First- and Second-Line Therapy for Metastatic Urothelial Carcinoma of the Bladder

Abstract

but little improvement has been achieved in the outcomes of patients with advanced or metastatic disease. Almost 90% of those patients eventually succumb to their cancer.For patients who relapse after first-line chemotherapy, the prognosis is generally poor. To date, there is no real consensus on how to best treat these patients, and most of the available evidence stems from small phase ii trials that have mostly failed to show survival benefit over supportive care. The present review provides an update on the management of metastatic bc, with a focus on first-line and secondline therapies. FIRST-LINE THERAPY Single-Agent TherapySingle-agent therapy has generally failed to provide adequate results in patients with advanced bc. In a phase iii trial of patients randomized to receive either cisplatin alone or in combination [methotrexate, vinblastine, doxorubicin, and cisplatin (mvac)], the overall response rate (or) was only 12% in the cisplatin arm, with only 4 of 122 patients (3.3%) remaining alive at 3 years of follow-up 4 . Similar results were observed in phase ii trials with carboplatin [or: 18%; median duration of survival (mds): 16 months] 5 . In a phase iii trial examining the role of lobaplatin, 2 of 17 patients (12%) achieved a partial response (pr), but the study was terminated because of high toxicity rates 6 . Other drugs investigated in phase ii trials have manifested variable activity against advanced urothelial cancer: oral piritrexim (or: 23%; mds: 22 weeks) 7 , trimetrexate (or: 17%; mds not reported) 8 , and docetaxel (or: 13%; mds: 9 months) 9 . However, some improved results were obtained with other single agents such as paclitaxel and gemcitabine 10,11 . In a phase ii trial of 26 patients with advanced bc treated with paclitaxel, the or was 42%, and the mds, 8.4 months 10 . Similarly, in a phase ii trial of gemcitabine in 40 patients, an or of 28% was reported, with a mds of 54 weeks 11 . ABSTRACTUrothelial cancer of the bladder is the 4th most common malignancy in American men and the 9th most common in women. Although it is a chemosensitive disease, advanced bladder cancer seems to have reached a plateau with regard to median survival of patients. Standard first-line therapy remains gemcitabine plus cisplatin (gc) or methotrexate, vinblastine, doxorubicin, and cisplatin (mvac). In patients deemed unfit to receive cisplatin, gemcitabine plus carboplatin or gemcitabine plus paclitaxel can be considered. To date, no standard therapy has been established for patients who recur or are refractory to first-line therapy. Second-line vinflunine, by way of superiority over best supportive care, has shown promise in a phase iii trial. Cisplatin-based therapy (mvac or gc) can also be offered to patients previously treated with cisplatin, especially if they responded previously and are considered platinum-sensitive. Novel targeted therapies are sorely needed to further improve the delivery and efficacy of chemotherapy.

Emerging concepts on drug resistance in bladder cancer: Implications for future strategies

“…Although bladder cancer is a relatively chemosensitive tumor, showing a response rate of 50-70% to frontline treatments, patients who recur after first-line chemotherapy have a very poor prognosis [5]. Interestingly, a tumor response to prior chemotherapy seems to not affect the outcome of patients treated with second-line chemotherapy, with a PFS that does not overcome 3 months for both patients with or without response to chemotherapy [6].…”

Current management of advanced bladder cancer

“…7 Other non-platinumbased regimens, such as gemcitabine in combination with a taxane, have been evaluated in phase 2 studies in this setting and shown to have efficacy, although response rates and overall survival are lower than in those receiving platinumbased chemotherapy. 8 As well as those not fit enough for a platinum-based regimen, some patients may have significant comorbidities or poor performance status (3 or 4), in which case best supportive care rather than active systemic therapy is recommended. Early palliative care input is crucial.…”

“…Combination chemotherapy generally improves response rates (0-61%) without improving overall survival (4-14 months). 8 Current UK guidelines support the off-licence use of gemcitabine in combination with either paclitaxel or carboplatin. 11 These data underline the urgent need for effective new treatments, and there is growing evidence that immunotherapy agents are active in this setting.…”

Translational research to realize the full potential of novel agents – an opportunity for vinflunine?

“…The lack of approved second-line treatment for TCCU may contribute to approval of VFL for the indication [6]. This is especially true from the perspective of clinical practice that best supportive care should be reserved for unfit patients and earlier provision of new treatments with similar survival benefit as salvage therapy might improve or delay disease-related symptoms [7].…”