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Published on 1 June 2003

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Advanced bladder cancer: new drug combinations

teaser

J Bellmunt
MD

Head of
Uro-oncological Unit
Medical Oncology Service
Hospital General Universitari Vall d’Hebron
E:bellmunt@hg.vhebron.es

S Albiol
Medical Oncologist
Medical Oncology Service
Clinica Quiron
Barcelona
Spain

Cisplatin-based combination chemotherapy regimens, such as MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and CMV (cisplatin, methotrexate, vinblastine) are standard treatment for patients with metastatic carcinoma of the urothelium.(1–3) The overall response rates (complete plus partial) to standard cisplatin-based combination regimens range from 50% to 70%, with complete responses in 15–25%.(3–7) Nonetheless, almost all responding patients ultimately relapse within the first year, with a median survival of approximately 12 months.(8)

Until recently, the MVAC combination continued to be the most common treatment regimen for advanced urothelial cancer. In randomised trials, MVAC produced a modest, although significant, benefit on survival when compared with cisplatin as a single agent,(9) with CAP (cisplatin, cyclophosphamide, doxorubicin),(10) and with carboplatin-based regimens.(11) The CMV regimen, widely used in Europe, proved to be superior to methotrexate plus vinblastine in a randomised trial.(12) However, long-term follow-up of MVAC-treated patients in the Intergroup trial showed that only 3.7% experienced more than six years of disease-free survival.(13,14) This poor long-term outcome has led to the search for new treatment approaches.

Two-drug regimens

Platinum/taxanes combinations
Regimens of combined paclitaxel and cisplatin were evaluated in three phase II studies involving a total of 106 patients (see Table 1), with an overall response rate of 50–70% (with complete responses from 15% to 32%).(15–17) The combination of docetaxel and cisplatin (see Table 1) every three weeks has also been evaluated in three studies.(18–20) With a total of 123 patients, the overall response rate ranged from 52% to 62%, and the median overall survival was reported to be between 8.2 and 13.6 months with this combination.

[[HPE09_table1_69]]

Although these initial phase II studies of two-drug combinations of docetaxel or paclitaxel with cisplatin have shown activity in untreated patients, with response rates that are in the same range as is obtained with MVAC, there are no published comparative data with MVAC.

The combination of paclitaxel and carboplatin, widely used in lung cancer, has been evaluated extensively in bladder cancer (see Table 1).(21–28) However, studies suggesting suboptimal efficacy of carboplatin-based chemotherapy have raised concerns as to whether carboplatin should be substituted for cisplatin in those patients who are sufficiently fit to tolerate a cisplatin-based regimen (see HPE Apr/May 2003;Issue 8:85-6).

Platinum/gemcitabine combinations
In view of evidence for synergistic effects between cisplatin and gemcitabine, this combination has been evaluated in bladder cancer in three phase II studies (see Table 2).(29–31) In total, 112 patients were treated, with an overall response rate of 41–57% and with complete response ranging from 13% to 22%. The median survival time was reported to be 12.5–14.3 months in these studies.(29–31)

[[HPE09_table2_71]]

Based upon these results, a large multinational phase III trial comparing gemcitabine and cisplatin (GC) with MVAC was conducted.(32) With a median follow-up of 19 months, overall survival was found to be similar in both arms (GC 13.8 months, MVAC 14.8 months), as were time to progressive disease (7.4 months in both arms) and overall response (GC, 49%; MVAC, 46%). Although the study failed to detect a significant difference in survival, which was the primary endpoint, the favourable risk–benefit ratio justifies consideration of these results and supports the use of GC in patients with locally advanced and/or metastatic transitional-cell carcinoma of the urothelium.

Gemcitabine and carboplatin has been evaluated in “unfit” bladder cancer patients in a dose-finding study. Using this combination(33) we reported an overall response rate of 43.5% with a median time survival of 14.4 months in 16 patients ineligible for the cisplatin-based regimen (“unfit” patient population). A randomised phase II/III trial comparing carboplatin plus gemcitabine with methotrexate, carboplatin and vinblastine in patients ineligible for cisplatin-based chemotherapy is ongoing.

Taxane/gemcitabine combinations
Paclitaxel and gemcitabine combination chemotherapy has been tested in four bladder cancer studies using different schedules.(34–37) Marini et al reported a response rate of 53% with a median response duration of 6.2 months in 16 patients previously treated with cisplatin-based chemotherapy.(34) In the phase II study by Meluch et al, which included 50 patients (13 previously treated), the overall response rate was 57% (42% in patients with prior chemotherapy and 54% in patients previously untreated), with a median survival of 15 months.(35) Kaufman et al reported worse response rates of 0% in six previously treated patients and 39% in 18 untreated patients using a twice-weekly schedule.(36) In a phase II study of weekly paclitaxel and gemcitabine the overall response rate was 61% (39% complete responses).(37) Three patients had grade 4 pulmonary events with one death. Thus the potential of life-threatening pulmonary toxicity with this regimen must be borne in mind.

Both paclitaxel and gemcitabine can be used in patients with impaired renal function, and phase II trials assessing paclitaxel–gemcitabine and docetaxel–gemcitabine combinations in patients with renal insufficiency are ongoing.

Three-drug regimens
The combination of paclitaxel, cisplatin and gemcitabine in advanced transitional-cell carcinoma of the urothelium has been evaluated in a phase I/II trial(38) by the Spanish Oncology Genitourinary Group (SOGUG). In the phase I component of this study, the dose-limiting toxicity was grade 3 and early-onset grade 2 asthenia. Twenty-seven patients developed grade 3–4 neutropenia, 11 patients grade 3–4 thrombocytopenia and 13 grade 3–4 anaemia. Febrile neutropenia was seen in eight patients. One patient died due to neutropenic sepsis. Fifty-eight patients were assessed for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed. Antitumour responses were seen at all dose levels and at all sites of disease, even in patients with both metastasic and locally advanced primary tumours. In patients with locally advanced, surgically incurable bladder tumours, in addition to a high response rate, four of the ten patients underwent successful surgical resection of their disease at the completion of therapy. This suggests that this regimen could have a significant impact on the outcome of patients with a lower burden of disease.

This trial confirms the high response rate observed using these new drugs in the treatment of advanced urothelial carcinoma with this schedule. Nevertheless, we need to take into account that the study population presented some favourable prognostic factors that could bias the results obtained.

The combination of carboplatin, paclitaxel and gemcitabine in 49 patients with advanced urothelial malignancy was evaluated in a phase II trial.(39) Of the 47 response- assessable patients, 32 (68%) demonstrated a major response (15 complete and 17 partial). Responses were seen in lymph nodes and in visceral and bony metastatic sites. The median survival was 14.7 months, with a one-year survival of 59%. The results from this trial indicated that combination chemotherapy with carboplatin, paclitaxel and gemcitabine was active and well tolerated in patients with advanced urothelial cancer. The major toxicities, neutropenia and thrombocytopenia, were resolved with dose modification.

Docetaxel, carboplatin and gemcitabine in poor prognosis and previously treated patients with urothelial carcinoma was assessed in a recent phase I/II trial.(40) Seventy patients were evaluable for toxicity. Grade 4 neutropenia was seen in six patients, grade 3 thrombocytopenia in five patients, and febrile neutropenia in four patients. Of the 13 patients evaluable for response, a response rate of 38% was observed, with three complete (two previously treated patients) and two partial responses. These preliminary results in patients who failed prior chemotherapy are encouraging; however, additional follow-up is necessary.

In a phase I/II study of paclitaxel, methotrexate and gemcitabine in advanced or metastatic urothelial carcinoma,(41) the overall response in 20 patients was 45% (six complete and three partial responses). Median overall and progression-free survivals were 18 and 6.3 months, respectively. Neutropenia was the most common grade 3 and 4 toxicity (32% and 18%, respectively).

The addition of taxanes to cisplatin–ifosfamide,(42,43) cisplatin–methotrexate, carboplatin–methotrexate(44,45) and cisplatin–epirubicin(46) have been investigated as first- and secondline therapies, with a reported response range of 40–68% (see Table 3).

[[HPE09_table3_73]]

Dose-dense sequential schedules
Sequential dose-dense administration of the two-drug regimen doxorubicin and gemcitabine (AG) administered every 15 days with granulocyte-specific colony-stimulating factor (G-CSF), followed by ifosfamide, paclitaxel and cisplatin (ITP), has been evaluated in patients with transitional cell carcinoma. In a phase I study with 15 patients, AG was well tolerated at all dose levels, and no grade 3 or 4 myelosuppression was observed.(47) The toxicity associated with ITP was largely haematological, with grade 4 neutropenia in three patients, grade 3 thrombocytopenia in two patients and neutropenic fever in one patient. Nine of 14 assessable patients had a major response (three complete and six partial responses) after completion of AG-ITP.

In a phase II trial of 21 patients, the overall response rate reported was 86% (95% CI, 71–100) and there were nine patients (43%) with complete response.(48) The toxicity was substantial, with grade 3 or 4 neutropenia in 57% of patients and febrile neutropenia in 10% of patients.

The same approach is being evaluated in patients with impaired renal function using AG but followed by paclitaxel and carboplatin in a phase I/II study.(49) In 19 evaluable patients, grade 3 or 4 toxicity included 73% neutropenia (one patient with fever), 33% anaemia and 17% thrombocytopenia. Of the 10 patients evaluated for response, one complete and four partial responses were observed.

It is too soon to evaluate the beneficial impact of sequential chemotherapy treatment on the outcome of patients with transitional-cell carcinoma of the urothelium, and more mature results of this approach are awaited.

High-dose intensity MVAC
The efficacy and safety of escalated dosages of MVAC with and without recombinant human G-CSF  (rhG-CSF) in patients with advanced urothelial carcinoma have been evaluated in several studies, with disappointing results.(50–52) More favourable results were recently reported in a phase III study(53) in which 263 patients with metastatic urothelial carcinoma were randomised to receive high-dose MVAC and rhG-CSF (HD-MVAC, 134 patients) or classic MVAC (129 patients). Toxicity was similar in both arms, with more grade 3–4 mucositis in MVAC patients. The response rate for HD-MVAC patients was 81/111 (73%), with 27 (24%) complete responses versus 64/111 (58%) for MVAC, with 12 (11%) complete responses. Progression-free survival was significantly better for HD-MVAC (9.1 months vs 8.2 months, p=0.03). Although time to progression and median overall survival rates (14.5 months for HD-MVAC vs 14.1 for MVAC) were similar in both arms, an advantage in two-year survival was observed in the HD-MVAC arm. However, HD-MVAC therapy remains an investigational approach and further follow-up is needed to establish definitive conclusions regarding the benefit of high-dose MVAC in patients with metastatic urothelial carcinoma.

Future agents
Improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new prognostic indices that can direct the appropriate choice of treatment for advanced disease. In addition, it will allow identification of specific genetic lesions and biochemical pathways upon which future therapeutic approaches can be focused.

Many human tumours express high levels of growth factors and their receptors. Tyrosine kinase receptors (TKR), including many growth factor receptors such as those for epidermal growth factor (EGF), insulin, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), are overexpressed in different tumour types. The erbB receptor family, which comprises four receptors (HER1 or EGFR, HER2/neu, HER3 and HER4), is overexpressed in many tumours.

Epidermal growth factor receptors (EGFRs), normally found only on the basal layer of bladder epithelial cells, are also richly expressed on the superficial layers of malignant tissue.(54) The EGFR gene is overexpressed in high-grade invasive tumours and is associated with more aggressive clinical behaviour.(55–58) EGFR inhibitors, such as ZD1839 (Iressa), OSI-774, PKI116 and CP358.774, have been developed and tested, alone or in combination with chemotherapy, in many tumours, but they have not yet been fully evaluated in patients with urothelial cancer. Monoclonal antibody therapy directed against the EGFR may be another interesting strategy for the treatment of urothelial cancer. Of these compounds, IMC-C225, a human/murine chimeric monoclonal antibody against EGFR, is in advanced development. In a recent preclinical study,(59) the activity of IMC-C225 was evaluated, alone and in combination with paclitaxel, in mice with metastatic human bladder transitional cell cancer. The results of this study indicate that IMC-C225 has significant activity against bladder cancer, especially when combined with paclitaxel.

HER2/neu is also overexpressed in a number of advanced bladder tumours. In a recent study,(60) HER-2/neu overexpression was detected by immunohistochemistry in 22 of 60 patients with metastatic transitional-cell carcinoma of the bladder. In another study,(61) HER2/neu protein overexpression was observed in 48% of grade 3 bladder transitional cell carcinoma specimens As with other anti-growth factor receptor agents, preclinical and clinical data show marked enhancement of the antitumour activity of conventional chemotherapy when a monoclonal antibody against HER2/neu (trastuzumab) is added. Several strategies now in clinical trials combine chemotherapy with carboplatin, paclitaxel with/without gemcitabine and trastuzumab in HER2/neu-positive advanced bladder cancer patients. A trial with GW016, a dual specific HER1 and HER2 tyrosine kinase inhibitor, in patients with previously treated advanced urothelial cancer is ongoing.

Several other strategies have been designed that target other elements involved in the activation of the cascade of biochemical and physiological responses that are involved in the mitogenic signal transduction pathway of cancer cells. Preliminary results with oral SCH66336 (a farnesyl protein transferase inhibitor) have indicated limited activity in previously treated patients with advanced/metastatic urothelial tract tumours.(62) An ongoing study by the European Organisation for the Research and Treatment of Cancer’s Early Clinical Study Group of the combination of SCH663366 with gemcitabine as secondline treatment in patients with advanced/metastatic urothelial tract tumours will test the potential role of this new agent with chemotherapy.

Studies already underway should assist us in defining the role of these promising agents and strategies in the treatment of advanced bladder cancer.

Conclusion
The cisplatin–gemcitabine combination is a valuable alternative for the vast majority of patients with metastatic bladder cancer, with the benefit of fewer side-effects. Other new double and triple combinations have demonstrated significant activity in several phase II studies. However, there are presently no data demonstrating that any of these regimens improve patient survival and produce a more lasting response than MVAC or cisplatin plus gemcitabine.

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