What is the administration protocol for cisplatin (cis-diamminedichloroplatinum) 70 mg/m^2 and gemcitabine 1000 mg/m^2 in a patient with carcinoma (Ca) of the urinary system (urinariae), stage pT1, grade 3 (G3), no lymph node involvement (N0), distant metastasis (M1) with suspected pulmonary metastases (Mts ad pulmonis)?

From the Guidelines

For a patient with metastatic urinary bladder cancer (pT1 G3 N0 M1) with suspected pulmonary metastases, cisplatin 70 mg/m² and gemcitabine 1000 mg/m² are typically administered as follows: Cisplatin 70 mg/m² is given intravenously on day 1, while gemcitabine 1000 mg/m² is administered intravenously on days 1 and 8 of a 21-day cycle. This regimen is usually continued for 4-6 cycles, depending on response and tolerability. Prior to administration, adequate hydration and antiemetic medications are essential to prevent cisplatin-induced nephrotoxicity and manage nausea/vomiting. Renal function should be assessed before each cycle, with a creatinine clearance of at least 60 mL/min recommended for cisplatin eligibility. Complete blood counts should be monitored before each drug administration, with dose adjustments or delays if significant myelosuppression occurs. This combination chemotherapy is a standard first-line treatment for metastatic urothelial carcinoma, offering improved survival outcomes compared to single-agent therapy, though treatment decisions should be individualized based on the patient's performance status and comorbidities 1.

Some key points to consider:

• The performance status of the patient is a major determinant of which regimen is used, and regimens with lower toxicity profiles are recommended in patients with compromised liver or renal status or serious comorbid conditions.
• In patients with a glomerular filtration rate (GFR) of less than 60 mL/min, carboplatin may be substituted for cisplatin in the regimen.
• The taxanes have been shown to be active as both frontline and palliative therapies, and several groups are exploring 2- and 3-drug combinations using these agents, with and without cisplatin, as initial therapy.
• Alternative regimens, including cisplatin/paclitaxel, gemcitabine/paclitaxel, cisplatin/gemcitabine/paclitaxel, carboplatin/gemcitabine/paclitaxel, and cisplatin/gemcitabine/docetaxel, have shown modest activity in bladder cancer in phase I and II trials.

It's worth noting that, the NCCN guidelines recommend enrollment in clinical trials of potentially less toxic therapies, and consideration of checkpoint inhibitors must be integrated into the therapeutic planning for all patients with locally advanced and metastatic disease 1.

From the FDA Drug Label

Advanced Bladder Cancer Cisplatin should be administered as a single agent at a dose of 50 to 70 mg/m 2IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy All Patients Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37. 5 g of mannitol, and infused over a 6 hour to 8 hour period.

Cisplatin 70 mg/m2 should be administered as an intravenous infusion over a 6 to 8 hour period, with pretreatment hydration and diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol. However, the FDA drug label does not provide information on the administration of gemcitabine 1000 mg/m2 2.

From the Research

Administration of Cisplatin and Gemcitabine

• Cisplatin 70 mg/m2 is given on day 1 of a 21-day cycle 3
• Gemcitabine 1000 mg/m2 is given on days 1 and 8 of a 21-day cycle 3
• This dosing regimen is used for the treatment of metastatic urothelial cancer
• The tolerability of gemcitabine plus cisplatin in the elderly population has been studied, with a common dosing regimen being gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 70 mg/m2 on day 1 every 21 days 4

Dosing Considerations

• The optimal dose and schedule for patients aged ≥ 65 years is not clear, but a lower gemcitabine dose of 1000 mg/m2 is better tolerated 4
• Dose modifications and treatment delays may be necessary due to hematologic toxicity 4
• Starting therapy at a reduced dose may be considered to minimize treatment interruptions, dose omissions, and side effects 5

Clinical Trials

• A phase 2 randomized clinical trial studied the effect of cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma 3
• A randomized phase III trial studied the addition of bevacizumab to gemcitabine and cisplatin in patients with advanced urothelial carcinoma 6
• A multicenter phase II clinical trial studied the use of gemcitabine and cisplatin as neoadjuvant chemotherapy for patients with high-grade upper tract urothelial carcinoma 7