. Surrogates in the cognitive-only preparedness state reported a significantly higher level of decisional conflict (ß = 3.010 [95% CI = 1.124, 4.896]) than those in the sufficient preparedness state. Surrogates in the no (adjusted odds ratio [AOR] [95% CI] = 0.293 [0.113, 0.733]) and emotional-only (AOR [95% CI] = 0.359 [0.149, 0.866]) preparedness states were less likely to suffer heightened decisional regret than those in the sufficient preparedness state. CONCLUSIONS: Surrogates' decisional conflict and heightened decisional regret are associated with their death-preparedness states. Improving emotional preparedness for the patient's death among surrogates in the cognitive-only preparedness state and meeting the specific needs of those in the no, emotional-only, and sufficient preparedness states are actionable high-quality EOL-care interventions that may lessen decisional conflict and decisional regret.

Proton beam radiotherapy combined with anti-PD1/PDL1 immune checkpoint inhibitors for advanced hepatocellular carcinoma.

Anti-Programmed cell Death protein 1 (Anti-PD1) or Programmed Death-Ligand 1 (PDL1) immune checkpoint inhibitors provide treatment options for advanced HCC patients with low response rates. Combination therapy is becoming a major issue to improve the unmet need. Proton beam radiotherapy (PBT) could effectively control the local tumor with a low-risk injury to peripheral liver parenchyma. We retrospectively reviewed the patients who have received PBT combined with anti-PD1/PDL1 to evaluate the efficacy and safety of the advanced HCC patients. This study reviewed 29 advanced HCC patients who have received PBT and anti-PD1/PDL1 during 2016 and 2019. All were Child-Pugh A and performance status 0-1. Seventeen patients (58.6%) had extrahepatic spreading. Concurrent PBT started during anti-PD1/PDL1 with a median of 96.6 grays equivalent dose. The PBT field covered all tumors in 13 (44.8%) patients under curative intent. Other patients (55.2%) received palliative PBT that covered only the principal tumors. All patients have completed the concurrent PBT protocol. The median anti-PD1/PDL1 duration was 3.9 months. After a median follow-up of 13.2 months, the rates of 1-year PBT infield tumor control, 1-year outfield tumor control, and overall response were 90.5%, 90.9%, and 61.5%, and 70.8%, 69.2%, and 43.8%, respectively for curative-intent and palliative-control PBT. Complete response was found in 4 (30.8%) curative-intent and 1 (6.3%) palliative-control patients. The median overall progression-free survival was 27.2 months for curative-intent patients and 15.9 months for palliative-control patients. The overall survival was non-reached for both groups. The ALBI grade and Child-Pugh score change at 3-month and 6-month after PBT initiation were nonsignificant. No unexpected adverse event occurred except nine patients (31.0%) had treatment-related adverse events higher than or equal to Grade 3, including 2 (6.9%) had a radiation-induced liver injury. PBT combined with anti-PD1/PDL1 was safe without unexpected adverse events. The concurrent therapy could effectively treat advanced HCC through sustained local tumor necrosis and effective systemic tumor control for the patients who received curative-intent or palliative-control PBT combined with anti-PD1/PDL1.

Caregivers' Death-Preparedness States Impact Caregiving Outcomes and Patients' End-of-Life Care.

BACKGROUND/OBJECTIVE: Preparing family caregivers, cognitively, emotionally, and behaviorally, for their relative's death is an actionable component of high-quality end-of-life care. We aimed to examine the never-before-examined associations of conjoint cognitive prognostic awareness and emotional preparedness for death with caregiving outcomes and end-of-life care received by cancer patients. DESIGN/SETTING/PARTICIPANTS/MAIN MEASURES: For this longitudinal study, associations of death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) with subjective caregiving burden, depressive symptoms, and quality of life (QOL) and patients' end-of-life care (chemotherapy and/or immunotherapy, cardiopulmonary resuscitation, intensive care unit care, intubation, mechanical ventilation support, vasopressors, nasogastric tube feeding, and hospice care) were evaluated using multivariate hierarchical linear and logistic regression modeling, respectively, for 377 caregivers in cancer patients' last 6 months and 1 month, respectively. KEY RESULTS: Caregivers in the cognitive-death-preparedness-only state experienced a higher level of subjective caregiving burden than those in the sufficient-death-preparedness state. Caregivers in the no-death-preparedness and cognitive-death-preparedness-only states reported significantly more depressive symptoms and worse QOL than those in the sufficient-death-preparedness state. Cancer patients with caregivers in the sufficient-death-preparedness state were less likely to receive chemotherapy and/or immunotherapy, intubation, mechanical ventilation, and nasogastric tube feeding than patients with caregivers in other death-preparedness states. However, patients' receipt of hospice care was not associated with their caregivers' death-preparedness states. CONCLUSION: Family caregivers' death-preparedness states were associated with caregiving outcomes and their relative's end-of-life care. Cultivating caregivers' accurate prognostic awareness and improving their emotional preparedness for their relative's death may facilitate more favorable end-of-life-caregiving outcomes and may limit potentially nonbeneficial end-of-life care.

Associations of death-preparedness states with bereavement outcomes for family caregivers of terminally ill cancer patients.

OBJECTIVE: Death preparedness involves cognitive prognostic awareness and emotional acceptance of a relative's death. Effects of retrospectively assessed cognitive prognostic awareness and emotional preparedness for patient death have been individually investigated among bereaved family caregivers. We aimed to prospectively examine associations of caregivers' death-preparedness states, determined by conjoint cognitive prognostic awareness and emotional preparedness for death, with bereavement outcomes. METHODS: Associations of caregivers' death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) at last preloss assessment with bereavement outcomes over the first two bereavement years were evaluated among 332 caregivers of advanced cancer patients using hierarchical linear models with the logit-transformed posterior probability for each death-preparedness state. RESULTS: Caregivers with a higher logit-transformed posterior probability for sufficient death-preparedness state reported less prolonged-grief symptoms, lower likelihoods of severe depressive symptoms and heightened decisional regret, and better mental health-related quality of life (HRQOL). Caregivers with a higher logit-transformed posterior probability for no-death-preparedness state reported less prolonged-grief symptoms, a lower likelihood of severe depressive symptoms, and better mental HRQOL. A higher logit-transformed posterior probability for cognitive-death-preparedness-only state was associated with bereaved caregivers' higher likelihood of heightened decisional regret, whereas that for emotional-death-preparedness-only state was not associated with caregivers' bereavement outcomes. CONCLUSIONS: Caregivers' bereavement outcomes were associated with their preloss death-preparedness states, except for physical health-related QOL. Interventions focused on not only cultivating caregivers' accurate prognostic awareness but also adequately preparing them emotionally for their relative's forthcoming death are actionable opportunities for high-quality end-of-life care and are urgently warranted to facilitate caregivers' bereavement adjustment.

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFß and PD-L1, in Patients with Esophageal Squamous Cell Carcinoma: Results from a Phase 1 Cohort in Asia.

BACKGROUND: Patients with esophageal squamous cell carcinoma (SCC) have limited treatment options. Blocking transforming growth factor-ß (TGFß), which can be overexpressed in these tumors, may enhance responses to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitors. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFß receptor II (TGFßRII) (a TGFß "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1. OBJECTIVE: The objective of this study was to investigate the safety and efficacy of bintrafusp alfa in Asian patients with pretreated, PD-L1-unselected esophageal SCC. PATIENTS AND METHODS: In a phase 1 study, Asian patients with pretreated esophageal SCC received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety/tolerability with a goal of exploring clinical activity. RESULTS: By the database cutoff of August 24, 2018, 30 patients (76.7% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks; two remained on treatment. Nineteen patients (63.3%) had treatment-related adverse events, seven (23.3%) with grade 3/4 events, and there were no treatment-related deaths. The confirmed objective response rate (ORR) per independent review was 10.0% (95% confidence interval [CI] 2.1-26.5); responses lasted 2.8-8.3 + months. All responses occurred in immune-excluded tumors. Investigator-assessed confirmed ORR was 20.0% (95% CI 7.7-38.6). Median overall survival was 11.9 months (95% CI 5.7-not reached). CONCLUSIONS: Bintrafusp alfa demonstrated a manageable safety profile and efficacy in Asian patients with pretreated esophageal SCC. CLINICAL TRIALS REGISTRATION: NCT02699515.

Depressive-Symptom Trajectories From End-of-Life Caregiving Through the First 2 Bereavement Years for Family Caregivers of Advanced Cancer Patients.

BACKGROUND: Family caregivers' distinct depressive-symptom trajectories are understudied and have been examined independently during end-of-life (EOL) caregiving or bereavement, making it difficult to validate two competing hypotheses (wear-and-tear vs. relief) of caregiving effects on bereavement. Existing studies may also miss short-term heterogeneity in depressive symptoms during the immediate postloss period due to lengthy delays in the first postloss assessment. PURPOSE: This secondary-analysis study examined distinct depressive-symptom trajectories for caregivers of advanced cancer patients from EOL caregiving through the first 2 bereavement years with closely spaced assessments. METHODS: Depressive symptoms were measured monthly during EOL caregiving and 1, 3, 6, 13, 18, and 24 months postloss among 661 caregivers using the Center for Epidemiologic Studies-Depression scale. Depressive-symptom trajectories were identified using latent-class growth analysis while controlling for gender and age. RESULTS: We identified seven distinct depressive-symptom trajectories (prevalence) characterized by the timing, intensity, and duration of depressive symptoms: minimal-impact resilience (20.4%), recovery (34.0%), preloss-grief only (21.6%), delayed symptomatic (9.1%), relief (5.9%), prolonged symptomatic (6.5%), and chronically persistent distressed (2.5%). CONCLUSION: Caregivers of advanced cancer patients responded heterogeneously to the stresses of EOL caregiving and bereavement. The majority of caregivers was resilient while providing caregiving and quickly rebounded to healthy levels of psychological functioning during bereavement, whereas a minority experienced delayed-symptomatic, prolonged-symptomatic, or chronically-persistent-distressing depressive-symptom trajectories. Linking caregivers' psychological experiences from caregiving through bereavement by closely spaced assessments can more comprehensively illustrate their depressive-symptom trajectories, which confirm both the wear-and-tear and relief hypotheses, and help in targeting interventions for distinct depressive-symptom trajectories.

Phase I first-in-human study of HLX07, a novel and improved recombinant anti-EGFR humanized monoclonal antibody, in patients with advanced solid cancers.

Purpose This study aimed to evaluate the safety and pharmacokinetic (PK) profiles of HLX07, a novel, recombinant, humanized anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced solid cancers who had failed standard therapy or for whom no standard therapy was available. Methods In this prospective, open-label, Phase I dose escalation study, patients aged ≥18 years (≥20 years for patients in Taiwan) with histologically-confirmed metastatic or recurrent epithelial carcinoma that had no K-RAS or B-RAF mutations were enrolled in a '3 + 3' escalation design. HLX07 was administered weekly by 2-h intravenous infusion at doses ranging from 50 to 800 mg. The primary endpoint was summary listing of participants reporting treatment-emergent adverse events (TEAEs). Secondary endpoints included PK analysis, serum anti-HLX07 antibody assessments and efficacy. Results In total, 19 patients were enrolled between 1 October 2016 and 16 July 2019 to receive HLX07 at doses of 50 (n = 3), 100 (n = 3), 200 (n = 3), 400 (n = 3), 600 (n = 3) and 800 (n = 4) mg per week. All patients experienced at least one TEAE, most commonly fatigue (68.4%), nausea (47.4%), paronychia (31.6%) and vomiting (31.6%). Serious TEAEs were reported in 11 patients but only one serious TEAE (dyspnea in 600 mg cohort) was regarded as possibly related to study treatment. No dose limiting toxicity (DLT) was reported. Systemic exposure to HLX07 increased proportionally with dose. Anti-HLX07 antibodies were not detected in any patients. Conclusion HLX07 was well tolerated (at dose levels up to 800 mg/week) and promising in patients with advanced solid cancers.Clinical Trial Registration: The study was registered at ClinicalTrials.gov : NCT02648490 (Jan 7, 2016).