Adjuvant immunotherapy for melanoma patients: progress and opportunities.

The majority of patients who are diagnosed with cutaneous melanoma are candidates for surgical resection and thus curable from their disease. However, the risk for a recurrence is high for many patients, including those with lymph node-negative melanoma, thus necessitating additional therapies beyond surgery. With the advent of anti-programmed cell death protein 1 (PD-1)-based immunotherapies, which are vastly more effective compared to previous standard-of-care treatments in the advanced setting, the landscape of adjuvant therapy has fundamentally changed in recent years. Anti-PD-1-based immune checkpoint inhibition therapy is now the standard of care for many patients with stage IIB or higher melanoma. Neoadjuvant approaches have demonstrated superior outcomes compared to adjuvant-alone therapy. However, a number of questions remain including treatment combinations such as combined anti-PD-1 + lymphocyte activation gene-3, optimal sequencing of therapies, and the use of predictive markers to further improve outcomes for patients with high-risk melanoma.

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806.

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal.

Background: Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma. Patients and methods: Patients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015. Results: Of the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease. Conclusion: In this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population. ClinicalTrials.gov: NCT02054806.

[Immediate results of combined treatment for soft tissue sarcomas including intraoperative radiation therapy].

Nowadays the most popular and justified, from oncological positions, method of treatment for soft tissue sarcomas is a combined approach with the use of conservative surgery followed by postoperative radiation therapy. In this regard, intraoperative radiation therapy (IORT) in a single dose of 10-20 Gy is a method that optimizes the role of radiation therapy in treatment of this pathology allowing precise localization of radiation zone within the "tumor bed", thereby minimizing damage of normal tissues and critical organs. The aim of the study was to investigate the effect of IORT on the frequency and structure of post-operative complications. Testing group (n = 49) was compared to the group without IORT (n = 57) and group with only surgery (n = 171). According to the study it was not obtained statistically significant differences in the incidence of postoperative complications in the groups (p = 0,57), not marked influence on the structure of post-operative complications.

[Results of combined treatment with intraoperative radial therapy of soft tissue sarcoma].

The intraoperative radiation therapy (IORT) in combined therapy of soft tissue sarcoma in a single dose 10-20 Gy is the method, which can optimize the role of radiation therapy in treatment of this nosology. This method allows exact localization of the irradiation zone in the frames of "tumor bed", thereby minimizing the damage of normal tissues and critical organs. The aim of the study was the influence of IORT on the rate and structure of postoperative complications and long-term results of treatment in the group under study (n = 49) in comparison with the group of combined treatment without IORT (n = 57) and the group of surgical treatment. No statistically reliable difference in the rate of postoperative complications in groups (p = 0.57) was obtained and there was no influence on the structure of postoperative complications. At the same time the statistically reliable increase of general survival rates (p = 0.025) and the survival without relapse in the main group (p < 0.025) were obtained. Thus, the application of IORT in combined treatment of soft tissue sarcomas showed the satisfactory profile of "surgical safety", provided the reliable increase of general survival rates and rates without relapse.

[Long-term results of combined treatment of soft tissue sarcoma with the use of intraoperative radiotherapy].

This retrospective study of long-term results of combined treatment of soft tissue sarcoma with the use of intraoperative radiotherapy (IORT) included 171 patients. Controls received adjuvant distant gamma-therapy (n = 57) or surgical treatment (n = 171). IORT significantly improved 5 year general (p = 0.025) and relapse-free (p < 0.025) survival rate and the same parameters in patients with a tumour larger than 5 cm (p = 0.0001). The intergroup difference regardless of tumour differentiation was insignificant (p =0.33), but survival rate tended to decrease in patients with moderately and weakly differentiated sarcomas (G2-3). It is concluded that combined treatment with IORT may be used as an alternative method for the treatment of moderately and weakly differentiated sarcomas.

Cost of cardiac care in the three years after coronary catheterization in a contained care system: critical determinants and implications.

OBJECTIVES: We sought to determine the clinical, angiographic, treatment and outcome correlates of the intermediate-term cost of caring for patients with suspected coronary artery disease (CAD). BACKGROUND: To adequately predict medical costs and to compare different treatment and cost reduction strategies, the determinants of cost must be understood. However, little is known about the correlates of costs of treatment of CAD in heterogeneous patient populations that typify clinical practice. METHODS: From a consecutive series of 781 patients undergoing cardiac catheterization in 1992 to 1994, we analyzed 44 variables as potential correlates of total (direct and indirect) in-hospital, 12- and 36-month cardiac costs. RESULTS: Mean (+/-SD) patient age was 65+/-10 years; 71% were men, and 45% had multiple vessel disease. The initial treatment strategy was medical therapy alone in 47% of patients, percutaneous intervention (PI) in 30% and coronary artery bypass graft surgery (CABG) in 24%. The 36-month survival and event-free (death, infarction, CABG, PI) survival rates were 89.6+/-0.2% and 68.4+/-0.4%, respectively. Median hospital and 36-month costs were $8,301 and $28,054, respectively, but the interquartile ranges for both were wide and skewed. Models for log(e) costs were superior to those for actual costs. The variances accounted for by the all-inclusive models of in-hospital, 12- and 36-month costs were 57%, 60% and 71%, respectively. Baseline cardiac variables accounted for 38% of the explained in-hospital costs, whereas in-hospital treatment and complication variables accounted for 53% of the actual costs. Noncardiac variables accounted for only 9% of the explained costs. Over time, complications (e.g., late hospital admission, PI, CABG) and drug use to prevent complications of heart transplantation became more important, but many baseline cardiac variables retained their importance. CONCLUSIONS: 1) Variables readily available from a comprehensive cardiovascular database explained 57% to 71% of cardiac costs from a hospital perspective over 3 years of care; 2) the initial revascularization strategy was a key determinant of in-hospital costs, but over 3 years, the initial treatment become somewhat less important, and late complications became more important determinants of costs.