Gallium nitrate in advanced bladdercarcinoma: Southwest oncology group study

doi:10.1016/0090-4295(91)80152-W

Urology

Volume 38, Issue 4, October 1991, Pages 355-357

https://doi.org/10.1016/0090-4295(91)80152-W Get rights and content

Abstract

Gallium nitrate is a heavy metal anticancer agent that has demonstrated widespread activity in a number of phase I studies. This phase II study employed a starting dose of 700 mg/m2 IV every two weeks in patients with advanced bladder carcinoma. Significant nephrotoxicity observed in 4 of the first 10 patients required extending the time between cycles to three weeks in the remaining 24 patients. One complete response and six partial responses were achieved. Nephrotoxicity was the major dose-limiting toxicity. Gastrointestinal toxicity and myelosuppression were minimal. Gallium nitrate appears to be an active agent in advanced carcinoma of the bladder. Further clinical trials with this agent are warranted.

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However, one of the main drawbacks is that the gallium(III) ion reacts with water, giving rise to compounds that precipitate [29]. Gallium(III) nitrate has shown efficacy against lymphomas [30], bladder carcinoma [31], and certain cisplatin-resistant carcinomas [32], in preclinical trials it showed nephrotoxicity as a side effect when administered intravenously [33]. In gallium(III) maltolate, gallium had a molecular radius close to iron and was able to bind to the enzyme ribonucleotide reductase, inhibiting mitochondrial activity and, consequently, retarding glioblastoma growth [34].
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At 17 months, however, the survival rates in both groups were equivalent. In summary, several studies of gallium nitrate as single agent [22–24] and in combination [25,26] have shown its activity in the treatment of advanced or refractory bladder cancer; however, some studies suggest significant toxicity. Evaluation in combination with new agents as gemcitabine and/or paclitaxel may also be warranted given its mechanism of action and nonoverlapping toxicity profiles.
The aim of the present paper is to review findings from the most relevant studies and evaluate the potential of new drugs in treatment of metastatic urothelial cancer.
Studies were identified by searching MEDLINE and Pubmed databases up to 2009 using both medical subject heading (Mesh) and a free text strategy with the name of known individual chemotherapeutic drug and the following key words: ‘muscle-invasive bladder cancer’, ‘urothelial/transitional carcinoma’, ‘chemotherapeutics drugs and agents’. At the end of our research in literature we selected 63 articles and we have considered only studies in which almost 30 patients were enrolled.
Radical cystectomy with pelvic lymph node dissection is the gold standard of treatment for clinically localized muscle-invasive bladder cancer. While more extensive lymph node dissection may have both prognostic and therapeutic significance, effective systemic therapies that eliminate micrometastases may improve outcome. Perioperative chemotherapy can be administered before (neoadjuvant) or after (adjuvant) cystectomy to eradicate subclinical disease and to improve survival.
The challenge remains as to how to integrate all of the relevant knowledge and data in a systematic manner so that researchers can gain the knowledge needed to devise the best therapeutic and diagnostic strategies. Future improvements in the treatment of advanced bladder cancer will rely not only on the optimization of currently available cytotoxic agents but also on the biologic profile of individual patient tumors and the appropriate therapies that target molecular aberrations unique to this malignancy.
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2007, Annals of Oncology
Citation Excerpt :
At 17 months, however, the survival rates in both groups were equivalent. In summary, several studies of gallium nitrate as single agent [25–27] and in combination [28, 29] have shown its activity in the treatment of advanced or refractory bladder cancer (Table 1); however, some studies suggest significant toxicity. Evaluation in combination with new agents as gemcitabine and/or paclitaxel may also be warranted given its mechanism of action and nonoverlapping toxicity profiles.
The prognosis for any patient with progressive or recurrent invasive transitional cell carcinoma remains poor. In this context, the focus of clinical research in these invasive cancers concentrates on identifying systemic treatment options and new agents in order to improve survival of patients. Cisplatin-based chemotherapy is standard treatment of patients with metastatic urothelial cancer; however, despite regimens as the cisplatin–gemcitabine combination, the overall response rates vary between 40% and 65%, with complete response in 15%–25% with survivals up to 16 months. This survival is frequently achieved with severe and life-threatening side effects. None the less, almost all responding patients relapse within the first year; therefore, the need for development of new and tolerable agents is urgent. This review highlights some new active chemotherapeutic as new platinum compounds (oxaliplatin, lobaplatin), gallium nitrate, ifosfamide, the antifolates piritrexim and pemetrexed (Alimta®, LY231514), vinflunine and molecular targeting agents such as farnesyltransferase inhibitors (lonafarnib, R115777, SCH66336), ribozyme (RPI.4610), histone deacetylase inhibitor (CI-994) and monoclonal antibodies (epidermal growth factor receptor, Her 2/neu).
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The aim of the study was to evaluate the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced urothelial cancer.
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We determined the activity and toxicity of gemcitabine plus cisplatin in patients with inoperable or metastatic transitional cell carcinoma of the urinary tract.
A total of 54 patients with transitional cell carcinoma, measurable disease and Eastern Cooperative Oncology Group performance status 2 or greater were enrolled in this multicenter phase II trial. Previous adjuvant or neoadjuvant therapy for locally advanced disease was acceptable if it had been completed more than 1 year before study entry. Every 4 weeks patients received 1,000 mg./m.² gemcitabine intravenously on days 1, 8 and 15, and 70 mg./m.² cisplatin intravenously on day 2.
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^*: This investigation was supported in part by the following PHSCooperative Agreement grant numbers awarded by the National Cancer Institute DHHS: CA-16385, CA-03096, CA-12213, CA-61930 CA-20319, CA-14028, CA-35996, CA-32734, CA-12644, CA-04919, CA -36020, CA-37981, CA-27057, CA-35117 CA-3392; CA-04915, CA-35995, CA-21116, CA-13238, CA-32102, and CA-12104.

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Gallium nitrate in advanced bladdercarcinoma: Southwest oncology group study*

Abstract

Chemotherapy of metastatic bladder cancer

Cancer

Phase 1-11 clinical trial of gallium nitrate (NSC 15200)

Cancer Clin Trials

Phase I study of gallium nitrate in patients with advanced cancer