Expert consensus on the clinical application of platinums in advanced breast cancer (2020 version)

Breast cancer is the most common and fatal malignant tumor in women, which causes great social burden throughout the world. At present, chemotherapy is still the most important treatment manner of advanced breast cancer, and platinum drugs are one of the commonly used chemotherapeutic drugs. Based on the substantial evidence, the expert committee deeply discusses the clinical application of platinum drugs in advanced breast cancer, gives the reasonable suggestions for its clinical usage, effectiveness and adverse effects. This consensus aims to guide physicians to use drugs reasonably and standardize the diagnosis and treatment. © 2021 Chinese Medical Journals Publishing House Co.Ltd     

A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer

Objective

This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed.

Methods

Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15 mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8 weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression.

Results

Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8 weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥ 20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (> 150 μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated.

Conclusion

Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.     

Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species

Objective

The acquired resistance to platinum-based drugs has become an obstacle in the management of ovarian cancer. We investigated the apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, in platinum-resistant human ovarian cancer cells, along with the molecular mechanism of action.

Methods

Costunolide and cisplatin were examined in platinum-resistant human ovarian cancer cells. MTT assay for cell viability, PI staining for cell cycle profiling, and Annexin V assay for apoptosis analysis. ROS production and protein expression was assessed by H₂DCFDA staining and Western blotting, respectively. Combination effect was determined using the Combination Index (CI) method.

Results

It was found that costunolide is more potent than cisplatin in inhibiting cell growth in three platinum-resistant ovarian cancer cell lines (MPSC1^PT, A2780^PT, and SKOV3^PT). Costunolide induced apoptosis of platinum-resistant cells in a time- and dose-dependent manner and suppressed tumor growth in SKOV3^PT-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, -8, and -9. Pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Additionally, the antioxidant N-acetyl-L-cysteine (NAC) significantly attenuated the costunolide-induced production of ROS, activation of caspases, down-regulation of Bcl-2, and apoptosis in platinum-resistant ovarian cancer cells. Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.

Conclusions

Taken together, these data suggest that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancer.     

Platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer

ObjectiveThe concept of platinum sensitivity and cross-resistance among platinum agents are widely known in the management of recurrent ovarian cancer. The aim of this study was to evaluate two hypotheses regarding the validity of the concept of platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer.MethodsIn this retrospective study, the clinical data of patients with recurrent cervical cancer, who had a history of receiving cisplatin based chemotherapy (including concurrent chemoradiotherapy [CCRT] with cisplatin) and who received second-line chemotherapy at the time of recurrence between April 2004 and July 2012 were reviewed.ResultsIn total, 49 patients-34 squamous cell carcinomas (69.4%) and 15 non-squamous cell carcinomas (30.6%)-were enrolled. The median age was 53 years (range, 26 to 79 years). Univariate and multivariate analysis showed that a platinum free interval (PFI) of 12 months has a strong relationship with the response rate to second-line chemotherapy. Upon multivariate analysis of survival after second-line platinum-based chemotherapy, a PFI of 12 months significantly influenced both progression-free survival (hazard ratio [HR], 0.349; 95% confidence interval [CI], 0.140 to 0.871; p=0.024) and overall survival (HR, 0.322; 95% CI, 0.123 to 0.842; p=0.021). In patients with a PFI of less than 6 months, the difference of progression-free survival between patients with re-administration of cisplatin (3.0 months) and administration of cisplatin analogue (7.2 months) as second-line chemotherapy was statistically significant (p=0.049, log-rank test).ConclusionThe concept of platinum sensitivity could be applied to recurrent cervical cancer and there is a possibility of noncross-resistance of cisplatin analogue with cisplatin.     

宫颈癌组织ERCC1、hMSH2表达及病理特征与铂类药物抵抗的相关性研究

目的 探究宫颈癌组织核苷酸切除修复交叉互补基因1（ERCC1）、错配修复基因2（hMSH2）表达与病理特征及铂类药物抵抗的相关性。方法 收集2019年1月～2022年3月我院86例宫颈癌患者病理组织为观察组，另收集同期72例因子宫肌瘤手术切除的正常宫颈组织为对照组。比较2组核苷酸切除修复交叉互补基因1、错配修复基因2表达情况，分析癌组织核苷酸切除修复交叉互补基因1、错配修复基因2表达与病理特征相关性，铂类药物抵抗患者病理特征、核苷酸切除修复交叉互补基因1、错配修复基因2表达情况及铂类药物抵抗的多因素分析，分析核苷酸切除修复交叉互补基因1、错配修复基因2表达对铂类药物抵抗的预测价值。结果 观察组核苷酸切除修复交叉互补基因1、错配修复基因2阳性率较对照组高（P＜0.05）；癌组织核苷酸切除修复交叉互补基因1、错配修复基因2表达与肌层浸润深度、分期、淋巴结转移有关（P＜0.05）；铂类药物抵抗患者与肌层浸润深度、分期、分化程度、淋巴结转移、核苷酸切除修复交叉互补基因1、错配修复基因2阳性有关（P＜0.05）；Logistic回归方程分析，结果显示，将肌层浸润深度、分期、分化程度、淋巴结转移控制后，癌组织核苷酸切除修复交叉互补基因1、错配修复基因2阳性仍为宫颈癌患者铂类药物抵抗的危险因素（P＜0.05）；ROC显示，核苷酸切除修复交叉互补基因1、错配修复基因2阳性联合预测铂类药物抵抗的AUC值最大，为0.702。结论 宫颈癌组织核苷酸切除修复交叉互补基因1、错配修复基因2呈高表达状态，且与病理特征及铂类药物抵抗有关，二者可用于预测铂类药物反应性，从而指导临床治疗。     

What can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis

BackgroundRandomized phase III trials showed interesting, but conflicting results, regarding the treatment of NSCLC, PS2 population. This meta-analysis aims to review all randomized trials comparing platinum-based doublets and single-agents in NSCLC PS2 patients.Materials and methodsData from all published randomized trials, comparing efficacy and safety of platinum-based doublets to single agents in untreated NSCLC, PS2 patients, were collected. Pooled ORs were calculated for the 1-year Survival-Rate (1y-SR), Overall Response Rate (ORR), and grade 3–4 (G3–4) hematologic toxicities.ResultsSix eligible trials (741 patients) were selected. Pooled analysis showed a significant improvement in ORR (OR: 3.243; 95% CI: 1.883–5.583) and 1y-SR (OR: 1.743; 95% CI: 1.203–2.525) in favor of platinum-based doublets. G3–4 hematological toxicities were also more frequent in this group.ConclusionThis meta-analysis suggests that platinum-combination regimens are superior to singleagent both in terms of ORR and survival-rate with increase of severe hematological toxicities.