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.

Platinum-based chemotherapy in metastatic prostate cancer: what possibilities?

Metastatic prostate cancer is a major health burden worldwide, necessitating the continuous development of effective treatment strategies. Androgen deprivation therapy remains the cornerstone of prostate cancer treatment, but novel approaches are needed for metastatic castration-resistant prostate cancer (mCRPC). Recent studies have highlighted the prevalence of mutations in DNA repair genes, including BRCA1 and BRCA2, in mCRPC patients, rendering them more susceptible to platinum-based chemotherapy and Poly (ADP-ribose) polymerase (PARP) inhibitors. Platinum-based chemotherapy, particularly in combination with taxanes, has demonstrated encouraging activity in mCRPC, as well as homologous recombination gene alterations have shown increased sensitivity to platinum compounds in these patients. The combination of platinum-based chemotherapy with PARP inhibitors represents a novel and potentially effective therapeutic strategy for this subgroup of patients. However, the optimal sequence of administering these agents and the potential for cross-resistance and cross-toxicities remain areas requiring further investigation. Prospective randomized studies are essential to elucidate the most effective treatment approach for this challenging patient population. This review aims to explore the potential of platinum-based chemotherapy in the context of prostate cancer, and more in detail in homologous recombination repair (HRR) mutated patients. We discuss the synergistic effects of combining platinum compounds with PARP inhibitors and the potential benefits of adopting specific therapeutic sequences.

Efficacy of Nivolumab and Pembrolizumab in Platinum-sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: This study evaluated the efficacy of nivolumab and pembrolizumab in treating platinum-sensitive recurrent or metastatic head and neck squamous cell carcinomas (R/M-HNSCC). PATIENTS AND METHODS: Platinum-sensitive patients with R/M-HNSCC were selected at Tokyo Medical University Hospital from May 1, 2017, to June 30, 2022. Patients with a history of treatment with nivolumab or pembrolizumab were included. Nivolumab was used in 21 cases and pembrolizumab in 15 cases. RESULTS: The median overall survival (OS) was 16.9 months in the nivolumab group and 19.2 months in the pembrolizumab group and no significant differences were observed between the two groups. The median progression-free survival (PFS) was 4.8 months in the nivolumab group and 9.3 months in the pembrolizumab group. No significant differences were observed between the two groups. The objective response rates (ORR) were 38% and 47% in the nivolumab and pembrolizumab groups, respectively. CONCLUSION: Nivolumab as well as pembrolizumab were found to be effective in platinum-sensitive patients with R/M-HNSCC. Nivolumab can be considered a potential treatment option for platinum-sensitive R/M-HNSCC in the future.

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.).

Cost-effectiveness analysis of niraparib maintenance therapy in Chinese patients with platinum-sensitive recurrent ovarian cancer.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of niraparib versus routine surveillance as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer in China. METHOD: A three-state partitioned survival model that adopted a lifetime horizon with a 4-week cycle length was developed. Efficacy data were derived from the NORA study. Cost and utility data were obtained from published studies and online databases. The cost and health outcomes were discounted at an annual rate of 5%. In this analysis, the primary outcomes included quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER). The willingness-to-pay (WTP) thresholds were set at 1 to 3 times the gross domestic product per capita of China in 2022 ($12,741 to $38,233/QALY). Sensitivity analyses were conducted to verify the robustness of the model results. RESULTS: In the base-case analysis, niraparib was not found to be cost-effective, with an ICER of $42,888/QALY compared with routine surveillance at the WTP thresholds. One-way deterministic sensitivity analyses indicated that the ICER value was most sensitive to the cost of subsequent treatment in placebo group. The probabilistic sensitivity analysis suggested that at the WTP thresholds, the probability of niraparib being cost-effective was 2.9% to 50.1%. CONCLUSIONS: Niraparib improves the survival benefit of platinum-sensitive recurrent ovarian cancer patients. However, it seems to be less cost-effective, as it has higher costs than routine surveillance at the WTP thresholds. Reasonable dose reduction according to the patient's actual situation or lowering the price of niraparib can improve its cost-effectiveness.

Systemic therapy for advanced cervical cancer: Leveraging the historical threshold of overall survival.

Cervical cancer (CC) is a worldwide problem, especially in low- and middle-income countries, where patients are often diagnosed with locally advanced disease. Until recently, all chemotherapy drugs achieved low ORR and 12-month overall survival (12- month OS) for advanced CC after failure for platinum compounds. Advances in systemic therapy with immunotherapy, targeted therapy, and antibody-drug conjugates (ADC) have leveraged the 12-month OS limit. Recently, immunotherapy (pembrolizumab) has become the standard of care in first-line advanced CC combined with platinum and taxane and in second-line after platinum doublet failure.

High expression of CETN2 is associated with platinum resistance and poor prognosis in epithelial ovarian cancer.

PURPOSE: The poor prognosis of ovarian cancer is largely due to platinum resistance. It has been demonstrated that nucleotide excision repair (NER) involving centrin-2(CETN2) is connected to platinum resistance in ovarian cancer. The molecular mechanism of CETN2 in ovarian cancer and the mechanism affecting the outcome of chemotherapy are unknown. METHODS: The protein-protein interaction (PPI) network was mapped after obtaining the interacting proteins of CETN2, and the interacting genes were subjected to enrichment analysis. To examine the relationship between CETN2 and platinum resistance, gene microarray data and clinical data related to platinum resistance in ovarian cancer were downloaded. The possible signaling pathway of CETN2 was investigated by Gene set enrichment analysis (GSEA). Immune infiltration analysis was performed. Immunohistochemistry (IHC) and quantitative real-time PCR (QRT-PCR) were used to examine the expression of CETN2 in clinical samples in relation to the effectiveness of chemotherapy. The capacity of CETN2 to predict chemotherapy results was proven by receiver operating characteristic (ROC) curves after the construction of two prediction models, the logistic regression model and the decision tree model. The impact of CETN2 on prognosis was examined using the Kaplan-Meier technique. RESULTS: CETN2 was associated with NER, oxidative phosphorylation (OXPHOS) and cell cycle pathways in ovarian cancer drug-resistant samples. In clinical samples, CETN2 showed its possible correlation with immune infiltration. The protein expression level of CETN2 was significantly higher in platinum-resistant patients than that in platinum-sensitive patients, and the expression level had some predictive value for chemotherapy outcome, and high CETN2 protein expression was associated with poorer progression-free survival. CONCLUSIONS: CETN2 protein had a significant effect on ovarian cancer platinum sensitivity and prognosis, which may be related to the activation of NER, OXPHOS and cell cycle pathways upon CETN2 upregulation. Further research is necessary to determine the therapeutic application value of CETN2, which may be a new biomarker of chemoresponsiveness.

Induction of immunogenic cell death by novel platinum-based anticancer agents.

Traditional platinum-based anticancer drugs, led by cisplatin, play an important role in chemotherapy. However, the development of platinum compounds is limited due to serious toxicity and side effects. In recent years, studies have showed that immunogenic cell death (ICD) may be one of the potential action mechanisms of classical platinum drugs, such as oxaliplatin. This strategy combining chemotherapy and immunotherapy can effectively utilize the body's immune system to help platinum compounds to fight against tumors, and the dose can be appropriately reduced to limit toxic side effects. The induction of ICD by platinum compounds has become a research hotspot and one of the future development directions of metal drugs. Here, the progress of platinum compounds were collected and comprehensively summarized, their capacity of ICD induction and mechanism of action are exposed, providing reference for the design and synthesis of new anticancer platinum ICD inducers.

CUL4B increases platinum-based drug resistance in colorectal cancer through EMT: A study in its mechanism.

Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer.

OBJECTIVE: BRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. METHODS: The study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. RESULTS: 147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. CONCLUSION: Germline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.

A comparison of neoadjuvant therapies for gastroesophageal and gastric cancer on tumour resection rate: A network meta-analysis.

BACKGROUND: Gastric cancer is one of the most common malignancies around the world, and a variety of neoadjuvant chemotherapies with different drug combinations are available for the treatment. R0 resection refers to a microscopically negative margin on resection, where no gross or microscopic tumour remains in the primary tumour. We aimed to find evidence on the relative effectiveness of neoadjuvant therapies for patients with advanced gastroesophageal and gastric cancer on the R0 resection rate. METHODS: Relevant randomised controlled trials were searched using appropriate keywords in health-related databases. We performed network meta-analysis within a frequentist framework. The endpoint assessed was the R0 resection rate. We assessed consistency and transitivity assumptions that are necessary for network meta-analysis. This study only used data from published studies. The need for consent from participants was waived by the Ethics Review Committee of the International Medical University in Malaysia. RESULTS: Six randomised controlled trials involving 1700 patients were identified. A network plot was formed with five neoadjuvant regimens [DLX (pyrimidine analogue + platinum compounds + chemoradiotherapy), DELX (pyrimidine analogue + epipodophylllotoxins/etoposide + platinum compounds + chemoradiotherapy), ADL (anthracycline + pyrimidine analogue + platinum compounds), ADM (anthracycline+ pyrimidine analogue + anti-folate compounds) and LTX (platinum compounds + taxane + chemoradiotherapy)] and surgery alone for management of patients with advanced gastroesophageal and gastric cancer. Assumptions required for a network meta-analysis such as consistency ((global test: Chi2 (1): 3.71; p:0.054)), and the transitivity in accord to the characteristics of interventions considered in this review were not violated. In the network comparison, surgery alone has a lower R0 resection rate compared with LTX (OR 0.2, 95%CI:0.01, 0.38) or DLX (OR 0.48, 95%CI: 0.29, 0.79). LTX has higher resection rate compared with DLX (OR 2.47, 95%CI: 1.08 to 5.63), DELX (OR 106.0, 95%CI: 25.29 to 444.21), ADM (OR 5.41, 95%CI: 1.56 to 18.78) or ADL (OR 3.12, 95%CI: 1.27 to 7.67). There were wide or very wide CIs in many of these comparisons. Overall certainty of the evidence was low or very low. Further research in this field is very likely to have an important impact on our confidence in the R0 resection rates between LTX versus other neoadjuvant chemotherapy is likely to change the estimate. CONCLUSIONS: Findings suggest that overall quality of evidence on the relative effectiveness of neoadjuvant chemotherapies was low to very low level. Therefore, we are very uncertain about the true effect of neoadjuvant therapies in the R0 resection rate in patients with gastroesophageal and gastric cancer. Future well-designed large trials are needed. To recruit large samples in this field, multicountry trials are recommended. Future trials also need to assess treatment-related adverse events, and patients-centered outcomes such as health-related quality of life.

Genetic polymorphisms in the mismatch repair pathway (MMR) genes contribute to hematological and gastrointestinal toxicity in North Indian lung cancer patients treated with platinum-based chemotherapy.

The present study investigated the relationship between MLH1, MSH2, MSH3, and MSH6 polymorphisms and toxicity due to platinum-based doublet chemotherapy for North Indian lung cancer patients. Polymerase chain reaction-restriction fragment length polymorphism technique was used to assess the polymorphism. For MSH2 IVS1 + 9G > C polymorphism variant type genotype reported a 1.4-fold increased risk of anemia (AOR = 1.4; 95% CI = 0.98-1.99; p = 0.04) and decreased risk of developing gastrointestinal toxicity (diarrhea) (AOR = 0.53; 95% CI = 0.28-1.01; p = 0.04). Further, we also reported a 10-fold increased risk of developing severe grade anorexia in combined genotype (GC + CC) (AOR = 9.18; 95% CI = 0.98-86.1; p = 0.05). For MSH2 T > C/-6 polymorphism, variant type reported a 3-fold and 2-fold increased risk of developing severe grade leukopenia (AOR = 3.37; 95% CI = 1.44-7.88; p = 0.005) and neutropenia respectively (AOR = 2.23; 95% CI = 1.07-4.66; p = 0.03). For MSH3 G > A polymorphism, heterozygous (GA) and combined genotype (GA + AA) reported a 7-fold and 6-fold increased risk of developing anemia (AOR = 7.23; 95% CI = 1.51-34.6; p = 0.01, AOR = 6.39; 95% CI = 1.53-26.6; p = 0.01). Our results suggest that polymorphisms in DNA mismatch repair genes are associated with hematological, and gastrointestinal toxicities and might be considered a predictor for pretreatment evaluation in lung cancer patients.

The EMT-activator ZEB1 is unrelated to platinum drug resistance in ovarian cancer but is predictive of survival.

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is an unusual model, as it is also cross-resistant to paclitaxel. IGROVCDDP, therefore, models the resistance phenotype of serous ovarian cancer patients who have failed frontline platinum/taxane chemotherapy. IGROVCDDP has also undergone epithelial-mesenchymal transition (EMT). We aim to determine if alterations in EMT-related genes are related to or independent from the drug-resistance phenotypes. EMT gene and protein markers, invasion, motility and morphology were investigated in IGROVCDDP and its parent drug-sensitive cell line IGROV-1. ZEB1 was investigated by qPCR, Western blotting and siRNA knockdown. ZEB1 was also investigated in publicly available ovarian cancer gene-expression datasets. IGROVCDDP cells have decreased protein levels of epithelial marker E-cadherin (6.18-fold, p = 1.58e-04) and higher levels of mesenchymal markers vimentin (2.47-fold, p = 4.43e-03), N-cadherin (4.35-fold, p = 4.76e-03) and ZEB1 (3.43-fold, p = 0.04). IGROVCDDP have a spindle-like morphology consistent with EMT. Knockdown of ZEB1 in IGROVCDDP does not lead to cisplatin sensitivity but shows a reversal of EMT-gene signalling and an increase in cell circularity. High ZEB1 gene expression (HR = 1.31, n = 2051, p = 1.31e-05) is a marker of poor overall survival in high-grade serous ovarian-cancer patients. In contrast, ZEB1 is not predictive of overall survival in high-grade serous ovarian-cancer patients known to be treated with platinum chemotherapy. The increased expression of ZEB1 in IGROVCDDP appears to be independent of the drug-resistance phenotypes. ZEB1 has the potential to be used as biomarker of overall prognosis in ovarian-cancer patients but not of platinum/taxane chemoresistance.

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.

DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study.

Platinum analogs are commonly used for cancer treatment. There is increasing interest in finding biomarkers which could predict and overcome resistance, because to date there is no reliable predictive/prognostic marker for these compounds. Here we studied the immunohistochemical expression of proteins involved in DNA damage response and repair (γH2AX, 53BP1, ERCC1, MLH1, and MSH2) in primary tumor tissues from patients treated with platinum-based chemotherapy. Levels and localization of Heat Shock Protein (HSP)27 and phospho-(Thr5/7)-HSP90α (p-HSP90α) were also determined. The implications in clinical response, disease-free survival and overall survival were analyzed. High γH2AX and 53BP1 expressions were associated with poor clinical response. Nuclear p-HSP90α, as well as nuclear absence and low cytoplasmic expression of HSP27 correlated with good response. Patients with high γH2AX and high cytoplasmic HSP27 expressions had shorter overall survival and disease-free survival. MLH1, MSH2, or ERCC1 were not associated with clinical response or survival. We report the potential utility of p-HSP90α, HSP27, γH2AX, and 53BP1 as predictive/prognostic markers for platinum-based chemotherapy. We present the first study that evaluates the predictive and prognostic value of p-HSP90α in primary tumors. Our research opens new possibilities for clinical oncology and shows the usefulness of immunohistochemistry for predicting chemotherapy response and prognosis in cancer.

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.

Dose Modification of Etoposide plus Platinum in Elderly Patients with Extensive-Disease Small-Cell Lung Cancer.

BACKGROUND: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. METHODS AND PATIENTS: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. RESULTS: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269-1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. CONCLUSIONS: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC.

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.).

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma in adults.

TARGET POPULATION: These recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM). QUESTION (Q1): In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy? RECOMMENDATION: Level III: Adult patients with pGBM might derive benefit in treatment with TMZ, especially those who progress after more than 5 months of TMZ-treatment free interval. LEVEL III: Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohyperthermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy. There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits. QUESTION (Q2): In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy? RECOMMENDATION: Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a recommendation about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen. QUESTION (Q3): In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy? RECOMMENDATION: Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM. LEVEL III: Other cytotoxic therapies like perillyl acohol or ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy. QUESTION (Q4): In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy? RECOMMENDATION: Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM. QUESTION (Q5): In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy? RECOMMENDATION: Level III: Oncolytic virotherapy is not suggested in patients with pGBM.