Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).

The Mechanisms of Current Platinum Anticancer Drug Resistance in the Glioma.

Gliomas are the most common and malignant primary tumors of the central nervous system (CNS). Glioblastomas are the most malignant and aggressive form of primary brain tumors and account for the majority of brain tumor-related deaths. The current standard treatment for gliomas is surgical resection supplemented by postoperative chemotherapy. Platinum drugs are a class of chemotherapeutic drugs that affect the cell cycle, and the main site of action is the DNA of cells, which are common chemotherapeutic drugs in clinical practice. Chemotherapy with platinum drugs such as cisplatin, carboplatin, oxaliplatin, or a combination thereof is used to treat a variety of tumors. However, the results of gliomas chemotherapy are unsatisfactory, and resistance to platinum drugs is one of the important reasons. The resistance of gliomas to platinum drugs is the result of a combination of influencing factors. Decreased intracellular drug concentration, enhanced function of cell processing active products, enhanced repair ability of cellular DNA damage, and blockage of related apoptosis pathways play an important role in it. It is known that the pathogenic properties of glioma cells and the response of glioma towards platinum-based drugs are strongly influenced by non-coding RNAs, particularly, by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miRNAs and lncRNAs control drug sensitivity and the development of tumor resistance towards platinum drugs. This mini-review summarizes the resistance mechanisms of gliomas to platinum drugs, as well as molecules and therapies that can improve the sensitivity of gliomas to platinum drugs.

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Effect of kangai injection combined with platinum-based chemotherapy on the immune function of patients with advanced non-small-cell lung cancer: A meta-analysis.

BACKGROUND: Kangai injection (KAI) is a well-known Chinese patent medicine applied for several different types of cancers in the clinic as an auxiliary therapeutic approach, which is refined from three herbal extracts (Astragalus, Ginseng and Matrine). PURPOSE: To systematically evaluate the effect of combination treatment of platinum-based chemotherapy and KAI on patients with advanced non-small-cell lung cancer (NSCLC). STUDY DESIGN: A meta-analysis of randomized clinical trials. MATERIALS AND METHODS: The randomized controlled trials (RCTs) about stage Ⅲ-Ⅳ NSCLC using KAI combined platinum-based chemotherapy were electronically retrieved from eight electronic databases up to July 2021. We applied RevMan 5.4, Stata 16.0, TSA 0.9.5.10 Beta and GRADE Pro-GDT to evaluate the quality of the included RCTs and perform the meta-analysis. RESULTS: 19 RCTs were included, consisting a total sample size of 1,389 cases. Meta-analysis revealed that compared with chemotherapy alone, KAI combined with platinum-based chemotherapy was associated with significantly higher objective response rate (ORR) [RR = 1.36, 95%CI (1.21,1.54), p< 0.00001], higher disease control rate (DCR) [RR = 1.15, 95%CI (1.09,1.21), p< 0.00001], greater Karnofsky performance status (KPS) [RR = 1.75, 95%CI (1.41,2.18), p< 0.00001], lower white blood cell toxicity [RR = 0.67, 95%CI (0.55,0.82), p = 0.0001], lower platelet toxicity [RR = 0.60, 95%CI (0.47,0.75), P  < 0.0001], and lower incidence of vomiting [RR = 0.66, 95%CI (0.57,0.76), p< 0.00001]. In terms of the immune function, KAI united with chemotherapy significantly raised the ratio of CD3+ cells [MD = 10.65, 95%CI (8.21,13.09), p< 0.00001], CD4+ cells [MD = 7.67, 95%CI (6.31,9.03), p< 0.00001], NK cells [MD = 4.97, 95%CI (3.03,6.92), p< 0.00001], and CD4+/ CD8+ [MD = 0.32, 95%CI (0.19,0.45), p< 0.00001], and decreased the percentage of CD8+ cells [MD = -5.56, 95%CI (-7.51,-3.61), p< 0.00001]. CONCLUSIONS: This meta-analysis identified that the combination treatment of KAI and platinum-based chemotherapy was more beneficial to patients with advanced NSCLC when compared to chemotherapy alone, which could significantly improve the clinical efficacy, enhance the immune function, and reduce chemotherapy toxicity. Our study provides a theoretical basis and treatment guidance for patients with NSCLC.

[The prospects of DNA damage repair variants guiding platinum compounds in the treatment of triple negative breast cancer].

Triple negative breast cancer (TNBC) is prone to recurrence and metastasis, which is the subtype of poorest prognosis. Chemotherapy is the main treatment, although there is lack of effective adjuvant chemotherapy regimens. The unsatisfactory efficacy of chemotherapy has been a bottleneck in improving the outcome of TNBC. Platinum compounds act directly on DNA to kill tumor cells, and they have a stronger killing effect on tumor cells carrying DNA damage repair (DDR) defects, which is an important entry point to improve the efficacy of TNBC. Biomarkers for predicting the efficacy of platinum drugs in TNBC treatment have always been a hot topic. The DDR pathway contains a large number of related genes, and recent studies have shown that deficiencies in the DDR pathway may be associated with the efficacy of platinum drugs, which is expected to be a biomarker for predicting the efficacy of platinum drugs in breast cancer treatment.

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

The prospects of DNA damage repair variants guiding platinum compounds in the treatment of triple negative breast cancer / 中华肿瘤杂志

Triple negative breast cancer (TNBC) is prone to recurrence and metastasis, which is the subtype of poorest prognosis. Chemotherapy is the main treatment, although there is lack of effective adjuvant chemotherapy regimens. The unsatisfactory efficacy of chemotherapy has been a bottleneck in improving the outcome of TNBC. Platinum compounds act directly on DNA to kill tumor cells, and they have a stronger killing effect on tumor cells carrying DNA damage repair (DDR) defects, which is an important entry point to improve the efficacy of TNBC. Biomarkers for predicting the efficacy of platinum drugs in TNBC treatment have always been a hot topic. The DDR pathway contains a large number of related genes, and recent studies have shown that deficiencies in the DDR pathway may be associated with the efficacy of platinum drugs, which is expected to be a biomarker for predicting the efficacy of platinum drugs in breast cancer treatment.

Clinical efficacy and safety of Huachansu injection combination with platinum-based chemotherapy for advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Huachansu injection (HCS) is a widely used traditional Chinese medicine for advanced non-small cell lung cancer (NSCLC) to alleviate the adverse drug reactions (ADRs) and enhance the clinical efficacy of chemotherapy. OBJECTIVE: To evaluate the efficacy and safety of HCS as an adjunctive treatment to platinum-based chemotherapy (PBC) for advanced NSCLC. METHODS: A systematic review and meta-analysis were conducted according to PRISMA guidelines. A total of nine databases were searched to select randomized controlled trials (RCTs) of HCS plus PBC to treat NSCLC from inception to October 10, 2020. RCTs on HCS plus PBC vs PBC alone for advanced NSCLC were included. Dichotomous data were pooled as risk ratio (RR) with 95% confidence intervals. RCTs compared to HCS plus PBC vs PBC alone were included. Primary outcomes were objective response rate (ORR) and disease control rate (DCR), and secondary outcomes were survival rate, quality of life (QOL), and adverse drug reactions (ADRs). GRADE software was used to access the quality of evidence. RESULTS: A total of 32 RCTs, including 2753 patients, were included. Compared to PBC alone, HCS plus PBC improved the ORR, DCR, 1- and 2-year survival rates, and QOL and alleviated neutropenia, thrombocytopenia, nausea, vomiting, anemia, liver injury, renal injury, and alopecia. CONCLUSIONS: Compared to PBC alone, HCS plus PBC improved the clinical efficacy and alleviated the ADRs in advanced NSCLC patients. Considering the limitations of the included RCTs, high-quality trials with longer follow-ups are needed to further confirm the results.

Artificial intelligence-based image analysis can predict outcome in high-grade serous carcinoma via histology alone.

High-grade extrauterine serous carcinoma (HGSC) is an aggressive tumor with high rates of recurrence, frequent chemotherapy resistance, and overall 5-year survival of less than 50%. Beyond determining and confirming the diagnosis itself, pathologist review of histologic slides provides no prognostic or predictive information, which is in sharp contrast to almost all other carcinoma types. Deep-learning based image analysis has recently been able to predict outcome and/or identify morphology-based representations of underlying molecular alterations in other tumor types, such as colorectal carcinoma, lung carcinoma, breast carcinoma, and melanoma. Using a carefully stratified HGSC patient cohort consisting of women (n = 30) with similar presentations who experienced very different treatment responses (platinum free intervals of either ≤ 6 months or ≥ 18 months), we used whole slide images (WSI, n = 205) to train a convolutional neural network. The neural network was trained, in three steps, to identify morphologic regions (digital biomarkers) that are highly associating with one or the other treatment response group. We tested the classifier using a separate 22 slide test set, and 18/22 slides were correctly classified. We show that a neural network based approach can discriminate extremes in patient response to primary platinum-based chemotherapy with high sensitivity (73%) and specificity (91%). These proof-of-concept results are novel, because for the first time, prospective prognostic information is identified specifically within HGSC tumor morphology.

Incorporating SULF1 polymorphisms in a pretreatment CT-based radiomic model for predicting platinum resistance in ovarian cancer treatment.

OBJECTIVE: Early detection of platinum resistance for ovarian cancer treatment remains challenging. This study aims to develop a machine learning model incorporating genomic data such as Single-Nucleotide Polymorphisms (SNPs) of Human Sulfatase 1 (SULF1) with a CT radiomic model based on pre-treatment CT images, to predict platinum resistance for ovarian cancer (OC) treatment. METHODS: A cohort of 102 patients with pathologically confirmed OC was retrospectively enrolled into this study from January 2006 to February 2018. All patients had platinum-based chemotherapy after maximal cyto-reductive surgery. This cohort was separated into two groups according to treatment response, i.e., the group with platinum-resistant disease (PR group) and the group with platinum-sensitive disease (PS group). We genotyped 12 SNPs of SULF1 for all OC patients using Mass Array Method. Radiomic features, SNP data and clinicopathological data of the 102 patients were used to build the differentiation models. The study participants were divided into two cohorts: the training cohort (n = 71) and the validation cohort (n = 31). Feature selection and predictive modeling were performed using least absolute shrinkage and selection operator (LASSO), Random Forest Classifier and Support Vector Machine methods. Model performance for predicting platinum resistance was assessed with respect to its calibration, discrimination, and clinical application. RESULTS: For prediction of platinum resistance, the approach combining the radiomics, clinicopathological data and SNP data demonstrated higher classification efficiency, with an AUC value of 0.993 (95 % CI: 0.83 to 0.98) in the training cohort and 0.967 (95 % CI: 0.83 to 0.98) in validation cohort, than the performance with only the SNPs of SULF1 model (AUC: training, 0.843 [95 %CI: 0.738-0.948]; validation, 0.815 [0.601-1.000]), or with only the radiomic model (AUC: training, 0.874 [95 %CI: 0.789-0.960]; validation, 0.832 [95 %CI: 0.687-0.976]). This integrated approach also showed good calibration and favorable clinical utility. CONCLUSIONS: A predictive model combining pretreatment CT radiomics with genomic data such as SNPs of SULF1 could potentially help to predict platinum resistance in ovarian cancer treatment.

Platinum versus immunotherapy for unresectable esophageal cancer: A protocol for systematic review and meta analysis.

BACKGROUND: Esophageal cancer is one of the most common malignant tumors, with early metastasis, highly malignant characteristics. Morbidity ranks 7th among all malignant tumors, and mortality ranks 6th. Esophageal adjuvant therapy can significantly improve overall survival in unresectable esophageal cancer patients. With the breakthrough and progress of immunotherapy, the possibility of curing esophageal cancer has greatly increased. Some clinical trials have reported that compared with traditional platinum-based chemotherapy, the use of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors alone can benefit patients and effectively prolong their overall survival. We compare the efficacy of single immunotherapy with traditional platinum-based chemotherapy in a systematic review and meta-analysis to provide a reliable basis for clinicians. METHODS: We will search PubMed, Medline, Embase, Web of Science, Cancerlit, Google Scholar, and the Cochrane Central Register of Controlled Trials for related studies published before December 1, 2019 without language restrictions. Two review authors will search and assess relevant studies independently. Randomized controlled trials (RCTs) or quasi-RCTs, and prospective cohort studies will be included. We will perform subgroup analysis in sex, age, ethnicity, and tumor stage of esophageal cancer patients. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: The results of this systematic review and meta-analysis will provide a basis for clinicians to formulate the best chemotherapy regimen for patients, as well as a research clue for clinical researchers in this field. The results of this study will expand the treatment options for esophageal patients, but due to the nature of the disease and intervention, large sample clinical trials are not abundant, so we will include some high-quality small sample trials, which may cause high heterogeneity. INPLASY REGISTRATION NUMBER: INPLASY2020110012.

Platinum versus immunotherapy for early resectable non-small cell lung cancer: A protocol for systematic review and meta analysis.

BACKGROUND: Lung cancer is one of the most common malignant tumors. Non-small cell Lung cancer (NSCLC) accounts for about 85% of the total lung cancer. For patients with resectable early NSCLC, conventional postoperative adjuvant therapy can significantly prolong the overall survival of patients and reduce the risk of tumor recurrence. With the emergence and maturity of molecular targeted therapy and immunotherapy, the strategy of postoperative chemotherapy for lung cancer patients has changed greatly. To evaluate the efficacy of postoperative chemotherapy (platinum based chemotherapy and immunotherapy) with or without radiotherapy for NSCLC patients, we will conduct a systematic review and meta-analysis of published or unpublished randomized controlled trials. METHODS: We will search Pubmed (Medline), Embase, Google Scholar, Cancerlit, and the Cochrane Central Register of Controlled Trials for related studies published without language restrictions before June 20, 2021. Two review authors will search and assess relevant studies independently. Randomized controlled trials and quasi-randomized controlled trials studies will be included. we will perform subgroup analysis in different methods of postoperative adjuvant therapy for patients with resectable early NSCLC. Because this study will be based on published or unpublished records and studies, there is no need for ethics approval. INPLASY registration number: INPLASY202080064. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: This study will compare the efficacy of platinum chemotherapy and immunotherapy in patients with resectable early NSCLC. Since the large sample randomized trials that meet the inclusion criteria of this study may be inadequate, we will consider incorporating some high quality small sample related tests, which may lead to heterogeneity and affect the reliability of the results.

Cost-Effectiveness and Net Monetary Benefit of Olaparib Maintenance Therapy Versus No Maintenance Therapy After First-line Platinum-based Chemotherapy in Newly Diagnosed Advanced BRCA1/2-mutated Ovarian Cancer in the Italian National Health Service.

PURPOSE: The aim of this study was to evaluate the cost-effectiveness and net monetary benefit of olaparib maintenance therapy compared with no maintenance therapy after first-line platinum-based chemotherapy in newly diagnosed advanced BRCA1/2-mutated ovarian cancer from the Italian National Health Service (NHS) perspective. METHODS: We developed a lifetime Markov model in which a cohort of patients with newly diagnosed advanced BRCA1/2-mutated ovarian cancer was assigned to receive either olaparib maintenance therapy or active surveillance (Italian standard of care) after first-line platinum-based chemotherapy to compare cost-effectiveness and net monetary benefit of the 2 strategies. Data on clinical outcomes were obtained from related clinical trial literature and extrapolated using parametric survival analyses. Data on costs were derived from Italian official sources and relevant real-world studies. The incremental cost-effectiveness ratio (ICER), incremental cost-utility ratio (ICUR), and incremental net monetary benefit (INMB) were computed and compared against an incremental cost per quality-adjusted life-year (QALY) gained of €16,372 willingness-to-pay (WTP) threshold. We used deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) to assess how uncertainty affects results; we also performed scenario analyses to compare results under different pricing settings. FINDINGS: In the base-case scenario, during a 50-year time horizon, the total costs for patients treated with olaparib therapy and active surveillance were €124,359 and €97,043, respectively, and QALYs gained were 7.29 and 4.88, respectively, with an ICER of €9,515 per life-year gained, an ICUR of €11,345 per QALY gained, and an INMB of €12,104. In scenario analyses, considering maximum selling prices for all other drugs, ICUR decreased to €11,311 per QALY and €7,498 per QALY when a 10% and 20% discount, respectively, was applied to the olaparib official price, and the INMB increased to €12,186 and €21,366, respectively. DSA found that the model results were most sensitive to the proportion of patients with relapsing disease in response to platinum-based chemotherapy, time receiving olaparib first-line maintenance treatment, and subsequent treatments price. According to PSAresults, olaparib was associated with a probability of being cost-effective at a €16,372 per QALY WTP threshold ranging from 70% to 100% in the scenarios examined. IMPLICATIONS: Our analysis indicates that olaparib maintenance therapy may deliver a significant health benefit with a contained upfront cost during a 50-year time horizon, from the Italian NHS perspective, providing value in a setting with curative intent.

Prognostic factors of overall survival for patients with FIGO stage IIIc or IVa ovarian cancer treated with neo-adjuvant chemotherapy followed by interval debulking surgery: A multicenter cohort analysis from the FRANCOGYN study group.

INTRODUCTION: The aim of this study was to identify prognostic factors of overall survival in patients with FIGO stage IIIc or IVa ovarian cancer (OC) treated by neo-adjuvant chemotherapy (NAC) followed by interval debulking surgery. MATERIALS AND METHODS: Data from 483 patients with ovarian cancer were retrospectively collected, from January 1, 2000 to December 31, 2016, from the FRANCOGYN database, regrouping data from 11 centers specialized in ovarian cancer treatment. Median overall survival was determined using the Kaplan-Meier method. Univariate and multivariate analysis were performed to define prognostic factors of overall survival. RESULTS: The median overall survival was 52 after a median follow up of 30 months. After univariate analysis, factors significantly associated with decreased overall survival were; no pelvic and/or para-aortic lymphadenectomy (p = 0.002), residual disease (CC1/CC2/CC3) after surgery (p < 0.001), positive cytology after NAC (p < 0.001), omental disease after NAC (p = 0.002), no pathologic complete response (pCR) (p = 0.002). In multivariate analysis, factors significantly associated with decreased overall survival were; residual disease after surgery (HR = 1.93; CI95% (1.16-3.21), p = 0.01) and positive cytology after NAC (HR = 1.59; CI95% (1.01-2.55), p = 0.05). Patients with no residual disease after surgery had a median overall survival of 64 months versus 35 months for patients with residual disease. Patients with negative cytology after NAC had a median overall survival of 71 months versus 43 months for patients with positive cytology after NAC. CONCLUSION: In this first and largest French based retrospective study, complete cytoreductive surgery in ovarian cancer remains the main prognostic factor of overall survival.

Virotherapy: From single agents to combinatorial treatments.

Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments.

Xiao-ai-ping injection adjunct with platinum-based chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Xiao-ai-ping injection (XAPI), as patented Chinese medicine, has shown promising outcomes in non-small-cell lung cancer (NSCLC) patients. This meta-analysis investigated the efficacy and safety of XAPI in combination with platinum-based chemotherapy. METHODS: A comprehensive literature search was conducted to identify relevant studies in Pubmed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Wangfang Database, VIP Database, and Chinese Biology Medical Database from the date of their inception to September 2018. The RevMan 5.3 software was applied to calculate the risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI). RESULTS: We included and analyzed 24 randomized controlled trials. The meta-analysis showed that XAPI adjunctive to platinum-based chemotherapy had better outcomes in objective tumor response rate (ORR) (RR: 1.27, 95% CI, 1.14-1.40); improved Karnofsky performance scores (KPS) (RR: 1.70, 95% CI, 1.48-1.95); reduction in occurrence of grade 3/4 leukopenia (RR: 0.49, 95% CI, 0.38-0.64), anemia (RR: 0.63, 95% CI, 0.46-0.87) and thrombocytopenia (RR: 0.53, 95% CI, 0.38-0.73), nausea and vomiting (RR: 0.57, 95% CI, 0.36-0.90); and enhanced immune function (CD8+ [MD: 4.96, 95% CI, 1.16-8.76] and CD4+/CD8+ [MD: 2.58, 95% CI, 1.69-3.47]). However, it did not increase dysregulated liver and kidney function, diarrhea, constipation, and fatigue. Subgroup analysis of ORR and KPS revealed that dosage, treatment duration, and methodological quality did not affect the outcome significantly. CONCLUSIONS: Our meta-analyses demonstrated that XAPI in combination with platinum-based chemotherapy had a better tumor response, improved the quality of life, attenuated adverse side effects, and enhanced immune function, which suggests that it might be used for advanced NSCLC. Moreover, low dosage (< 60 ml/d) and long-term treatment of XAPI might be a choice for advanced NSCLC patients.

Surgery with Radical Intent: Is There an Indication for G3 Neuroendocrine Neoplasms?

BACKGROUND: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. PATIENTS AND METHODS: Multicenter analysis of a series of stage I-III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. RESULTS: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5-187 months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14 months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. CONCLUSIONS: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Compound Kushen injection plus platinum-based chemotherapy for stage IIIB/IV non-small cell lung cancer: A protocol for meta-analysis of randomized clinical trials following the PRISMA guidelines.

BACKGROUND: Compound Kushen injection (CKI) is a commonly used anti-tumor Chinese patent medicine, which is extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae) and has been widely prescribed as an add-on therapy to platinum-based chemotherapy (PBC) for advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain controversial. METHODS AND ANALYSIS: A systematic review and meta-analysis will be performed following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. All randomized controlled trials (RCTs) comparing CKI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. The disease control rate (DCR) will be defined as the primary outcome, and the objective response rate (ORR), quality of life (QOL), survival rate, and toxicities will be the secondary outcomes. RESULTS: This study will systematically evaluate the efficacy and safety of Compound Kushen injection combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results of this study will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review and meta-analysis of eligible randomized controlled trials will evaluate the effects of Compound Kushen injection as adjunctive therapy to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical use of this combination therapy for the specific subsets of patients. PROSPERO REGISTRATION NUMBER: CRD42019134892.