Zhang 2018.
| Study characteristics | ||
| Methods | Prospective, open‐label, multicentre, randomised, phase 3 trial at 12 institutions or hospitals in China. | |
| Participants | 240 Chinese participants (236 analysed) with breast cancer aged 18 to 70 years who had metastatic triple‐negative breast cancer (mTNBC) histologically confirmed at the primary tumour, with clinical, imaging, histological or cytological evidence of metastatic (stage IV) disease. Median age 47 and 48 years in platinum and control arms, respectively. Age interquartile range 42 to 57 and 43 to 55 years in platinum and control arms, respectively. 100% mTNBC. 100% 1st‐line. 152 (64%) of the 236 participants had received anthracyclines. 195 (83%) of the 236 participants had received taxanes. |
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| Interventions | Cisplatin + gemcitabine vs paclitaxel + gemcitabine. Platinum ARM: Cisplatin plus gemcitabine (cisplatin 75 mg/m2 on day 1; gemcitabine 1250 mg/m2 on days 1 and 8) intravenously every 3 weeks for a maximum of eight cycles, or until disease progression or intolerable toxic effects developed. Control ARM: Paclitaxel plus gemcitabine (paclitaxel 175 mg/m2 on day 1; gemcitabine 1250 mg/m2 on days 1 and 8) intravenously every 3 weeks for a maximum of eight cycles, or until disease progression or intolerable toxic effects developed. |
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| Outcomes | OTRR.
OS.
PFS, defined as "the time from the date of randomisation to progression or death from any cause". Adverse events. |
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| Notes | 4 participants were randomised but not analysed for OS or PFS (i.e. modified ITT). An additional 9 participants were not assessable for response. Estimated min follow‐up = 3 months (based on first censoring tick on OS curve). Estimated max follow‐up = 35 months (based on last censoring tick on OS curve). Median PFS was 7.73 months (95% CI 6.16 to 9.30) in the cisplatin plus gemcitabine group and 6.47 months (5.76 to 7.18) in the paclitaxel plus gemcitabine group. Median survival time was 22.3 months in the cisplatin plus gemcitabine group and 18.6 months in the paclitaxel plus gemcitabine group; not reported in the text of the study paper but estimated from Kaplan‐Meier curve. 118 of 120 randomised metastatic participants were analysed in time‐to‐event PFS analyses (modified ITT). The study was funded by Shanghai Natural Science Foundation and gemcitabine was provided by Eli Lilly. This study was included in Egger 2017 and labelled "Hu 2015". Updated OS and PFS results were extracted for pooling from Zhang 2018. |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomisation was done centrally via a block randomization of size eight, with no stratification factors, via an interactive web‐response system." |
| Allocation concealment (selection bias) | Low risk | Central allocation. Quote: "Randomisation was done centrally…" and "After checking the inclusion criteria, the study coordinator sent the allocated treatment back to the investigator by fax." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label trial. |
| Blinding of outcome assessment (detection bias) (overall survival) | Low risk | Unlikely that assessment of OS would be influenced by lack of blinding. |
| Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life) | Unclear risk | The extent and/or the effectiveness of intended blinding was not clear. Quote: "Tumour response was assessed by a team of local investigators … and when needed, with independent central assessment, every two cycles until disease progression." Assessment of toxicity appeared to be unblinded. Quote: "Adverse events were recorded at each treatment visit, at each follow‐up visit, and at the end‐of‐study visit." |
| Incomplete outcome data (attrition bias) (time‐to‐event outcomes) | Unclear risk | 118 of 120 and 118 of 120 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis (modified intent‐to‐treat analysis). |
| Incomplete outcome data (attrition bias) (binary outcomes) | Low risk | 8 of 120 and 5 of 120 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (5.4% of all randomised participants). 2 of 120 and 2 of 120 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (1.7% of all randomised participants). |
| Selective reporting (reporting bias) | Low risk | OS was not listed under 'outcomes' in ClinicalTrials.gov record (https://clinicaltrials.gov/ct2/show/NCT01287624) but it was mentioned in the 'purpose' section of the record. All other outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa. |
| Other bias | Unclear risk | Baseline characteristics were generally similar across groups except for ECOG performance status, number of metastatic organ sites and menopausal status. |
AUC: Area under the curve bid and BID: Twice a day Ce: Cetuximab C: Carboplatin CI: Confidence interval CT: X‐ray image made using computerized axial tomography D: Docetaxel ECOG: Eastern Cooperative Oncology Group EGFR: Epidermal growth factor receptor ER: oestrogen receptor G/C: gemcitabine plus carboplatin GemCap: Gemcitabine, capecitabine GemCis: Gemcitabine, cisplatin GemVin: Gemcitabine, vinorelbine HER2: Human epidermal growth factor receptor 2 ICR‐CTSU: The Institute of Cancer Research Clinical Trials & Statistics Unit ITT: Intention‐to‐treat IV: Intravenous Max: Maximum Min: Minimum mTNBC: metastatic triple‐negative breast cancer MRI: Magnetic resonance imaging nab‐P/C: nab‐paclitaxel plus carboplatin nab‐P/G: nab‐paclitaxel plus gemcitabine ORR: Objective response rate OS: overall survival OTRR: Objective tumour response rate P: Cisplatin p.: Page po: by mouth PCP: Placebo plus carboplatin/paclitaxel. PFS: progression‐free survival PR and PgR: Progesterone receptor QD: one a day QoL: Quality of life RECIST: Response Evaluation Criteria In Solid Tumors SD: Standard deviation T: Paclitaxel TNBC: Triple‐negative breast cancer TP: Docetaxel, cisplatin TTF: Time to treatment failure TTP: Time to progression TTTF: Time to treatment failure TX: Docetaxel, capecitabine VCP: Veliparib plus carboplatin/paclitaxel VP‐16: Oral etoposide VT: Veliparib with temozolomide