The MRC Randomised-controlled Trial of Interferon-α, Interleukin-2 and 5-Fluorouracil vs Interferon-α Alone in Patients with Advanced Renal cell Carcinoma (RE04): Rationale and Progress

Abstract

Renal cell carcinoma is diagnosed in over 6000 people, and accounts for about 2% of malignant disease annually in the UK [1James K. CancerStats monograph.0-9546256-2-52004Google Scholar]. For early stage disease, surgery with curative intent is the treatment of choice, although 30–40% of patients diagnosed with disease, apparently limited to the kidney, subsequently will relapse systemically [2Rabinovitch R.A. Zelefsky M.J. Gaynor J.J. et al.Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy.J Clin Oncol. 1994; 12: 206-212Crossref PubMed Scopus (187) Google Scholar]. A further 25% of patients have metastatic disease at presentation.The prognosis for metastatic renal-cell carcinoma is poor, with a median survival of 6–8 months [3Selli C. Hinshaw W. Woodward B.H. Paulson D.F. Stratification of risk factors in renal cell carcinoma.Cancer. 1983; 52: 899-903Crossref PubMed Scopus (153) Google Scholar]. Response rates to combination chemotherapy [4Yagoda A. Bander W.H. Failure of cytotoxic chemotherapy 1983–1988 and the emerging role of monoclonal antibodies for renal cancer.Urol Int. 1989; 142: 1173Google Scholar] and hormonal agents [5Harris D.T. Hormonal therapy and chemotherapy of renal cell cancer.Semin Oncol. 1983; 10: 422-430PubMed Google Scholar] have been around 5–10%. It has been known for some time that the immune system has a role in the natural history of renal-cell carcinoma. For example, spontaneous regressions are rare but well documented [6Oliver R.T. Nethersell A.B. Bottomley J.M. Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma.Br J Urol. 1989; 63: 128-131Crossref PubMed Scopus (137) Google Scholar, 7Gleave M.E. Elhilali M. Fradet Y. et al.Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma.N Engl J Med. 1998; 338 (Canadian Urologic Oncology Group): 1265-1271Crossref PubMed Scopus (259) Google Scholar]. Immunotherapy with interferon (IFN) in metastatic disease produces response rates of around 10–20%, with median response durations of 3–16 months [8Horoszewicz J.Z. Murphy G.P. An assessment of the current use of human interferons in therapy of urological cancers.J Urol. 1989; 142: 1173-1180PubMed Google Scholar]. Retrospective data have also shown that patients with a performance status of 0 or 1 are more likely to gain benefit (i.e. increase in median survival) from immunotherapy than are patients with a performance status of 2 or worse [9Fossa S. Jones M. Johnson P. et al.Interferon-alpha and survival in renal cell cancer.Br J Urol. 1995; 76: 286-290Crossref PubMed Scopus (48) Google Scholar]. Randomised-controlled trials have shown a survival advantage to IFN compared with non-immunotherapy. A randomised trial comparing IFN-α plus vinblastine (VLB) with VLB alone reported a median survival of about 16 months for the 79 patients receiving IFN plus VLB, and 9 months for the 81 patients treated with VLB (P=0.0049). Overall response rates were 16.5% for patients treated with IFN plus VLB and 2.5% for patients treated with VLB alone (P=0.0025) [10Pyrhonen S. Salminen E. Ruutu M. et al.Prospective randomised trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.J Clin Oncol. 1999; 17: 2859-2867Crossref PubMed Google Scholar]. The randomised MRC trial RE01 reported a 12% 1-year absolute survival advantage (43% vs 31%) and a 2.5 month median increase in overall survival (from 6 months to 8.5 months, P=0.017) in 167 patients treated with IFN-α compared with 168 patients treated with medroxyprogesterone acetate [11MRC Renal Cancer CollaboratorsInterferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial.Lancet. 1999; 353: 14-17Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. A Cochrane review and meta-analysis has confirmed the value of IFN-α in metastatic renal-cell carcinoma [12Coppin C. Porzsolt F. Awa A. Kumpf J. Coldman A. Wilt T. Immunotherapy for advanced renal cell cancer.in: The Cochrane Library. John Wiley and Sons, Ltd, Chichester, UK2005Google Scholar].Other immunotherapeutic agents, such as interleukin-2 (IL-2), have also been investigated in the treatment of renal-cell carcinoma. Although higher response rates and median survival may be seen in patients treated with IL-2 compared with IFN-α [13Minasian L.M. Motzer R.J. Gluck L. et al.Interferon alpha-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.J Clin Oncol. 1993; 11: 1368-1375Crossref PubMed Scopus (261) Google Scholar, 14Rosenberg S.A. Yang J.C. Topalian S.L. et al.Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.JAMA. 1994; 27: 907-913Crossref Scopus (1053) Google Scholar, 15Fyfe G. Fisher R.I. Rosenberg S.A. et al.Results of treatment of 255 patients with metastatic renal cell carcinoma ho received high-dose recombinant interleukin-2 therapy.J Clin Oncol. 1995; 13: 688-696Crossref PubMed Scopus (1140) Google Scholar], a randomised study did not show any difference in efficacy between these two agents in the treatment of renal-cell carcinoma [16Negrier S. Escudier B. Lasser C. Douillard J. Recombinant human interleukin-2, recombinant human interferon-α2a, or both in metastatic renal cell carcinoma.N Engl J Med. 1998; 338: 1272-1278Crossref PubMed Scopus (888) Google Scholar]. The same trial also showed low response rates (2–5%) after crossing over from one treatment to the other after therapeutic failure of the first agent. However, although high-dose intravenous (HDIV) IL-2 causes substantial toxicity, in non-randomised trials about 9% of patients with metastatic renal-cell carcinoma will have a complete response to treatment, and in 70–80% of these patients, the complete responses are prolonged [17Rosenberg S.A. Yang J.C. White D.E. Steinberg S.M. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response.Ann Surg. 1998; 228: 307-319Crossref PubMed Scopus (448) Google Scholar]. A randomised trial comparing HDIV with low-dose intravenous (LDIV) and subcutaneous (SC) IL-2 in metastatic renal-cell carcinoma [18Yang J.C. Sherry R.M. Steinberg S.M. et al.Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer.J Clin Oncol. 2003; 21: 3127-3132Crossref PubMed Scopus (688) Google Scholar] reported a higher response rate with HDIV (21%) compared with LDIV (13%) and SC IL-2 (10%; P=0.048 for HDIV vs LDIV; P=0.03 for HDIV vs SC) but no overall survival difference. Response durability and survival in completely responding patients were superior with HDIV compared with LDIV IL-2 (P=0.04). A randomised trial comparing HDIV IL-2 with SC IL-2+IFN-α [19McDermott D.F. Regan M.M. Clark J.I. et al.Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma.J Clin Oncol. 2005; 23: 133-141Crossref PubMed Scopus (693) Google Scholar] similarly reported a response rate of 23.2% for HDIV IL-2 compared with 9.9% for IL-2/IFN-α (P=0.018). Median survival was again not statistically different between the groups (17.5 months in the HDIV IL-2 vs 13 months in the IL-2/IFN-α group [P=0.24]), but for patients with bone or liver metastases (P=0.001) or a primary tumour in situ (P=0.04), survival was superior with HDIV IL-2. These data show that high-dose IL-2 therapy has a role in selected fit patients with metastatic renal-cell carcinoma.The combination of IL-2 and IFN-α results in superior response rates and progression-free, but not overall survival [16Negrier S. Escudier B. Lasser C. Douillard J. Recombinant human interleukin-2, recombinant human interferon-α2a, or both in metastatic renal cell carcinoma.N Engl J Med. 1998; 338: 1272-1278Crossref PubMed Scopus (888) Google Scholar] in metastatic renal-cell carcinoma. As a consequence, the current standard therapy for patients with metastatic renal-cell carcinoma is single-agent IFN-α given until the development of either unacceptable toxicity or progressive disease. Some phase II studies have suggested that combining biological agents with 5-fluorouracil (5-FU) may improve activity. For example, 48% of 35 patients responded to an outpatient regimen of subcutaneous IFN-α, IL-2 and bolus 5-FU [20Atzpodien J. Kirchner H. Hanninen E.L. Deckert M. Interleukin-2 in combination with interferon-α and 5-fluorouracil for metastatic renal cell cancer.Eur J Cancer. 1993; 29A: S6-S8Abstract Full Text PDF PubMed Scopus (161) Google Scholar], whereas 31% of 55 patients responded to a similar regimen when 5-FU was given by protracted venous infusion [21Allen M.J. Vaughan M. Webb A. et al.Protracted venous infusion 5-fluorouracil in combination with subcutaneous interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer: a phase II study.Br J Cancer. 2000; 83: 980-985Crossref PubMed Scopus (32) Google Scholar]. The side-effects reported for this combination included anorexia, fatigue, fever, diarrhoea, neutropenia and hypertension, but systemic toxicity was manageable, and there was no 5-FU-related mucositis and no dose-limiting adverse effects of IL-2. Since 1993, a number of further studies have been reported using this regimen, with a response rate ranging between 14 and 39%.A randomised trial comparing this regimen with tamoxifen treatment [22Atzpodien J. Kirchner H. Franzke A. et al.Results of a randomised trial comparing sc interleukin-2, sc α-2a-interferon, and iv bolus 5-fluorouracil against oral tamoxifen in progressive metastatic renal cell carcinoma patients.Proc Am Soc Clin Oncol. 1997; 16: 1164Google Scholar] has shown a survival benefit for triple therapy. A further randomised trial has shown a survival benefit for triple therapy compared with IFN-α plus vinblastine [23Atzpodien J. Kirchner H. Jonas U. et al.Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).J Clin Oncol. 2004; 22: 1188-1194Crossref PubMed Scopus (206) Google Scholar], but a randomised comparison between triple therapy and IFN-α has not been carried out. This was the rationale for the MRC trial RE04, which began recruiting in April 2001. In this trial, patients with metastatic renal-cell carcinoma of performance status 0 or 1 are randomised to treatment with either IFN-α alone or with IFN-α, IL-2 and 5-FU. The primary end point of the trial is overall survival, and secondary end points are progression-free survival, toxicity, quality of life and health economics.In the IFN-α-only arm of the trial, IFN-α is given by subcutaneous injection three times a week on days 1, 3 and 5. For the first week, 5 MU is given on days 1 and 3, with the dose increased to 10 MU on day 5. All subsequent doses, if tolerated, are given at 10 MU. In the triple-therapy arm, IFN-α, IL-2 and 5-FU are given intermittently over an 8-week cycle (Fig. 1). Response to treatment is assessed during week 9, and treatment repeated, starting in week 11, if there are no signs of disease progression or unacceptable toxicity. The trial protocol does not recommend any more than two cycles of treatment with triple therapy due to an anticipated high level of toxicity.The trial has been designed to achieve a 90% probability of detecting a benefit of 4 months in median survival with a two-sided type I error of α=0.05. To this end, a total of about 670 patients (510 events) are required; recruitment of these patients was anticipated to take about 4 years and, as of 1 January 2005, 658 patients had been recruited.It is anticipated that the results of the RE04 trial will be reported in 2006 or 2007. What are the likely subsequent developments in the management of metastatic renal-cell cancer? The kinase inhibitors BAY43-9006 [24Ratain MJ, Flaherty KT, Stadler WM, et al. Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT) [abstract 4501]. Proceedings of the Annual Meeting of the American Society of Clinical Oncology, 2004.Google Scholar], CCI-779 [25Atkins M.B. Hidalgo M. Stadler W.M. et al.Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.J Clin Oncol. 2004; 22: 909-918Crossref PubMed Scopus (890) Google Scholar] and SU011248 [26Motzer RJ, Rini BI, Michaelson MD, et al. SU011248, a novel tyrosine kinase inhibitor, shows antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma: results of a phase 2 trial [abstract 4500]. Proceedings of the Annual Meeting of the American Society of Clinical Oncology, 2004.Google Scholar] have shown significant activity and little toxicity in the treatment of metastatic renal-cell cancer. Response rates of 30–40% and disease stabilisation over at least 12 weeks in a similar proportion of patients have been reported. Given this activity, the further evaluation of these drugs, both alone and in combination with existing approaches, is a priority in improving the poor outcomes associated with this disease. Renal cell carcinoma is diagnosed in over 6000 people, and accounts for about 2% of malignant disease annually in the UK [1James K. CancerStats monograph.0-9546256-2-52004Google Scholar]. For early stage disease, surgery with curative intent is the treatment of choice, although 30–40% of patients diagnosed with disease, apparently limited to the kidney, subsequently will relapse systemically [2Rabinovitch R.A. Zelefsky M.J. Gaynor J.J. et al.Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy.J Clin Oncol. 1994; 12: 206-212Crossref PubMed Scopus (187) Google Scholar]. A further 25% of patients have metastatic disease at presentation. The prognosis for metastatic renal-cell carcinoma is poor, with a median survival of 6–8 months [3Selli C. Hinshaw W. Woodward B.H. Paulson D.F. Stratification of risk factors in renal cell carcinoma.Cancer. 1983; 52: 899-903Crossref PubMed Scopus (153) Google Scholar]. Response rates to combination chemotherapy [4Yagoda A. Bander W.H. Failure of cytotoxic chemotherapy 1983–1988 and the emerging role of monoclonal antibodies for renal cancer.Urol Int. 1989; 142: 1173Google Scholar] and hormonal agents [5Harris D.T. Hormonal therapy and chemotherapy of renal cell cancer.Semin Oncol. 1983; 10: 422-430PubMed Google Scholar] have been around 5–10%. It has been known for some time that the immune system has a role in the natural history of renal-cell carcinoma. For example, spontaneous regressions are rare but well documented [6Oliver R.T. Nethersell A.B. Bottomley J.M. Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma.Br J Urol. 1989; 63: 128-131Crossref PubMed Scopus (137) Google Scholar, 7Gleave M.E. Elhilali M. Fradet Y. et al.Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma.N Engl J Med. 1998; 338 (Canadian Urologic Oncology Group): 1265-1271Crossref PubMed Scopus (259) Google Scholar]. Immunotherapy with interferon (IFN) in metastatic disease produces response rates of around 10–20%, with median response durations of 3–16 months [8Horoszewicz J.Z. Murphy G.P. An assessment of the current use of human interferons in therapy of urological cancers.J Urol. 1989; 142: 1173-1180PubMed Google Scholar]. Retrospective data have also shown that patients with a performance status of 0 or 1 are more likely to gain benefit (i.e. increase in median survival) from immunotherapy than are patients with a performance status of 2 or worse [9Fossa S. Jones M. Johnson P. et al.Interferon-alpha and survival in renal cell cancer.Br J Urol. 1995; 76: 286-290Crossref PubMed Scopus (48) Google Scholar]. Randomised-controlled trials have shown a survival advantage to IFN compared with non-immunotherapy. A randomised trial comparing IFN-α plus vinblastine (VLB) with VLB alone reported a median survival of about 16 months for the 79 patients receiving IFN plus VLB, and 9 months for the 81 patients treated with VLB (P=0.0049). Overall response rates were 16.5% for patients treated with IFN plus VLB and 2.5% for patients treated with VLB alone (P=0.0025) [10Pyrhonen S. Salminen E. Ruutu M. et al.Prospective randomised trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.J Clin Oncol. 1999; 17: 2859-2867Crossref PubMed Google Scholar]. The randomised MRC trial RE01 reported a 12% 1-year absolute survival advantage (43% vs 31%) and a 2.5 month median increase in overall survival (from 6 months to 8.5 months, P=0.017) in 167 patients treated with IFN-α compared with 168 patients treated with medroxyprogesterone acetate [11MRC Renal Cancer CollaboratorsInterferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial.Lancet. 1999; 353: 14-17Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. A Cochrane review and meta-analysis has confirmed the value of IFN-α in metastatic renal-cell carcinoma [12Coppin C. Porzsolt F. Awa A. Kumpf J. Coldman A. Wilt T. Immunotherapy for advanced renal cell cancer.in: The Cochrane Library. John Wiley and Sons, Ltd, Chichester, UK2005Google Scholar]. Other immunotherapeutic agents, such as interleukin-2 (IL-2), have also been investigated in the treatment of renal-cell carcinoma. Although higher response rates and median survival may be seen in patients treated with IL-2 compared with IFN-α [13Minasian L.M. Motzer R.J. Gluck L. et al.Interferon alpha-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.J Clin Oncol. 1993; 11: 1368-1375Crossref PubMed Scopus (261) Google Scholar, 14Rosenberg S.A. Yang J.C. Topalian S.L. et al.Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.JAMA. 1994; 27: 907-913Crossref Scopus (1053) Google Scholar, 15Fyfe G. Fisher R.I. Rosenberg S.A. et al.Results of treatment of 255 patients with metastatic renal cell carcinoma ho received high-dose recombinant interleukin-2 therapy.J Clin Oncol. 1995; 13: 688-696Crossref PubMed Scopus (1140) Google Scholar], a randomised study did not show any difference in efficacy between these two agents in the treatment of renal-cell carcinoma [16Negrier S. Escudier B. Lasser C. Douillard J. Recombinant human interleukin-2, recombinant human interferon-α2a, or both in metastatic renal cell carcinoma.N Engl J Med. 1998; 338: 1272-1278Crossref PubMed Scopus (888) Google Scholar]. The same trial also showed low response rates (2–5%) after crossing over from one treatment to the other after therapeutic failure of the first agent. However, although high-dose intravenous (HDIV) IL-2 causes substantial toxicity, in non-randomised trials about 9% of patients with metastatic renal-cell carcinoma will have a complete response to treatment, and in 70–80% of these patients, the complete responses are prolonged [17Rosenberg S.A. Yang J.C. White D.E. Steinberg S.M. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response.Ann Surg. 1998; 228: 307-319Crossref PubMed Scopus (448) Google Scholar]. A randomised trial comparing HDIV with low-dose intravenous (LDIV) and subcutaneous (SC) IL-2 in metastatic renal-cell carcinoma [18Yang J.C. Sherry R.M. Steinberg S.M. et al.Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer.J Clin Oncol. 2003; 21: 3127-3132Crossref PubMed Scopus (688) Google Scholar] reported a higher response rate with HDIV (21%) compared with LDIV (13%) and SC IL-2 (10%; P=0.048 for HDIV vs LDIV; P=0.03 for HDIV vs SC) but no overall survival difference. Response durability and survival in completely responding patients were superior with HDIV compared with LDIV IL-2 (P=0.04). A randomised trial comparing HDIV IL-2 with SC IL-2+IFN-α [19McDermott D.F. Regan M.M. Clark J.I. et al.Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma.J Clin Oncol. 2005; 23: 133-141Crossref PubMed Scopus (693) Google Scholar] similarly reported a response rate of 23.2% for HDIV IL-2 compared with 9.9% for IL-2/IFN-α (P=0.018). Median survival was again not statistically different between the groups (17.5 months in the HDIV IL-2 vs 13 months in the IL-2/IFN-α group [P=0.24]), but for patients with bone or liver metastases (P=0.001) or a primary tumour in situ (P=0.04), survival was superior with HDIV IL-2. These data show that high-dose IL-2 therapy has a role in selected fit patients with metastatic renal-cell carcinoma. The combination of IL-2 and IFN-α results in superior response rates and progression-free, but not overall survival [16Negrier S. Escudier B. Lasser C. Douillard J. Recombinant human interleukin-2, recombinant human interferon-α2a, or both in metastatic renal cell carcinoma.N Engl J Med. 1998; 338: 1272-1278Crossref PubMed Scopus (888) Google Scholar] in metastatic renal-cell carcinoma. As a consequence, the current standard therapy for patients with metastatic renal-cell carcinoma is single-agent IFN-α given until the development of either unacceptable toxicity or progressive disease. Some phase II studies have suggested that combining biological agents with 5-fluorouracil (5-FU) may improve activity. For example, 48% of 35 patients responded to an outpatient regimen of subcutaneous IFN-α, IL-2 and bolus 5-FU [20Atzpodien J. Kirchner H. Hanninen E.L. Deckert M. Interleukin-2 in combination with interferon-α and 5-fluorouracil for metastatic renal cell cancer.Eur J Cancer. 1993; 29A: S6-S8Abstract Full Text PDF PubMed Scopus (161) Google Scholar], whereas 31% of 55 patients responded to a similar regimen when 5-FU was given by protracted venous infusion [21Allen M.J. Vaughan M. Webb A. et al.Protracted venous infusion 5-fluorouracil in combination with subcutaneous interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer: a phase II study.Br J Cancer. 2000; 83: 980-985Crossref PubMed Scopus (32) Google Scholar]. The side-effects reported for this combination included anorexia, fatigue, fever, diarrhoea, neutropenia and hypertension, but systemic toxicity was manageable, and there was no 5-FU-related mucositis and no dose-limiting adverse effects of IL-2. Since 1993, a number of further studies have been reported using this regimen, with a response rate ranging between 14 and 39%. A randomised trial comparing this regimen with tamoxifen treatment [22Atzpodien J. Kirchner H. Franzke A. et al.Results of a randomised trial comparing sc interleukin-2, sc α-2a-interferon, and iv bolus 5-fluorouracil against oral tamoxifen in progressive metastatic renal cell carcinoma patients.Proc Am Soc Clin Oncol. 1997; 16: 1164Google Scholar] has shown a survival benefit for triple therapy. A further randomised trial has shown a survival benefit for triple therapy compared with IFN-α plus vinblastine [23Atzpodien J. Kirchner H. Jonas U. et al.Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).J Clin Oncol. 2004; 22: 1188-1194Crossref PubMed Scopus (206) Google Scholar], but a randomised comparison between triple therapy and IFN-α has not been carried out. This was the rationale for the MRC trial RE04, which began recruiting in April 2001. In this trial, patients with metastatic renal-cell carcinoma of performance status 0 or 1 are randomised to treatment with either IFN-α alone or with IFN-α, IL-2 and 5-FU. The primary end point of the trial is overall survival, and secondary end points are progression-free survival, toxicity, quality of life and health economics. In the IFN-α-only arm of the trial, IFN-α is given by subcutaneous injection three times a week on days 1, 3 and 5. For the first week, 5 MU is given on days 1 and 3, with the dose increased to 10 MU on day 5. All subsequent doses, if tolerated, are given at 10 MU. In the triple-therapy arm, IFN-α, IL-2 and 5-FU are given intermittently over an 8-week cycle (Fig. 1). Response to treatment is assessed during week 9, and treatment repeated, starting in week 11, if there are no signs of disease progression or unacceptable toxicity. The trial protocol does not recommend any more than two cycles of treatment with triple therapy due to an anticipated high level of toxicity. The trial has been designed to achieve a 90% probability of detecting a benefit of 4 months in median survival with a two-sided type I error of α=0.05. To this end, a total of about 670 patients (510 events) are required; recruitment of these patients was anticipated to take about 4 years and, as of 1 January 2005, 658 patients had been recruited. It is anticipated that the results of the RE04 trial will be reported in 2006 or 2007. What are the likely subsequent developments in the management of metastatic renal-cell cancer? The kinase inhibitors BAY43-9006 [24Ratain MJ, Flaherty KT, Stadler WM, et al. Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT) [abstract 4501]. Proceedings of the Annual Meeting of the American Society of Clinical Oncology, 2004.Google Scholar], CCI-779 [25Atkins M.B. Hidalgo M. Stadler W.M. et al.Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.J Clin Oncol. 2004; 22: 909-918Crossref PubMed Scopus (890) Google Scholar] and SU011248 [26Motzer RJ, Rini BI, Michaelson MD, et al. SU011248, a novel tyrosine kinase inhibitor, shows antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma: results of a phase 2 trial [abstract 4500]. Proceedings of the Annual Meeting of the American Society of Clinical Oncology, 2004.Google Scholar] have shown significant activity and little toxicity in the treatment of metastatic renal-cell cancer. Response rates of 30–40% and disease stabilisation over at least 12 weeks in a similar proportion of patients have been reported. Given this activity, the further evaluation of these drugs, both alone and in combination with existing approaches, is a priority in improving the poor outcomes associated with this disease.