Gemcitabine and cisplatin in locally advanced and/or metastatic bladder cancer
Introduction
Transitional cell carcinoma (TCC) of the urothelium is considered a chemosensitive tumour. None the less, chemotherapy confers only a modest survival benefit to these patients, and metastatic disease remains essentially incurable with only a small number of patients achieving long-term disease control.
A number of available drugs have significant single-agent activity against urothelial cancer, including cisplatin, methotrexate, doxorubicin, vinblastine, ifosfamide, and, more recently, gemcitabine and paclitaxel. Despite this activity, however, single-agent treatment generally achieves only partial responses (PRs) of short duration (median, 3–4 months).
Combination chemotherapy for advanced and metastatic TCC of the urothelium has been based most often on the most active single agents, cisplatin and methotrexate, which yield single-agent response rates of 30–35% [1]. As previously mentioned the MVAC combination (methotrexate, vinblastine, doxorubicin, cisplatin) is considered the standard for treatment of metastatic bladder cancer [2] with response rates of 40–72% 3, 4, 5, 6, 7, 8 and median survival times of 12–13 months 9, 10. In a recent long-term study, however, only 3.7% of patients randomised to MVAC were alive and continuously disease free at 6 years [11]. The regimen is also associated with considerable treatment-related toxicity.
For these reasons, developing more effective and less toxic drug regimens to treat patients with TCC of the urothelium is vital. In this regard, gemcitabine has shown promising activity, with overall response rates of approximately 25% and complete response (CR) rates of approximately 10% 12, 13, 14; toxicity, particularly myelosuppression, is mild.
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Gemcitabine and cisplatin in patients with locally advanced or metastatic bladder cancer
The encouraging activity and tolerability of single-agent gemcitabine, coupled with its synergistic potential to inhibit DNA repair after a cell has been exposed to DNA-damaging agents like cisplatin [15], made it logical to study the combination of gemcitabine and cisplatin. Table 1 shows efficacy data from four phase II trials of this combination given to patients with locally advanced or metastatic TCC 16, 17, 18, 19.
In the first phase II study, a European study, our group administered
Conclusion
Gemcitabine and cisplatin represent an encouraging two-drug combination in patients with locally advanced or metastatic TCC of the urothelium. Toxicities are generally manageable although the weekly cisplatin schedule resulted in a high degree of grade 3–4 neutropenia and thrombocytopenia. Thus, cisplatin doses of 75 or 70 mg/m2 given every 28 days as opposed to the weekly schedule appears to be the optimal cisplatin schedule for the combination.
The four phase II studies of gemcitabine plus
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Cited by (16)
Urothelium-adherent, ion-triggered liposome-in-gel system as a platform for intravesical drug delivery
2017, Journal of Controlled ReleaseCitation Excerpt :However, drug efficacy is limited by the permeability barrier of the bladder urothelium [8], which prevents drug diffusion into the bladder wall, by drug dilution during bladder filling and subsequent washing out during voiding, necessitating repeated drug infusions. Primary chemotherapeutic agents used in bladder cancer are gemcitabine [9], epirubicin [10], cisplatin [11], paclitaxel [12], mitomycin C [13], etc., which need multiple instillations. Paclitaxel has been used in combination therapy for urinary bladder cancer, but its low solubility requires the use of Cremophor® excipient for stabilization in an aqueous solution, resulting in severe systemic toxicity [14].
Intravesical drug delivery: Challenges, current status, opportunities and novel strategies
2010, Journal of Controlled ReleaseCitation Excerpt :At present, the most common intravesical treatments for bladder cancer are immunomodulators like BCG and interferon-α [37,40], and administration of chemotherapeutic agents such as doxorubicin, gemcitabine, epirubicin [39], mitomycin C (MMC) and thiotepa [12,38,41,42,47]. Other anti-cancer drugs such as paclitaxel [43] and cisplatin [44] have also shown promise in treatment of bladder cancer [45,48]. Treatment of interstitial cystitis (IC) involves control of the afferent nerve stimulus in the bladder.
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