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Several trials currently under way examining systemic agents in the adjuvant setting are detailed in Table 4. The European Organisation for Research and Treatment of Cancer (EORTC) has coordinated a phase III adjuvant trial to further evaluate IL-2, IFN-α, and 5-FU for patients with high risk of relapse after surgical treatment for RCC (EORTC protocol 30955). In this study, 550 patients have been randomized to either treatment or observation after surgery. Now closed to recruitment, analysis will determine DFS and OS in each arm (53).

RCC is highly vascular, with disordered angiogenesis. Due to its antiangiogenic effects, thalidomide has been studied in mRCC. A phase III trial for patients with stage IV disease randomized patients to receive IFN-α with or without thalidomide. This study demonstrated an improvement in PFS using thalidomide (66). Based on these findings, a phase III adjuvant study was initiated at the MD Anderson Cancer Center for patients with high-risk RCC, comparing thalidomide to controls after nephrectomy (67). In a recent interim analysis with 46 patients randomized, there was no difference between groups with regard to DFS, although the treatment group demonstrated significantly

128 Adjuvant and Neoadjuvant Therapy for Renal Cell Carcinoma

Table 4.

Current clinical trials of adjuvant and neoadjuvant treatment for renal cell carcinoma (RCC)

Trial

Setting

Study group

Placebo

Treat- ment duration

Inclusion criteria

Adjuvant Rencarex Immu-

notherapy Phase III Trial to Study Efficacy in Non- metastatic Renal Cell Carcinoma (ARISER)

Adjuvant

G250 mAb

Yes

54 wk

Clear cell RCC No evidence of M+ disease Meets stage criteria: Stage T3b/c N0/X or T4 N0/X Any T stage with N+ disease T1b N0/X or T2 N0/X with micro- scopic vascular invasion and grade

≥

III or T3a N0/X and

grade

≥

III

No evidence of residual disease

Adjuvant Sorafenib Sunitinib

for Unfavorable Renal Cell Carcinoma (ASSURE)

Adjuvant

Sunitinib, sorafenib

Yes

1 yr

Clear cell and non–clear cell tumors Stage T2-4 and stage T1b with high grade (3) Nx, N0, N1, or N2 if all positive nodes removed No evidence of M+ disease No evidence of residual or recurrent disease

Sorafenib for Patients with

Resected Primary Renal Cell Carcinoma (SORCE)

Adjuvant

Sorafenib

Yes

3 yr

Clear cell and non–clear cell tumors Intermediate- or high-risk disease RCC No evidence of residual macroscopic disease after resection

Adjuvant and Neoadjuvant Therapy for Renal Cell Carcinoma 129

Sunitinib Trial in Adjuvant

Renal Cancer (STAR)

Adjuvant

Sunitinib

Yes

High-risk RCC per University of Cal- ifornia, Los Angeles Integrated Staging System criteria No prior systemic therapy

Phase II Single Arm Prospec-

tive Study of Neoadjuvant Sutent (University Health Network, Toronto)

Neoadjuvant

Sunitinib

No

12 wk

Clear cell RCC Clinical stage T1a or T1b No evidence of nodal or metastatic disease No prior therapy of any kind for RCC

Phase II Prospective Study of

Neoadjuvant Sorafenib (University of North Carolina)

Neoadjuvant

Sorafenib

No

8 wk

Radiographic RCC Stage II or higher May have N+ or M+ disease Not yet undergone nephrectomy

N = node; M = metastasis; T = tumor.

130 Adjuvant and Neoadjuvant Therapy for Renal Cell Carcinoma

better CSS compared to observation (56). Additionally, patients in the treatment arm of this study have experienced significant toxicity requiring dose reductions and early ter- mination of therapy (56). This study closed due to poor accrual.

One novel approach toward treatment of RCC focuses on heat shock proteins (HSPs), ubiquitous molecules that function to protect living cells from injury and stress. HSPs can inhibit apoptosis in tumor cells and can act as foreign antigens to elicit an immune response and subsequent cell destruction (53,68). Vaccines have been developed that consist of HSP-peptide complexes isolated from a patient’s tumor. After vaccination, antigenic tumor peptides induce a much more potent antitumor immune response than the tumor itself (53). The largest phase III adjuvant clinical trial has been completed evaluating the vaccine HSPPC-96 (Vitespen®, Antigenics, Inc., New York, NY) as adju- vant therapy for high-risk, non-mRCC. In this study, 818 patients enrolled at 145 inter- national clinical sites have been randomized to surgical extirpation, followed by treatment with HSPPC-96 or surgery alone. Although final results of this trial are pend- ing, interim analysis failed to show a significant difference between the observation and treatment groups with regard to DFS or OS (56). However, early analysis does demon- strate an apparent benefit in a subset of patients with better prognostic factors—a group correlating with “intermediate risk” patients (69).

Another currently ongoing clinical trial involves the use of a monoclonal antibody against G250, a transmembrane protein associated with RCC, which is identical to CA IX (70). cG250 (WX-G250, Rencarex®, Wilex Pharmaceuticals, Munich, Germany) is a monoclonal immunoglobulin G1 antibody administered intravenously that binds to CA IX on clear cell RCC and may recruit effector cells or activate complement to result in cell death (53). In 2004, an international randomized, phase III trial, ARISER (Adjuvant Rencarex Immunotherapy trial to Study Efficacy in nonmRCC), opened to accrual to evaluate cG250 versus placebo after nephrectomy for 612 patients with high-risk non- metastatic clear cell RCC (53,67). This trial is currently accruing with a goal of 1,332 patients.

Sorafenib (Nexavar®, Bayer HealthCare Pharmaceuticals, Wayne, NJ) is an orally available, small-molecule inhibitor of RAF kinase that competitively binds to the ATP binding site of some kinases in the RAF family relevant to RCC. In this way, sorafenib inhibits the signaling pathway mediating tumor cell proliferation and angiogenesis (67). Data support an inhibitory effect of sorafenib on angiogenesis in human studies (71). Sev- eral clinical trials using sorafenib have demonstrated efficacy in mRCC, including studies for cytokine-refractory disease and combination studies with cytokines (67). Sunitinib (Sutent®, Pfizer Pharmaceuticals, New York, NY) is an oral TKI, which has been shown to be superior to IFN in the management of mRCC (72). Both agents have recently received U.S. Food and Drug Administration approval and are marketed for the management of patients with mRCC. On this basis, a phase III trial is currently under way, randomizing patients to receive either sorafenib, sunitinib, or a placebo after definitive surgery. The study, named A.S.S.U.R.E. (adjuvant sorafenib sunitinib for unfavorable renal cell carci- noma) is sponsored by ECOG. Eligible patients will have locally advanced nonmetastatic

Adjuvant and Neoadjuvant Therapy for Renal Cell Carcinoma 131 disease with or without lymph node involvement, with PFS as the primary end point. Patients may be registered for this trial based on unfavorable pathologic findings after sur- gical resection or preoperatively based on high-risk radiographic findings, thus allowing for tissue correlative studies. Secondary end points include OS and toxicity in the adjuvant setting. Another phase III trial examining the use of sorafenib in the adjuvant setting, spon- sored by the Medical Research Council, is currently under development. SORCE (sor- afenib for patients with resected renal cell carcinoma) is a randomized controlled study comparing sorafenib administered for 3 years, or 1 year with placebo, in patients with resected primary RCC at high or intermediate risk of relapse. This study aims to recruit approximately 331 patients per year for each of 5 years, with an additional 3 years of fol- low-up. The primary end point is metastasis-free survival, and secondary measures include CSS, OS, cost effectiveness, and toxicity. This study is not yet open. The ongoing clinical trials of adjuvant therapy for high-risk RCC patients are summarized in Table 4. The STAR (sunitinib trial in adjuvant renal cancer) trial is a randomized, double-blind, phase III study comparing adjuvant sunitinib versus placebo for patients classified as high risk, according to the UISS, after surgical resection. The primary end point in this study is DFS, and secondary end points include RFS as well as OS.