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BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitors are the first-line treatment for advanced non-small-cell lung cancer (NSCLC) patients. However, their efficacy in metastatic NSCLC patients remains controversial. AIM OF THE STUDY: The aim of our study was to evaluate the prognosis of advanced metastatic NSCLC patients treated with PD-1 inhibitors, and discuss the predictive effect of metastatic site on the long-term outcome. METHODS: The Embase, Ovid Medline, Cochrane Central Register of Controlled Trials, and PubMed databases were systematically screened up to February 10, 2020. Twenty-five eligible studies, involving 8,067 patients that assessed the impact of metastatic sites on survival outcome were incorporated in our study. Overall survival (OS) and progression-free survival (PFS) were described as hazard ratio (HR) with 95% confidence interval (CI). RESULTS: Among the advanced NSCLC patients, the median proportion of brain, liver, bone, and adrenal gland metastases were 21%, 17%, 35%, and 21%, respectively. Patients with metastases to the brain, liver, and bone had worse OS compared to patients without these metastases when treated with PD-1 inhibitors. Similarly, patients with metastasis to the brain and liver were more likely to progress when treated with PD-1 inhibitors. Besides, patients with multiple metastatic sites had worse PFS compared to patients with one metastatic site, while no significant difference was found in terms of OS. CONCLUSIONS: Based on the findings of our systematic review and meta-analysis, metastatic sites were independent predictors of the survival outcome for advanced NSCLC patients treated with PD-1 inhibitors.

The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-γ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (∼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.

Sarcomas are rare but malignant tumors with high risks of local recurrence and distant metastasis. Anti-angiogenic therapy is a potential strategy against un-controlled and not-organized tumor angiogenesis. We aimed to assess the safety and efficacy of apatinib, an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, in patients with advanced sarcoma. Thirty-one patients who received initial apatinib between September 2015 and August 2016 were retrospectively reviewed. Among them, 19 (61.3%) patients were heavily pretreated with two or more lines of cytotoxic chemotherapy. Apatinib was given at a start-dose of 425 mg qd. During therapy, 9 (29.0%) patients required dose interruption and 7 (22.6%) needed dose reduction, and the mean dosage of apatinib was 372.9 ± 68.4 mg/day. In the study cohort, one patient was treated as adjunctive therapy and 6 patients stopped treatment before radiographic response assessment. Thus, 24 patients were eligible for tumor response evaluation. The objective response rate was 33.3% and clinical benefit rate was as high as 75.0%. The progression free survival was 4.25 (95% confidence interval [CI], 2.22-5.11) months, whereas the overall survival was 9.43 (95% CI, 6.64-18.72) months. Compared with other histological subtypes, leiomyosarcoma did not show significant survival benefits. Most of the adverse events (AEs) were at grade 1 or 2. The main grade 3 AEs were hypertension (6.5%), hand foot skin reaction (6.5%), and diarrhea (3.2%). In conclusion, apatinib showed promising efficacy and acceptable safety profile in metastatic or recurrent sarcoma, giving rationale clinical evidence to conduct clinical trials.

Attempts for identifying targeted therapy strategies in metastatic gastric and gastroesopheal junction cancer (upper-GI) revealed that the inhibition of human epidermal growth factor receptor-2 (HER2) by monoclonal antibody trastuzumab improves survival of these patients. Hence, adding trastuzumab to doublet chemotherapy has become the standard treatment in this setting. Although the patient survival is extended among clinical trials, the knowledge on the real-time setting is limited. With this retrospective, single center analysis of the patient data of the Medical University of Vienna, we sought to investigate the clinical characteristics and outcome of patients, who received trastuzumab-based chemotherapy for metastatic upper-GI tumor. All patients, who received trastzumab at least once were included to the analysis. Clinical and pathological data were recorded. This search revealed 33 patients. The demographic data was comparable with that of the previous clinical trials. Progression free survival (PFS) was 11 months, whereas overall survival (OS) was 21 months. OS was significantly associated with initially favorable response to treatment. Thirteen patients (39%) received trastuzumab as maintenance treatment with a median cycle number of 6. Toxicity profile was acceptable with only one patient detected to have cardiotoxicity. Taken together, trastuzumab based treatment induced a considerable PFS and OS in metastatic or advanced upper-GI tumors with acceptable toxicity profile. The maintenance therapy with trastuzumab was safe and effective in patients who had initially a favorable response to chemotherapy. The optimal duration of the maintenance therapy should be tested in future clinical trials.

Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (+/−3.93) years, who received salvage radiotherapy with a mean of 69.66 (+/− 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (+/− 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral (t) and peripheral stroma (p) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis (d) and relapse times (R). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1+ cells. Our analysis revealed that higher CD8p,R+ and lower PD-1R+ TIL scores correlated to a longer bPFS. Higher CD8p,R+ and CCR7t,R+ TIL scores and lower CD45p,R+ and FoxP3p,R+ TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

Women with advanced stage ovarian cancer (OC) have a five-year survival rate of less than 25%. OC progression is associated with accumulation of epigenetic alterations and aberrant DNA methylation in gene promoters acts as an inactivating ?hit? during OC initiation and progression. Abnormal DNA methylation in OC has been used to predict disease outcome and therapy response. To globally examine DNA methylation in OC, we used next-generation sequencing technology, MethylCap-sequencing, to screen 75 malignant and 26 normal or benign ovarian tissues. Differential DNA methylation regions (DMRs) were identified, and the Kaplan?Meier method and Cox proportional hazard model were used to correlate methylation with clinical endpoints. Functional role of specific genes identified by MethylCap-sequencing was examined in in vitro assays. We identified 577 DMRs that distinguished (p < 0.001) malignant from non-malignant ovarian tissues; of these, 63 DMRs correlated (p < 0.001) with poor progression free survival (PFS). Concordant hypermethylation and corresponding gene silencing of sonic hedgehog pathway members ZIC1 and ZIC4 in OC tumors was confirmed in a panel of OC cell lines, and ZIC1 and ZIC4 repression correlated with increased proliferation, migration and invasion. ZIC1 promoter hypermethylation correlated (p < 0.01) with poor PFS. In summary, we identified functional DNA methylation biomarkers significantly associated with clinical outcome in OC and suggest our comprehensive methylome analysis has significant translational potential for guiding the design of future clinical investigations targeting the OC epigenome. Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of OC outcome.

In this paper, we introduce some system functions and macros to create study specific survival variables for oncology clinical trials. We present five variables which show overall survival time, time to disease progression, duration of response, progression free survival and time to treatment failure for one particular study. We will be using survival analysis based on overall survival and censoring information. The purpose of this paper is to show the power and usefulness of SAS in clinical research, specifically studies which require time to event analysis based on death and survival information, such as cancer and HIV.

The most frequent radioactive (RAI) refractory thyroid cancers are papillary thyroid carcinoma, followed by poorly differentiated thyroid carcinoma. They are rare and lethal. In recent years, significant therapeutic progress has been achieved.This paper offers insights on refractoriness to RAI treatment and the optimization of treatment initiation and treatment choice. Clinical trials performed with anti-angiogenic kinase inhibitors and with targeted inhibitors in patients with BRAF, RAS mutation or RET, TRK or ALK fusion are discussed.These treatments provide high response rates. Anti-angiogenic kinase inhibitors improve median progression-free-survival; however, their benefit in terms of overall survival has been shown in only few subsets of patients. Treatment sequencing is challenging; in the absence of targetable abnormality, lenvatinib should be used as first-line treatment. Options for second-line treatment include lenvatinib (if not given at first line), cabozantinib or the addition of an anti-checkpoint antibody. In patients with a targetable abnormality, specific inhibitors, might be used as first-line treatment and lenvatinib as second line or vice-versa. Further studies are needed, based on documented genomic and immunologic characteristics of the tumor to assess the potential role of combination and redifferentiation therapy.

Introduction: Even with the currently recommended chemotherapeutic and immunotherapeutic treatment, the five year survival rate for advanced nonsquamous and squamous NSCLC without oncogenic drivers remains poor. However, several different chemo-immunotherapy combinations are presently being investigated - with favorable results- in order to increase the PFS and OS rates of these patients. Areas covered: Therefore, this paper aims to discuss the most promising trials investigating chemo-immunotherapy combinations and their present and future impact on advanced NSCLC treatment paradigms. Expert opinion: First line chemo-immunotherapy combinations are starting to and will certainly revolutionize the current paradigm of metastatic non small cell lung cancer treatment due to their superior performances - both in terms of PFS and OS - when compared to the actual standard of care platinum based chemotherapy. However, these associations are not devoid of problems, in fact, combining immunotherapy with chemotherapy obviously leads to enhanced treatment-related toxicities and to higher discontinuation rates; therefore these treatments should be administered carefully.

Background and aims Several studies were conducted to explore the prognostic value of platelet-to-lymphocyte ratio (PLR) in pancreatic cancer and have reported contradictory results. This study aims to summarize the prognostic role of PLR in pancreatic cancer. Materials and methods Embase, PubMed and Cochrane Library were completely searched. The cohort studies focusing on the prognostic role of PLR in pancreatic cancer were eligible. The overall survival (OS) and progression-free survival (PFS) were analyzed. Results Fifteen papers containing 17 cohort studies with pancreatic cancer were identified. The results showed patients that with low PLR might have longer OS when compared to the patients with high PLR (hazard ratio=1.28, 95% CI=1.17–1.40, P

Despite improvements in the diagnosis and management of early stage breast cancer, about one third of the patients still progress to metastatic disease. Most of the patients with metastatic breast cancer have a hormone receptor positive and human epidermal growth factor receptor 2 negative subtype with a median survival of more than 3 years. For these patients, endocrine therapy with its favorable toxicity profile is the current standard of care. However, patients with metastatic breast cancer have an incurable disease. Therefore, not only efficacy but also quality of life are key when selecting a therapy regimen. Areas covered: This paper aims to discuss the efficacy and toxicity profile of the new endocrine-based therapy option palbociclib together with endocrine treatment. Expert opinion: The addition of targeted agents like palbociclib can overcome intrinsic or acquired resistance to endocrine therapy and substantially prolong progression free survival. The combination of palbociclib plus endocrine therapy is associated with a tolerable and well manageable toxicity profile as well as maintenance of quality of life. Thus, addition of palbociclib to endocrine therapy offers a new and important treatment option for hormone receptor positive metastatic breast cancer.

Since high-grade malignant gliomas can seldom be treated curatively, the main aim of first line therapy is to improve progression free survival (PFS), to reduce morbidity, and to preserve, if not restore neurological functions and the capacity to perform daily activities. Focusing on a single clinical efficacy parameter in clinical trials may provide a potentially biased result, as for patients the overall result of treatment entails a more complex picture of weighing and balancing gains and losses on different outcome measures. In this paper we address different clinical outcomes measures separately and we illustrate the value of multiple outcome measures using the results of a recent clinical trial comparing temozolomide with procarbazine in the treatment of Glioblastoma Multiforme. Compared with procarbazine, temozolomide not only prolonged PFS, but also maintained neurological functioning and performance status for a longer period of time, and also improved health-related quality of life (HRQL). All these statistically significant outcomes demonstrate a remarkable consistency. In addition, temozolomide showed a trend of extending overall survival over procarbazine.