cisplatin
Regulatory sources consulted
Approved indications
- Combination treatment of advanced testicular cancer.
- Treatment of advanced ovarian cancer, in combination or as monotherapy according to the regimen.
- Single-agent treatment of advanced bladder cancer.
- Treatment of metastatic or advanced head and neck, non-small cell or small cell lung tumors, and in combination with radiotherapy for cervical carcinoma.
Contraindications
Absolute
- Hypersensitivity to cisplatin or other platinum compounds.
- Creatinine clearance below 60 mL/min according to the CIMA label.
- Dehydration.
- Myelosuppression.
- Pre-existing hearing impairment.
- Cisplatin-induced neuropathy.
- Concomitant yellow fever vaccination.
- Breastfeeding.
Clinical warnings
- Boxed warning · It can cause severe cumulative nephrotoxicity, including acute kidney injury. Ensure adequate hydration and monitor renal function, magnesium, sodium, potassium, and calcium before and during each cycle. — DailyMed, Cisplatin injection set_id 508496cb-3441-46b3-a4fe-e0d440e6adc6
- Boxed warning · It can cause cumulative, irreversible, disabling peripheral neuropathy. Perform regular neurologic assessment and reconsider dose or continuation if symptoms occur. — DailyMed, Cisplatin injection set_id 508496cb-3441-46b3-a4fe-e0d440e6adc6
- Boxed warning · It is highly emetogenic. Give effective antiemetic premedication and monitor dehydration and electrolyte disturbances. — DailyMed, Cisplatin injection set_id 508496cb-3441-46b3-a4fe-e0d440e6adc6
- Boxed warning · Myelosuppression can be severe or fatal because of infection. Monitor blood counts and delay, reduce, or discontinue according to recovery. — DailyMed, Cisplatin injection set_id 508496cb-3441-46b3-a4fe-e0d440e6adc6
- Major warning · Ototoxicity can be irreversible and is more severe in pediatric patients. Perform audiometry before treatment and before each cycle; delayed hearing loss may occur. — AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107
- Major warning · Anaphylactic reactions and cross-reactivity with other platinum agents can occur. Administer where immediate support for a severe reaction is available. — AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107
Drug interactions
- HighNephrotoxic or ototoxic drugs
Mechanism: They can additively increase renal or auditory toxicity.
Recommendation: Avoid the combination when possible; if essential, intensify renal, electrolyte, and hearing monitoring.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.htmlDailyMed, Cisplatin injection set_id 508496cb-3441-46b3-a4fe-e0d440e6adc6https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=508496cb-3441-46b3-a4fe-e0d440e6adc6
- ModerateLithium
Mechanism: Cisplatin can reduce blood lithium concentrations.
Recommendation: Monitor lithium concentration and coordinate adjustment with the prescribing team.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.html
- ModerateOral anticoagulants
Mechanism: Chemotherapy can variably alter anticoagulation.
Recommendation: Monitor INR more frequently.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.html
- ModeratePhenytoin and other anticonvulsants
Mechanism: Cisplatin can reduce their concentrations and compromise seizure control.
Recommendation: Monitor concentrations and clinical response; adjust if needed.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.html
- HighLive vaccines
Mechanism: Immunosuppression increases the risk of generalized vaccine infection; yellow fever vaccine is contraindicated.
Recommendation: Avoid live vaccines during treatment and for 3 months afterward; do not administer yellow fever vaccine.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.html
- HighPaclitaxel
Mechanism: Giving cisplatin before paclitaxel reduces paclitaxel clearance by about 33% and can increase neurotoxicity.
Recommendation: Coordinate regimen sequence and monitor neurotoxicity.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.html
- HighPyridoxine with altretamine
Mechanism: The combination with cisplatin was associated with a poorer response.
Recommendation: Avoid the combination.
AEMPS CIMA, CISPLATINO PHARMACIA, registro 62107https://cima.aemps.es/cima/dochtml/ft/62107/FT_62107.html
Adverse events
Common (≥1%)
leukopenia · thrombocytopenia · anemia · nausea and vomiting · anorexia · diarrhea · nephrotoxicity · ototoxicity
Rare but serious
secondary acute leukemia · thrombotic microangiopathy or hemolytic uremic syndrome · anaphylaxis · posterior reversible encephalopathy syndrome · blindness or optic neuritis · myocardial infarction or cardiac arrest
Pregnancy and lactation
FDA category: D
Historical FDA Pregnancy Category D: it can cause fetal harm. Explain the risk if used during pregnancy. Cisplatin and active metabolites enter breast milk; do not breastfeed during treatment or for 4 weeks after the last dose.
Recent literature (PubMed)
Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus
Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherap
In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (34
Cisplatin is an effective chemotherapeutic agent for various solid tumours, but its use is limited by adverse effects in normal tissues. In particular, cisplatin is nephrotoxic and can cause acute kidney injury and chronic kidney disease. Preclinical studies have provided insights into the cellular and molecular mechanisms of cisplatin nephrotoxicity, which involve intracellular stresses including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress. Stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation have key roles in the pathogenesis of cisplatin nephrotoxicity. In addition, emerging evidence suggests a contribution of epigenetic changes to cisplatin-induced acute kidney injury and chronic kidney disease. Further research is needed to determine how these pathways are integrated and to identify the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity. A number of potential therapeutic targets for cisplatin nephrotoxicity have been identified. However, the effects of renoprotective strategies on the efficacy of cisplatin chemotherapy needs to be thoroughly evaluated. Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding of the complex cellular and molecular mechanisms of cisplatin nephrotoxicity and potentially lead to the identification of specific targets to protect the kidney without compromising the chemotherapeutic efficacy of cisplatin.
No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy. In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine-cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine-cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes. A total of 608 patients underwent randomization (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval [CI], 0.63 to 0.96; P = 0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P = 0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine-cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine-cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively. Combination therapy with nivolumab plus gemcitabine-cisplatin resu