Renal cell carcinoma: review of novel single-agent therapeutics and combination regimens

R. J. Amato*

The Methodist Hospital, Baylor College of Medicine, Scott Department of Urology, Section of Genitourinary Oncology, Houston, TX, USA

* Correspondence to: Dr R. J. Amato, D.O. 6560 Fannin Street, Suite 2100, Houston, TX 77030, USA. Tel: +1-713-798-8720; Fax: +1-713-798-5553; Email: ramato{at}bcm.tmc.edu


    Abstract
 Top
 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
A search of the Medline database and ASCO 2003 conference proceedings was conducted to identify clinical trials currently underway using single-agent therapy for renal cell carcinoma (RCC). Combination trials were identified using the ASCO 2003 conference proceedings. Fourteen single-agent therapies employing different mechanisms of action were identified in the published literature: imatinib mesylate (Gleevec®); bevacizumab (Avastin®); thalidomide (Thalomid®); gefitinib (ZD1839) (Iressa®); cetuximab (IMC-C225) (ErbituxTM); bortezomib (PS-341) (Velcade®); HSPPC-96 (Oncophage®); BAY 59–8862; ABT-510; G250; CCI-779; SU5416; PTK/ZK; and ABX-EGF. Six distinct fields of clinical research have emerged: monoclonal antibodies, small molecules, vaccines, second-generation taxanes, nonapeptides and immunomodulators. Five combination regimens, primarily biological response modifiers (interleukin-2 or interferon-{alpha}), chemotherapy- or thalidomide-based, were identified. All therapies demonstrated acceptable toxicity profiles. Clinical benefit was assessed based on each study's reported criteria: antitumor response (regression or stability) ranged from 5% to 71%. In the past several years, significant advances in the underlying biological mechanisms of RCC, particularly the role of tumor angiogenesis, have permitted the design of molecularly targeted therapeutics. Based on preliminary and limited studies, combination therapies offer the greatest clinical benefit in the management of this malignancy, although additional basic research is still warranted.

Key words: bevacizumab, imatinib mesylate, renal cell carcinoma, thalidomide


    Introduction
 Top
 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
Despite significant progress in understanding the biology of renal cell carcinoma (RCC), it is estimated that over 31 000 people in the United States will be diagnosed and approximately 12 000 will die from this disease in 2003. RCC presently ranks 10th as the leading cause of cancer death and constitutes 3% of all solid neoplasms. For reasons not entirely well understood, 62% of the estimated new cases will occur in men and only 38% in women [1Go]. However, the incidence of RCC is rising in women: from 1975 to 1995, it rose by 3.1% and 4.3% in white and black women, respectively, whereas in white and black men it rose by 2.3% and 3.9%, respectively [2Go].

The majority of renal tumor malignancies are classified as RCC and originate from the proximal tubal epithelium [3Go]. Alternatively known as clear-cell cancer or renal adenocarcinoma, RCC is characterized by a distinct clear or granular cell appearance visible by light microscopy, and the majority are associated with the inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene [3Go, 4Go]. When detected at an early stage, RCC can often be successfully treated by radical nephrectomy with nephron-sparing surgery, if feasible. However, as many as 20% to 30% of patients develop metastatic disease following this procedure [5Go]. Approximately one-third to one-half of RCC patients present with locally advanced or stage IV disease, having missed characteristic, though non-specific symptoms such as fatigue, weight loss, malaise, fever and/or night sweats [5Go, 6Go]. The 5-year survival rate for these patients is <2% [5Go].

Treatment for RCC is limited. In contrast to many other malignancies, RCC is generally resistant to both chemotherapy and hormone therapy [7Go]. With the advent of non-specific biological response modifiers in the 1980s and their subsequent approval, single-agent interleukin-2 (IL-2) and interferon-{alpha} (IFN-{alpha}) achieved response rates (complete response + partial response) of 10% to 20% [3Go]. Though modest, these responses were clearly superior to chemotherapy and represented a significant advance. Long-term survival, however, is achieved in few patients [7Go]. To improve upon these findings and exploit the impressive synergy observed in in vitro models, combination IL-2 plus IFN-{alpha} trials were subsequently conducted. For reasons not clearly understood, response rates rarely exceeded 20% to 30%: an early indication that cancer cell lines could not always predict clinical outcome [3Go].

Since the approval of IL-2 for the treatment of metastatic RCC, no other drugs have demonstrated significant enough antitumor activity to warrant Food and Drug Administration (FDA) approval. Complicating the issue is that response rates are often difficult to discern from the natural history of the disease, and therefore must be carefully scrutinized [8Go]. In the past several years, however, promising new agents have proven successful in not only preclinical, but also early phase I and II clinical testing. The development of many of these new agents has been driven by the extraordinary progress in understanding many of the biological mechanisms that contribute to oncogenesis, such as immune regulation dysfunction, inappropriate activation of signal transduction pathways, and tumor angiogenesis.

This review highlights the mechanism of action and clinical trial results of a select number of novel single agents and combination regimens used in the treatment of metastatic RCC (Tables 1 and 2). Given the burgeoning research in this field, not every experimental therapy is covered.


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Table 1. Single-agent trials for metastatic renal cell carcinoma

 

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Table 2. Combination therapy trials for metastatic renal cell carcinoma

 

    Single-agent therapy
 Top
 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
Monoclonal antibodies
Mechanism of action
Since the late 1990s, several monoclonal antibodies have been approved for hematologic malignancies and breast cancer and are now an integral part of disease management [9Go–11Go]. Four high-affinity monoclonal antibodies have recently been tested in the RCC setting. Two of these antibodies, cetuximab (ErbituxTM, ImClone, New York, NY, USA) and ABX-EGF, (Fremont, CA, USA), target the same molecule, the epidermal growth factor receptor (EGFR). The rationale for targeting this receptor was recently reviewed in this journal. In summary, EGFR is reported to be as high as 85% overexpressed in RCC and inappropriately activated in many tumor types, and both factors correlate with aggressive disease [12Go, 13Go]. Another antibody, bevacizumab, targets vascular endothelial growth factor (VEGF), a key regulator in endothelial cell proliferation and hence angiogenesis [14Go]. In metastatic colorectal cancer, bevacizumab (AvastinTM; Genentech, South San Francisco, CA, USA) has been shown statistically to improve overall survival by inhibiting tumor angiogenesis [15Go]. The fourth monoclonal antibody, G250, recognizes a tumor-associated antigen expressed on the cell surface of RCC but not detected on normal kidney cells. In preclinical studies, G250 was shown to be upregulated by IFN-{alpha} and IFN-{gamma}, and the chimeric monoclonal antibody (cG250) directed against this target antigen induced potent antibody-dependent cellular cytotoxicity (ADCC) [16Go]. The possibility of these findings of immune effector activity translating in a clinical setting was recently reported.

Clinical results
In recent studies, ABX-EGF, a fully human anti-EGFR monoclonal, and cetuximab, a chimeric (human : murine) anti-EGFR monoclonal, reported dissimilar findings. In a phase II trial evaluating the safety and efficacy of ABX-EGF, 20 patients were treated at 1.0 mg/kg, 23 at 1.5 mg/kg and 15 at 2.0 mg/kg. Grade 2/3 adverse events reported were skin rash, pruritus, dyspnea, fatigue, diarrhea, abdominal pain, and nausea and vomiting. Two of 31 patients evaluated who failed or were unable to receive IL-2/IFN-{alpha} achieved objective responses and 58% had minor responses or stable disease [17Go]. In contrast to ABX-EGF, in 55 patients treated with cetuximab administered intravenously (i.v.) at a loading dose of 400 or 500 mg/m2 followed by weekly maintenance doses at 250 mg/m2, no patients achieved either a complete or partial response [18Go]. Given these disappointing results and the lack of prolongation of time to progression compared with historical controls (IFN-{alpha}), the investigators concluded that further study of cetuximab was not recommended [18Go]. Trials with ABX-EGF are ongoing in RCC and in colorectal cancer [19Go].

Small trials with cG250, a chimeric monoclonal antibody directed against a tumor-specific, heat-sensitive surface antigen, are attempting to establish appropriate therapeutic targeting. In a small dose-escalation study, the cG250 antibody was labeled with trace 131I and unlabeled cG250 on weeks 1 and 5; radioimmunotherapy trials were conducted. Twelve patients had cG250 gamma camera imaging when dosed at 5, 10, 25 and 50 mg/m2. One patient experienced a grade 3 infusion-related sacral pain at the tumor site, and one patient developed a human antichimeric antibody response that warranted discontinuation of treatment. At the completion of the first 6-week cycle, one patient had a complete response and eight patients achieved stable disease [20Go]. Further studies with cG250 are ongoing.

In an effort to inhibit tumor angiogenesis by neutralizing circulating VEGF, a randomized phase II trial with a humanized anti-VEGF antibody, bevacizumab, was recently conducted. The rationale for targeting VEGF is based on recent progress in identifying a mutated tumor suppressor gene (VHL) in hereditary RCC, resulting in overproduction of VEGF through hypoxia-inducible factor {alpha}, and other reports indicating that circulating VEGF levels may be used as prognostic factors in this disease. In this trial, 116 patients were first stratified based on whether they had received IL-2 therapy and then assigned to either placebo, low-dose antibody (3 mg/kg) or high-dose antibody (10 mg/kg). Treatment or vehicle-only placebo was administered i.v. every 2 weeks. Bevacizumab was well tolerated: there were no grade 4 toxicities. Hypertension, asymptomatic proteinuria and chest pain grade 3 events were reported in eight, five and two patients, respectively. In comparison with placebo, time to progression in patients receiving 10 mg of bevacizumab was prolonged by a factor of 2.55 (P <0.001) and in the low-dose group prolonged by a factor of 1.26 (P=0.053). Probability of being progression-free at 4 months was also reported: in the high-dose cohort (64%), in the low-dose (39%) and in the placebo (20%). Overall, no significant differences in survival between the three groups were observed. One finding was that the plasma level of VEGF rose, the significance of which is not clear. One hypothesis suggested by the authors was diminished clearance of antibody-bound inactive VEGF [14Go]. Nevertheless, these impressive response rates, coupled with a favorable toxicity profile, are very encouraging and clearly support its therapeutic potential.

Small molecules
Mechanism of action
Targeted small molecules, exemplified by the designer tyrosine kinase inhibitors imatinib mesylate, ZD1839, PTK/ZK and SU5416, represent the emergence of a new paradigm for the treatment of malignancy: the identification of a specific molecular defect and development of a potent inhibitor of that defect. In the case of the remarkable discovery of the aberrant genetic defect, Bcr-Abl, found in patients with chronic myelogenous leukemia, and the dramatic success of imatinib mesylate (GleevecTM, Novartis, East Hanover, NJ, USA), durable remissions with minimal toxicity have been achieved. The mechanism of action of this agent is to turn off the constitutively active kinase activity of Bcr-Abl by binding to the nucleotide-binding site, thereby blocking access to adenosine triphosphate (ATP) and inhibiting signaling pathways associated with proliferation. Imatinib mesylate has also been shown to inhibit selectively two other tyrosine kinases: c-kit (stem cell factor) and platelet-derived growth factor (PDGF) receptor [21Go]. This latter finding has prompted the rationale of treating patients with RCC with this compound to be questioned, because high expression of the PDGF-{alpha}{alpha} receptor has been identified in RCC and is associated with adverse outcomes [22Go]. Overexpression of c-kit in a specific subtype of RCC, chromophobe RCC, was reported using high-density oligonucleotide arrays [23Go].

Another tyrosine kinase inhibitor, ZD1839 (IressaTM; AstraZeneca, Wilmington, DE, USA), was recently approved for locally advanced or metastatic non-small-cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel. ZD1839 targets the ATP binding site of the cytoplasmic domain of the EGFR, thereby attenuating activation of downstream signaling pathways in EGFR-expressing cells [13Go].

Two tyrosine kinase inhibitors of the VEGF receptor (VEGFR), PTK/ZK and SU5416, both target this key regulator of angiogenesis by blocking its autophosphorylation, thereby blocking constitutive signaling leading to proliferation and ultimately neovascularization. Whereas PTK/ZK inhibits all three isoforms of VEGFR, VEGFR-1, VEGFR-2, and VEGFR-3, SU5416 inhibits VEGFR-1 and VEGFR-2 [24Go, 25Go].

Clinical results
Results from a recent phase II trial in 12 patients treated with a once daily oral dose of 400 mg imatinib mesylate yielded modest results: no major responses were observed, median time to progression was 3 months, and four patients remain on treatment and are progression-free with stable disease at 1, 3 and 4 months. Adverse events were tolerable and included grade 3 nausea and vomiting in three patients (21%) and grade 3 diarrhea and gastrointestinal (GI) bleed in one (7%) patient. Notably, only one tumor (8%) expressed c-kit by immunohistochemistry [26Go]. Given the minimal toxicity of this regimen, combination trials with imatinib mesylate with a more tolerable IFN-{alpha} (pegylated) are being explored.

In a phase II study in 21 patients treated with 500 mg ZD1839 once daily as a 28-day cycle, stable disease was reported in eight patients (38%), all of whom had previously been progressing. Median progression-free survival was 2.7 months and median overall survival was 8.3 months: the difference in overall survival between stable disease and progressive disease was 16 + and 6.1 months, respectively (P=0.0007). Grade 3 toxicity included diarrhea. An unexpected high frequency of central nervous system (CNS) progression was observed in 38%. No correlation between EGFR expression and stable versus progressive disease was observed [27Go].

The oral VEGFR inhibitor PTK/ZK was assessed for dose-limiting toxicity, maximum tolerated dose (MTD), tumor response and overall survival in 45 patients in an open label phase I dose-escalation trial. At the time of this report, five dose levels had been completed and the MTD had not been reached. Forty-one patients had received >1000 mg/day. Eight patients discontinued due to adverse events. Of the remaining patients, two patients at different dose levels experienced one grade 3 adverse event each: headache (1 000 mg/day) and hypertension (1500 mg/day). Of 37 patients evaluated, seven (19%) achieved a measurable response (one partial, six minor) with median time to progression 5.5 months. Seventeen patients (46%) achieved stable disease. One-year overall survival was 63.7% [24Go]. Phase II trials are being explored.

Twenty-nine patients were enrolled in a phase II study of SU5416, a VEGFR inhibitor. In contrast to the other small molecules that are oral, SU5416 is delivered i.v. twice weekly. One cycle of treatment is completed over a period of 4 weeks; all but two patients received more than one cycle. Of 24 patients evaluated, confirmed stable disease was observed in five patients (20.8%) and not confirmed in three (12.5%) because of discontinuation in one patient and adverse events in two others. Median progression-free survival was 59 days and median overall survival was 276 days. Serious adverse events in all patients included renal insufficiency with metabolic acidosis (one), fatal myocardial infarction (one), jugular vein thrombosis (one), deep venous thrombosis (DVT) in the left iliacal vein (one), intestinal obstruction (one), renal insufficiency and urinary tract infection (one), diarrhea with metabolic acidosis (one), and diarrhea with dehydration and renal insufficiency (one). The only serious adverse event attributed to SU5416 was a thrombolic event. The investigators of this trial attributed its low efficacy to three possible factors: (i) low bioavalibility of SU5416 in tumors; (ii) other proangiogenic stimulators such as basic fibroblast growth factor (bFGF); and (iii) possible receptor heterodimerization (VEGFR with other growth factor receptors). In summary, although SU5416 was well tolerated, its lack of efficacy suggests that inactivation of the VEGF receptor alone may be insufficient to inhibit tumor growth [25Go].

Proteasome inhibitor
Mechanism of action
Bortezomib (PS-341) (VelcadeTM; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA) is a small molecular weight reversible inhibitor of the intracellular 26S proteasome, a large protein (enzyme) complex. Responsible for degrading specific ubiquitin-tagged proteins, in vitro models have demonstrated that through the selective inhibition of this pathway, proteins destined for degradation are maintained, thus disrupting signaling pathways and ultimately leading to cell death [28Go]. Identification of proteins relevant to uncontrolled proliferation and implicated in chemoresistance include nuclear factor (NF) -{kappa}B and its activation [29Go]. The FDA recently approved PS-341 for multiple myeloma [28Go]. In addition to RCC, PS-341 is undergoing testing in lymphoma, prostate cancer and lung cancer [29Go].

Clinical results
Two independent phase II trials of PS-341 were presented at ASCO 2003 [30Go, 31Go]. In a study reported by Drucker and colleagues, PS-341 was administered i.v. twice weekly. Patients received the drug 2 out of every 3 weeks. Based on toxicity in the first 25 patients receiving a starting dose of 1.5 mg/m2, the dose was decreased to 1.3 mg/m2. Of 32 patients evaluated, three patients achieved a partial response (9%) and the remaining patients had either stable or progressive disease. Reported time to progression was 1.4 months. All responders had progressed with cytokine therapy. Serious adverse events included grade 2/3 fatigue (53%), constipation (53%), neuropathy (28%) and thrombocytopenia (28%). There were no grade 4 toxicities. The investigators of this study concluded that additional research of PS-341 in combination with other agents should be explored because of responses achieved in refractory patients [30Go].

A separate phase II study reported by Davis and colleagues used a starting dose of 1.5 mg/m2 PS-341 administered i.v. twice weekly for 2 out of every 3 weeks. In the absence of grade 3/4 toxicity, the starting dose was escalated to 1.7 mg/m2. Proteasome inhibition was measured by core biopsy. Grade 3 toxicities included thrombocytopenia (four), hemorrhage (one), anemia (two), febrile neutropenia (one), gastrointestinal (four), pain (four), fatigue (two), neuropathy (two) and electrolyte disturbances (three). Grade 4 toxicities included arthralgia (one), diarrhea (one) and vomiting (one). One objective response was observed. Unfortunately, despite attempts to measure inhibition of proteasome activity, there were too few sample numbers and timing was deemed inadequate. In contrast to the trial reported by Drucker and colleagues that recommended additional study of PS-341, the investigators of this study recommended against further study given its apparent lack of clinical activity [31Go].


    Chemotherapy
 Top
 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
Second-generation taxanes
Mechanism of action
BAY 59-8862 is a second-generation taxane (paclitaxel analogue) currently under investigation. BAY 59-8862 is 20–30 times more potent than paclitaxel or docetaxel in human breast and colon tumor cell lines expressing the multidrug-resistant P-glycoprotein 170 [32Go]. Similar to the first-generation taxanes, BAY 59-8862 exhibits antiangiogenic activity by downregulating both VEGF and bFGF in prostate carcinoma cell lines and reducing tumor microvessel density in tumor xenografts [33Go].

Clinical results
In a phase II study conducted to assess safety and efficacy, 75 mg/m2 BAY 59-8862 was administered i.v. over 1 h every 3 weeks. Fifty-four patients entered the study. The median number of cycles was 3.7, with 11 patients receiving six or more. Grade 3/4 toxicities included neutropenia (28), anemia (three) and leukopenia (10). Of 42 patients evaluated, there were no complete or partial responders. Stable disease was reported in six patients with a median duration of 4.5 months [32Go].

Epothilone
Mechanism of action
Epothilone EP0906 is a microtubular stabilizer that inhibits cell growth in a broad range of cancer cell lines.

Clinical results
In a phase II study conducted to assess safety and efficacy, 2.5 mg/m2 oral EP0906 was administered i.v. over 5 min once weekly for 3 weeks, followed by 1 week off. Grade 3/4 toxicities included septic shock (one), diarrhea (four), asthenia (two) and anemia (two). Of 52 patients evaluated, two had a partial response of 3 and 5 months' duration and 24 patients had stable disease to 16 weeks of therapy [34Go].

Vaccines
Mechanism of action
One novel approach to the treatment of RCC is a therapeutic vaccine. The basic theory being tested is that active specific immunotherapy in the form of cytolytic T lymphocytes can be generated using gp96, a chaperone for tightly bound immunogenic peptides. The heat-shock protein–peptide complex vaccine (HSPPC-96) uses purified complexes from an individual patient's tumor: each vaccine is unique to each patient's tumor. Heat-shock proteins (HSPs) are linked to tumor antigen peptides [35Go]. Thus, when re-administered to patients, these tumor peptides can be expressed on antigen-presenting cells (dendritic cells or macrophages), stimulating a potent antitumor response. Using the same technology, trials are ongoing in melanoma, gastric cancer and pancreatic cancer. However, the ability to extract HSPs can vary substantially between tumor types due to varying levels of protease in each tissue [36Go].

Clinical results
In a phase II study reported at ASCO 2003 assessing the efficacy of HSPPC-96 and activity of additional IL-2 for patients whose cancer progressed while on HSPPC-96, 25 µcg of HSPPC-96 was administered intradermally at weekly intervals in weeks 1–4, followed by every 2 weeks until progression. At 10 weeks, patients were evaluated for progression following vaccination and at 8-week intervals thereafter. Interleukin-2 was administered 5 days a week with 4 weeks on and 4 weeks off (11 million units) and added to the vaccine at the time of progression in selected patients. No adverse events were reported. Sixty-one patients received a minimum of one dose of HSPPC-96. Of these 61 patients, two achieved a partial response, one a complete response (remains with no evidence of disease after 2.5 years) and 18 had stable disease. Of those that progressed, seven of 16 responded to IL-2 and achieved stable disease. Median progression-free survival was 18 weeks, whereas those receiving vaccine and IL-2 were 25 weeks. Two years after initiation of vaccine, 30% remain alive [37Go]. Given these encouraging findings, expanded phase III clinical trials using HSPPC-96 at 80 clinical sites are underway [36Go].

CCI-779
Mechanism of action
CCI-779 is a derivative of rapamycin, the macrolide antibiotic. Its mechanism of action is to inhibit the kinase mammalian target of rapamycin (mTOR), thereby suppressing growth and proliferation in tumor cell lines [38Go] and, in the presence of IFN, xenograft models [39Go]. By targeting mTOR, CCI-779 indirectly downregulates specific mRNAs of many proteins required for progression through the cell cycle, thereby causing G1 arrest [40Go].

Clinical results
In a double-blind phase II study, 110 patients were randomized to receive weekly infusions of one of three doses of CCI-779: 25, 75 or 250 mg. Patients were evaluated every 8 weeks. Serious adverse events (grades 3 and 4) included hyperglycemia and anemia. Tumor response rates did not differ significantly between treatment arms. Overall, 5% of patients achieved a partial response and 40% stable disease. Median length of treatment was 4.6 months. Median time to progression and overall survival were 5.8 and 12 months, respectively. A minimum of 15 patients remained on study for over 1 year. In summary, the investigators concluded that further study of CCI-779 in a combination setting was warranted because many patients had previously received IL-2 (94%) or IFN-{alpha} (44%) [40Go]. A phase III study of CCI-779 with IFN-{alpha} is ongoing [41Go].

ABT-510
Mechanism of action
ABT-510 is a substituted nonapeptide that potently inhibits angiogenesis by blocking multiple proangiogenic signals and causing apoptosis in endothelial cells. In preclinical canine models, ABT-510 mimics the antiangiogenic activity of an endogenous protein, thrombospondin-1 (TSP-1) by competing for its cellular receptor CD36, thereby inhibiting spontanteous tumor growth and blocking activated endothelial cells [42Go].

Clinical results
In a small, randomized phase IB trial of ABT-510 reported at ASCO 2003, its safety proflile was presented in six different cancer types. Favorable safety and preliminary data of antitumor activity were reported [42Go]. Given these encouraging results, a phase III trial in RCC is presently underway.

Thalidomide versus medroxyprogesterone
Mechanism of action
Single-agent thalidomide (ThalomidTM; Celgene Corporation, Warren, NJ, USA) has been widely tested in advanced metastatic RCC. In a recent assessment of nine phase II clinical trials evaluating its efficacy as a single agent, response rates and progression-free survival were comparable to those observed with IFN-{alpha} and IL-2 [8Go]. On average, 40% to 45% of patients derived clinical benefit from thalidomide. Thalidomide is a potent immunomodulatory drug with antiangiogenic properties [8Go]. Approved for erythema nodosum leprosum, an inflammatory complication of leprosy, single-agent thalidomide has demonstrated measurable activity in both hematologic cancers and solid tumor malignancies [43Go]. Although its precise mechanism of action remains uncertain, in clinical trials of multiple myeloma, Kaposi's sarcoma and recurrent gliomas, thalidomide exhibits potent antitumor activity, even in patients who have failed high-dose chemotherapy [44Go, 45Go]. In relapsed multiple myeloma, a disease characterized by persistent neovascularity, several trials have reported a 25% to 35% response rate. Some of the antiangiogenic and immunomodulatory properties attributed to thalidomide's potent biological activity include inhibition of bFGF in a rabbit model [46Go], acceleration of TNF-{alpha} (an angiogenic factor) mRNA degradation (thus suppressing inflammation) [47Go], selective modification of cell adhesion molecule expression and the subsequent influencing migration of leukocytes [48Go] and increasing IL-10 [45Go]. In in vitro models it has been demonstrated to inhibit IL-6, a growth factor produced by macrophages found in RCC patients [49Go].

Clinical results
In a phase II/III study [50Go], 59 patients were randomized to either thalidomide or medroxyprogesterone. All patients had either progressed on immunotherapy or were not eligible for immunotherapy. Patients received daily oral thalidomide (100 mg) for 2 weeks, escalated by 100 mg every 2 weeks (if tolerated) to a maximum dose of 400 mg daily. Oral medroxyprogesterone was administered daily (300 mg) until disease progression. Of the 16 patients evaluated for toxicity on thalidomide arm, grade 3 adverse events included fatigue (6%) constipation (13%) and neuropathy (6%). There were no grade 4 adverse events. Patients who had received a minimum of 4 weeks' treatment were assessed for response. All 24 patients on the medroxyprogesterone arm progressed. Of the 19 patients evaluated for efficacy on the thalidomide arm, one patient (5%) achieved stable disease at 3 months and is continuing on treatment. The remaining 18 patients experienced progressive disease. The median survival for thalidomide on this trial was 12.2 months and 4.8 months for medroxyprogesterone (P=0.37). Median duration of treatment for thalidomide was 74 days and for medroxyprogesterone 84 days.


    Combination therapy
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 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
At the 2003 ASCO convention, six presentations of phase II clinical trials were delivered on the safety and efficacy of combination regimens. Because of its tolerable safety profile and demonstrated efficacy in numerous clinical trials, many of the combination regimens being tested included thalidomide: low-dose thalidomide and IFN-{alpha}, thalidomide and IL-2, 5-fluorouracil (5-FU), IFN-{alpha} and IL-2 (FUNIL), and thalidomide. The other two studies included: gemcitabine (Gemzar®; Eli Lilly and Co., Indianapolis, IN, USA) plus capecitabine (Xeloda®; Roche Pharmaceuticals, Nutley, NJ, USA) and capecitabine plus IFN-{alpha}.

Low-dose thalidomide and IFN-{alpha}
Clinical results
The underlying rationale for combination trials of thalidomide with IL-2, IFN-{alpha} and FUNIL is that activity has been achieved in each of the four regimens individually. In a phase II trial of low-dose thalidomide and IFN-{alpha}, 19 patients received 3 mIU/day IFN-{alpha}, and 100 mg/day oral thalidomide. Dose reduction was permitted for grade 3/4 toxicity and greater than grade 2 neuropathy. Responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) group criteria. There were 11 grade 3 events requiring dose reduction of IFN-{alpha}: these included asthenia, headache, neutropenia and neutropenic fever. Two patients discontinued due to persistent headache and a mild visual cerebrovascular event. One patient died, unrelated to therapy. Of 14 patients evaluated, three patients (21.4%) achieved a partial response, and seven patients (50%) obtained stable disease. The overall non-progression rate was 71.4% and overall survival was 17.4 months: 16 patients were still alive at the time of publication [52Go]. Given the high stable disease response, future trials using this combination are underway.

Thalidomide and IL-2
Clinical results
A phase II study of the biological response modifier IL-2 in combination with thalidomide was presented by Amato and colleagues [52Go]. In this phase II study of 37 patients who had received no previous chemotherapy or immunotherapy, the starting dose of thalidomide was 200 mg and escalated every 48 h to 400 mg. IL-2 was administered at 7 mIU/m2 starting at week 1, days 1–5, for 4 consecutive weeks followed by a 2-week rest. Response was assessed every two therapy cycles. This regimen was very well tolerated with no reported grade 3 or 4 adverse events. Of 36 patients evaluated, there was one complete response, 14 partial responders, and 11 patients who achieved stable disease. Time on therapy ranged from 3 to 15 months. Twenty-six patients (69%) remain on treatment with either an objective response or stable disease. Based on this promising combination with a high objective response rate, a phase III randomized trial of thalidomide plus IL-2 versus IL-2 versus thalidomide is underway.

FUNIL and thalidomide
Clinical results
Response rates of FUNIL in RCC range from 2% to 48%. In this small phase I/II trial of eight patients, FUNIL was combined with thalidomide. A total of 1750 mg/m2 5-FU was administered as a continuous infusion over 24 h on day 1, IFN-{alpha} 6 mIU/m2 subcutaneous days 1, 3 and 5, and IL-2 6 mIU/m2 as a continuous infusion on days 2–5 every week for the first 4 weeks in 6-week cycles. Thalidomide was given daily starting at 200 mg, and increasing by 200 mg every 14 days to a target dose of 1 200 mg/day. Grade 3 adverse events included: fatigue (25%), parasthesias (12.5%), mucositis (12.5%) and hand–foot syndrome (12.5%). Grade 4 adverse events included neutropenia (12.5%) and hypotension (12.5%). One patient was removed from the study due to intractable hypotension. The mean dose of thalidomide tolerated was 285 mg. The mean number of cycles received was 2.6 (range 0–12). The overall response rate in this trial was 14%. The mean time to progression was 161.4 days. One patient was reported to have had a radiographic complete response of bone and pulmonary lesions after 10 cycles and was still alive at the time of publication [53Go].

Capecitabine and IFN-{alpha}
Clinical results
Capecitabine (CAPE) is an orally administered chemotherapeutic approved for metastatic colorectal and breast cancer. CAPE, a fluoropyrimidine carbamate, is converted to 5-FU in vivo. The metabolites of 5-FU, 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) exploit the high concentrations of thymidine phosphorylase in tumor tissue, thereby causing inhibition of DNA synthesis, RNA processing, protein synthesis and, ultimately, cell death [54Go]. A phase II combination study of CAPE and IFN-{alpha} was recently reported. CAPE was administered twice daily (1250 mg/m2) for 2 weeks followed by 1-week rest. Subcutaneous IFN-{alpha} was delivered three times weekly (6 mIU/m2). Tumor measurements were assessed every 6 weeks. The median number of 3-week cycles was 4.6. Of 24 patients, the overall response rate was 25%, all partial responses. Stable disease was observed in 33% of patients. Median survival time was 257 days and median time to progression was 127 days. Median duration of response was 134 days. Grade 3 toxicities were reported in nine patients and grade 4 in one patient. Adverse events included fatigue (33%), nausea, hand–foot syndrome (both 12.5%), anorexia (8.3%), vomiting, anemia and neutropenia (all 4.2%). Dose reduction of CAPE and IFN-{alpha} was necessary in 11 patients and five patients, respectively. The investigators of this trial concluded that the clinical activity of this combination warranted a randomized trial to confirm these results [55Go].

Gemcitabine and Capecitabine
In a phase I trial of gemcitabine (GEM)/CAPE, full single-agent doses were deemed tolerable. In this larger phase II trial, 16 patients received 1200 mg/m2 on days 1 and 8 plus CAPE 1300 mg/m2 twice daily for 2 weeks every 3 weeks. Grade 3/4 toxicities included the following: lethargy (6.3%), vomiting (6.3%), diarrhea (12.5%), hand–foot syndrome (18.8%), rash (12.5%), anemia (6.3%), neutropenia (56.3%), thrombocytopenia (18.8%) and infection (18.8%). Two patients experienced thromboembolic events while on treatment. Overall response with this regime was 21.4%; three patients achieved a partial response and five had stable disease [56Go].


    Future directions
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 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
The outlook for more promising therapeutic alternatives, coupled with far less toxicity than traditional therapies, reflects the progress in our fundamental knowledge of RCC biology on a molecular level. However, despite the wealth of new clinical data on numerous innovative single agents, responses are still modest and none exhibit more activity than historical controls, except in the case of thalidomide. The reasons for low response rates are multifold: optimal dosing may not have been achieved in the tumor microenvironment, the complexity of the signaling pathway may not be sufficiently understood, and therapeutic targets, however specific, may exist in other isoforms. This may partially account for the better response rate in the PTK/ZK trial than the SU5416. Both agents are small molecular weight tyrosine kinase inhibitors of the VEGF receptor, but PTK/ZK inhibits all three isoforms and SU5416 only two. Conflicting results with PS-341 were also observed and will require greater analysis; patient characteristics are the most obvious explanation for the disparity in response rates. Thus, most of these single agents will require additional testing either to establish the optimal regimen as a single agent or in the context of a combination regimen to establish potential additive or synergistic effects.

Relatively few objective responses were achieved in all the trials reported in this review. Overall, the greatest response rates were in the combination regimens, with the thalidomide/IL-2 combination reporting the highest response (69%). Notably, the percentage of patients achieving stable disease was a relatively consistent outcome in many trials. For instance, in the combined trial of low-dose thalidomide and IFN-{alpha}, 50% of patients achieved stable disease, 46% in the single-agent PTK/ZK trial and 38% in the single agent ZD1839 trial. Reproducibly high reports of stable disease have also been achieved with single-agent thalidomide. These findings suggest that stable disease may reflect biological activity that is cytostatic due to therapy and warrants closer examination. In a recent report by Motzer and colleagues [57Go], long-term stable disease was proposed as a more appropriate treatment end point than objective responses on the basis of tumor shrinkage with certain antiangiogenesis agents and in patients who have failed cytokine therapy. Therefore, it may be appropriate in the design of future clinical evaluation methods to consider criteria such as stable disease as a valid measure of antitumor activity.


    Conclusions
 Top
 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
 References
 
The treatment of metastatic RCC remains a highly difficult and perplexing challenge due to its resistance to both chemotherapy and hormonal therapy and limited response to cytokines. Despite recent advances in our fundamental knowledge of RCC biology and development of molecular therapeutics, more clinical research will be required to best guide our use of these exciting new agents in combination regimens.


    Acknowledgements
 
Clinical research for this study was supported by Celgene Corporation.

Received for publication January 22, 2004. Revision received March 15, 2004. Accepted for publication July 21, 2004.


    References
 Top
 Abstract
 Introduction
 Single-agent therapy
 Chemotherapy
 Combination therapy
 Future directions
 Conclusions
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