Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study.

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function. APPROACH AND RESULTS: In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes. CONCLUSIONS: This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.

Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study.

BACKGROUND AND AIMS: Different approaches are available after the progression of disease (PD) to immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC), including the continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiological patterns of progression and survival post-ICI, also appraising treatment strategies. METHODS: We screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut-off. We evaluated post-progression survival (PPS) according to the treatment strategy at PD and verified its relationship with radiological patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI). RESULTS: Of 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95% CI: 4.4-6.9; 271 events). At the data cut-off, 165 patients (45%) received no post-progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95% CI: 1.21-2.22]; p = .0013) and nVI (HR 2.15 [95% CI: 1.38-3.35]; p = .0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line and albumin-bilirubin grade and Eastern Cooperative Oncology Group performance status at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95% CI: 0.09-0.32; p < .0001) or without subsequent TKI (HR 0.39, 95% CI: 0.26-0.58; p < .0001) as predictors of prolonged PPS versus no anticancer therapy. CONCLUSIONS: ICI-TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict a poorer prognosis. Despite lack of recommendation, the continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma.

BACKGROUND AND AIMS: Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. METHODS: 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated. RESULTS: The elderly (n = 116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65-2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54-1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p = .31) and bevacizumab-related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. CONCLUSIONS: Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.

Role of sacituzumab govitecan in solid tumors.

OBJECTIVE: To evaluate the antibody-drug conjugate- sacituzumab govitecan, its pharmacological properties, toxicity, data supporting efficacy against a wide variety of solid tumors beyond breast cancer, and potential future uses. DATA SOURCES: Articles in MEDLINE/PubMed databases and the National Institutes of Health Clinical Trials Registry (http://www. clinicaltrials.gov) between January 1, 2015, and July 1, 2021 using MeSH terms sacituzumab govitecan(- hziy) and solid tumors were reviewed. DATA SUMMARY: Antibody-drug conjugates (ADC's) are a subclass of emerging cancer therapeutics which combines chemotherapy with targeted antibodies. Sacituzumab govitecan (SG) is a novel antibody drug conjugate that has recently been approved by the Food and Drug Administration (FDA) in adult patients for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval of sacituzumab govitecan provides a new option for solid tumors that need to be further explored. In this review article, we discussed the pharmacokinetics, pharmacodynamics, safety profile of sacituzumab govitecan and various ongoing clinical trials on sacituzumab govitecan. CONCLUSION: Sacituzumab is a significant advancement made in cancer therapy. SG has showed significantly improved Health-related quality of life (HRQoL) in addition to prolonged progression free survival and Over all survival in addition to maintaining a good safety profile. Multiple clinical trials on SG are ongoing to evaluate the potential use of SG as neoadjuvant therapy in triple negative breast cancer, as an Adjuvant therapy, in combination with immunotherapy, and also for various solid tumors.

Quantifying the relationship between age at diagnosis and breast cancer-specific mortality.

PURPOSE: The relationship between age at diagnosis and breast cancer-specific mortality (BCSM) is unclear. The aim of this study was to examine the nature of this relationship using rigorous statistical methodology. METHODS: A historical cohort study of adult women with invasive breast cancer in the SEER database from 2000 to 2015 was conducted. Multivariable Cox's cause-specific hazards model was used to evaluate the association of age at diagnosis with risk of BCSM. Functional relationship of age was assessed using cumulative sums of Martingale residuals and the Kolmogorov-type supremum test. RESULTS: A total of 206,332 women were eligible for study. Mean age at diagnosis was 59.7 ± 13.8 years. Median follow-up was 80 months. During the study period, 21,771 women (10.6%) died from breast cancer and 18,566 (9.0%) died from other causes. Cumulative incidence of BCSM at 120 months post-diagnosis was 14.4% (95% CI 14.2-14.6%). Age was found to be quadratically related to the risk of BCSM (p < 0.001), with a nadir at 45 years of age. The final Cox model suggests that a 30-year-old woman has approximately the same adjusted BCSM risk (HR 1.187, 95% CI 1.187-1.188) as a 60-year-old woman (HR 1.174, 95% CI 1.174-1.175). CONCLUSIONS: Women diagnosed with breast cancer at the extremes of age suffer disproportionate rates of cancer-specific mortality. The relationship between age at diagnosis and adjusted risk of BCSM is complex, consistent with a quadratic function. With the growing appreciation for breast cancer as a heterogeneous disease, it is essential to accurately address age as a prognostic risk factor in predictive models.

Post-Treatment Symptoms of Pain, Anxiety, Sleep Disturbance, and Fatigue in Breast Cancer Survivors.

BACKGROUND: In part because of improvements in early detection and treatment, the number of breast cancer survivors is increasing. After treatment, however, breast cancer survivors often experience distressing symptoms, including pain, sleep disturbance, anxiety, and fatigue; at the same time, they have less frequent contact with health care providers. Pain commonly co-occurs with other symptoms and the combination of symptoms contribute to the amount of distress experienced by survivors. Previous studies of post-treatment symptoms include primarily urban and white women. AIMS: The purpose of this study was to describe the post-treatment cluster of symptoms, to examine the correlations among these symptoms, and to examine the role pain intensity may play in understanding the variation in sleep disturbance, fatigue, and anxiety in a racially diverse sample of rural breast cancer survivors. DESIGN: The theoretical framework for this descriptive correlational study was the theory of unpleasant symptoms. SETTINGS: Outpatient university-affiliated cancer clinic. PARTICIPANTS/SUBJECTS: Forty women who were between 6 months and 5 years post breast cancer diagnosis. METHODS: Participants completed the following self-report instruments: Patient Reported Outcomes Measurement Information System of pain intensity, pain interference, anxiety, and sleep disturbance and the Piper Fatigue Short Form 12. RESULTS: The average age of participants was 58 years, and 57.5% were black. Most women reported sleep disturbance (78%), pain interference (68%), and pain intensity (63%) above the national average for an American adult. Black women reported higher pain intensity than whites. There were moderate to strong correlations among the symptoms (range r = 0.35-0.89). CONCLUSIONS: Nurses and health care providers in primary care settings need to screen for symptoms, and nursing interventions are needed to assist breast cancer survivors to manage distressing symptoms.

Primary tumor resection in metastatic breast cancer: A propensity-matched analysis, 1988-2011 SEER data base.

Primary tumor resection (PTR) in metastatic breast cancer is not a standard treatment modality, and its impact on survival is conflicting. The primary objective of this study was to analyze impact of PTR on survival in metastatic patients with breast cancer. A retrospective study of metastatic patients with breast cancer was conducted using the 1988-2011 Surveillance, Epidemiology, and End Results (SEER) data base. Cox proportional hazards regression models were used to evaluate the relationship between PTR and survival and to adjust for the heterogeneity between the groups, and a propensity score-matched analysis was also performed. A total of 29 916 patients with metastatic breast cancer were included in the study, and 15 129 (51%) of patients underwent primary tumor resection, and 14 787 (49%) patients did not undergo surgery. Overall, decreasing trend in PTR for metastatic breast cancer in last decades was noted. Primary tumor resection was associated with a longer median OS (34 vs 18 months). In a propensity score-matched analysis, prognosis was also more favorable in the resected group (P = .0017). Primary tumor resection in metastatic breast cancer was associated with survival improvement, and the improvement persisted in propensity-matched analysis.

Emerging Role of Immune Checkpoint Blockade in Pancreatic Cancer.

Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD-1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with high morbidity and mortality. Based on available data, it's obvious that ICB has limited success in PDACs, which can be explained by the low immunogenicity and immunosuppressive tumor microenvironment of these tumors. In this review article, we focus on PD-L1 expression and microsatellite instability (MSI) in PDAC, and their roles as prognostic and predictive markers. We also discuss data supporting combination therapies to augment cancer immunity cycle. Combining anti-PD-1/PD-L1 agents with other modalities such as vaccines, chemotherapy, and radiation could potentially overcome resistance patterns and increase immune responsiveness in PDAC.

Acute Pancreatitis Associated With Ado-Trastuzumab Emtansine.

Ado-trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate with current FDA recommendation for second-line treatment of HER-2-positive metastatic breast cancer. It is a human epidermal growth factor receptor (HER-2)-targeted antibody-drug conjugate composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). Ado-trastuzumab emtansine improved both progression-free and overall survival as reported in EMILIA trial. With ongoing clinical trials in adjuvant and first-line setting for HER-2-positive early and metastatic breast cancer, it is prudent to recognize, report, and treat any adverse events related to T-DM1. We report a case of acute pancreatitis in a 54-year-old woman with metastatic breast cancer after she received her first dose of ado-trastuzumab emtansine. To the best of our knowledge, this is the first reported case of acute pancreatitis with probable association with ado-trastuzumab emtansine.

Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.

PURPOSE: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.

Impact of Race on Outcomes of Advanced Stage Non-Small Cell Lung Cancer Patients Receiving Immunotherapy.

BACKGROUND: The impact of race in advanced stage non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) is conflicting. Our study sought to examine racial disparities in time to treatment initiation (TTI), overall survival (OS), and progression-free survival (PFS) using a population that was almost equally black and white. METHODS: This was a retrospective cohort study of stage IV NSCLC patients > 18 years receiving immunotherapy at our center between 2014 and 2021. Kaplan-Meier curves and the multivariate Cox proportional hazards model determined the predictors of OS and PFS. Analyses were undertaken using IBM PSAW (SPSS v.28). RESULTS: Out of 194 patients who met the inclusion criteria, 42.3% were black (n = 82). In the multivariate analysis, there was no difference in PFS (HR: 0.96; 95% CI: 0.66,1.40; p = 0.846) or OS (HR: 0.99; 95% CI: 0.66, 1.48; p = 0.966). No difference in treatment selection was observed between white and black patients (p = 0.363), nor was there a difference observed in median time to overall treatment initiation (p = 0.201). CONCLUSIONS: No difference was observed in OS and PFS in black and white patients. Black patients' reception of timelier immunotherapy was an unanticipated finding. Future studies are necessary to better understand how race impacts patient outcomes.

Original Research: Can a Palliative Care Lay Health Advisor-Nurse Partnership Improve Health Equity for Latinos with Cancer?

PURPOSE: A palliative care infrastructure is lacking for Latinos with life-threatening illness, especially in rural regions of the United States. The purpose of this study was to develop and evaluate a community-based palliative care lay health advisor (LHA) intervention for rural-dwelling Latino adults with cancer. METHODS: An exploratory mixed-methods participatory action research design was carried out by an interprofessional research team that included community and academic members. Fifteen Latino community leaders completed a 10-hour palliative care training program and then served as palliative care LHAs. Although 45 Latinos with cancer initially agreed to participate, four withdrew or died and six were not reachable by the LHAs, for a final total of 35 patient participants.The trained palliative care LHAs delivered information on home symptom management and advance care planning to assigned participants. Palliative care nurses led the training and were available to the LHAs for consultation throughout the study. The LHAs made an average of three telephone calls to each participant. The Edmonton Symptom Assessment System-Revised (ESAS-r) and the four-item Advance Care Planning Engagement Survey (ACPES-4) were administered pre- and postintervention to determine the intervention's effectiveness. Encounter forms were transcribed, coded, and analyzed using case comparison. RESULTS: The major finding was that significant improvements were shown for all four items of the ACPES-4 among both the LHAs (posttraining) and the participants (postintervention). Information on advance care planning was shared with 74.3% of the 35 participants. Participants showed clinical improvement in physical symptom scores and clinical deterioration in emotional symptom scores following the intervention, although these changes did not reach statistical significance. The advisors noted that participants were anxious about how to explain cancer to children, the uncertainty of their prognosis, and medical expenses. This sample was younger than those of other cancer studies; 51.4% were under age 50 and 73.1% had at least one child in the home. CONCLUSIONS: A community-based palliative care LHA-nurse partnership was shown to be a feasible way to engage in conversations and deliver information about advance care planning to rural-dwelling Latino adults with cancer. The positive results led to the regional cancer center's decision to select "cultural care" as its 2022 goal for maintaining its accreditation with the Commission on Cancer.

Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.

Background: In patients with cirrhosis, portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, promoting an inflammatory state that can lead to the progression of liver disease and development of hepatocellular carcinoma (HCC). We aimed to investigate whether beta blockers (BBs), which can mediate portal hypertension, conferred survival benefits in patients treated with immune checkpoint inhibitors (ICIs). Methods: We conducted a retrospective, observational study of 578 patients with unresectable HCC treated with ICI from 2017 to 2019 at 13 institutions across three continents. BB use was defined as exposure to BBs at any time during ICI therapy. The primary objective was to assess the association of BB exposure with overall survival (OS). Secondary objectives were to evaluate the association of BB use with progression-free survival (PFS) and objective response rate (ORR) according to RECIST 1.1 criteria. Results: In our study cohort, 203 (35%) patients used BBs at any point during ICI therapy. Of these, 51% were taking a nonselective BB. BB use was not significantly correlated with OS (hazard ratio [HR] 1.12, 95% CI 0.9-1.39, P = 0.298), PFS (HR 1.02, 95% CI 0.83-1.26, P = 0.844) or ORR (odds ratio [OR] 0.84, 95% CI 0.54-1.31, P = 0.451) in univariate or multivariate analyses. BB use was also not associated with incidence of adverse events (OR 1.38, 95% CI 0.96-1.97, P = 0.079). Specifically, nonselective BB use was not correlated with OS (HR 0.94, 95% CI 0.66-1.33, P = 0.721), PFS (HR 0.92, 0.66-1.29, P = 0.629), ORR (OR 1.20, 95% CI 0.58-2.49, P = 0.623), or rate of adverse events (OR 0.82, 95% CI 0.46-1.47, P = 0.510). Conclusion: In this real-world population of patients with unresectable HCC treated with immunotherapy, BB use was not associated with OS, PFS or ORR.