Ronald M. Bukowski, MD

ABSTRACT: Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.

The medical management of metastatic renal cell carcinoma (RCC) has undergone a transformation in recent years. Initial attempts at treatment with hormonal or chemotherapeutic agents produced little success. The historical standard of cytokine immunotherapy, including interleukin (IL)-2 (Proleukin) and interferon (IFN)-alpha, resulted in limited clinical benefit in unselected cohorts. More recently, systemic therapy targeted at the vascular endothelial growth factor (VEGF) protein and related pathway elements has produced robust clinical effects in metastatic RCC, leading to regulatory approval of sorafenib (Nexavar), sunitinib (Sutent), and temsirolimus (CCI-779, Torisel), an inhibitor of the mammalian target of rapamycin (mTOR). Bevacizumab (Avastin) has also demonstrated antitumor activity in metastatic RCC and is awaiting regulatory approval in the United States.

It is useful to review the existing data from each of these approaches to formulate an overall management strategy of metastatic RCC patients. Further, we will discuss ongoing investigative efforts including sequencing, combination therapy and novel agents.

Systemic anticancer agents such as medroxyprogesterone acetate and cytotoxic chemotherapy were initially applied to metastatic RCC patients. These agents produced minimal objective response rates of approximately 2% to 5%.[1-4] While symptom palliation can be observed in some patients, the benefit for the entire cohort of RCC patients is extremely low. Despite combination chemotherapy regimens resulting in slightly higher response rates, such regimens are not in routine use pending further study of novel agents or additional patient selection efforts.

The immunogenic nature of RCC and the lack of benefit from chemotherapy and hormone therapy resulted in the clinical application of immunotherapeutic cytokines. Two phase III randomized trials have examined the benefit of high-dose IL-2 and low-dose cytokine (IL-2 monotherapy or IL-2 plus IFN-alpha) regimens (Table 1).[5,6] Both studies demonstrated an objective response rate advantage for the high-dose IL-2 arms, without any difference in disease-free or overall survival. Taken together, these data suggest that high-dose IL-2 has a higher overall and complete response rate compared with low-dose cytokines, with the majority of benefit realized in patients who experience a durable complete response. The limited benefit, however, precluded demonstration of a disease-free or overall survival advantage with high-dose IL-2 for the entire cohort. Further, the lack of applicability of high-dose IL-2 to the broad RCC population has dampened enthusiasm for this approach.

  
Summary of Agents and Approaches in Renal Cell Carcinoma 

Low-dose IFN-alpha monotherapy has also been investigated (Table 1). A meta-analysis that reviewed 53 randomized controlled trials with IL-2 or IFN-alpha in metastatic RCC provides the most comprehensive view.[7] Four trials (N = 644) randomized patients to IFN-alpha vs a non–IFN-alpha control arm. The weighted median survival improvement with IFN-alpha treatment vs the control group was 3.8 months (

= .007), with an odds ratio for death at 1 year of 0.56 for IFN-alpha (95% confidence interval = 0.40–0.77). The investigators found no evidence of a dose-response relationship and no correlation between response rate and overall survival. Despite multiple attempts, no prospective randomized trial has demonstrated a benefit to adding any additional cytokine/immunotherapeutic or noncytokine agent to cytokine monotherapy, with the notable exception of IFN-alpha plus bevacizumab trials.

The role of cytokine therapy in metastatic RCC is currently evolving and unclear. As noted above, cytokine monotherapy is of modest benefit in unselected populations, but select patients should be considered for high-dose IL-2 therapy, solely on the basis of the small but real chance of a durable complete response. Whether or not this durable complete response benefit is preserved when high-dose IL-2 is given after targeted therapy is not clear at present. Current investigative efforts are appropriately focused on additional patient selection efforts and combination therapy. For example, tumors expressing carbonic anhydrase IX (CAIX, also called G250) have been associated with a higher rate of objective response to IL-2 in retrospective analyses, and further prospective trials are ongoing.[8,9] In addition, based on nonoverlapping mechanisms of action, cytokines are being investigated in combination with targeted therapy, as discussed below.

The premise of targeted therapy in all oncologic endeavors is the fundamental reliance of tumor cells on given biologic pathways that drugs can be designed to disrupt. A growing understanding of the underlying molecular biology of RCC has established the VEGF and mTOR pathways as relevant therapeutic targets.

The pathogenesis of RCC was elucidated by the discovery of the von Hippel-Lindau (VHL) gene, which is named for the familial cancer syndrome in which it is implicated.[10] VHL is a tumor-suppressor gene in which biallelic gene inactivation promotes a tumor phenotype. One allele is inactivated through a deletion (also known as loss of heterozygosity) observed in over 90% of sporadic clear cell RCC cases.[11,12] The remaining VHL allele can be inactivated either through a gene mutation (approximately 50% of clear cell RCC[13,14]) or through gene silencing by methylation (approximately 5% to 10% of cases).[15,16])

Under normal conditions, VHL encodes a protein that targets a crucial transcription factor called hypoxia-inducible factor (HIF) for proteolysis.[17] As a result of the VHL gene inactivation, a defective VHL protein is produced and HIF is not subject to proteolysis and inactivation. Activated HIF then translocates into the nucleus and leads to the transcription of a variety of genes that play a central role in tumor progression. Transcription genes include VEGF,[18] platelet-derived growth factor (PDGF),[19] transforming growth factor (TGF)-alpha,[20] and basic fibroblast growth factor (bFGF). Clinical testing has identified the VEGF protein and its receptor (VEGFR) as the most relevant targets in anti-RCC therapy.

Sunitinib is a small-molecule inhibitor of the tyrosine kinase portion of VEGFR and related receptors. Updated data from the initial phase II trials of sunitinib in metastatic RCC patients (N = 169) who had failed prior cytokine-based therapy demonstrated an investigator-assessed pooled objective response rate of 45%, a median duration of response of 11.9 months, and median progression-free survival (PFS) of 8.4 months (Table 1).[21]

A phase III trial in untreated, metastatic RCC patients (N = 750) of sunitinib vs IFN-alpha demonstrated a significant advantage in objective response rate (39% vs 8%, 

< .000001) for sunitinib-treated patients (Table 1).[22] Baseline clinical features predictive of improved PFS at 12 months in sunitinib-treated patients identified Eastern Cooperative Oncology Group (ECOG) performance status 0, time from diagnosis ≥ 1 year and corrected serum calcium ≤ 10 mg/dL as favorable characteristics.[22]

Based on these data, sunitinib has emerged as a front-line standard of care in metastatic RCC. This drug is notable for a superior objective response rate compared to other agents, balanced against toxicity including fatigue, hand-foot syndrome, and diarrhea. Final analysis of the survival data from this trial is pending

Sorafenib is a small-molecule inhibitor of VEGFR and related receptors in addition to inhibition of an intracellular-signaling enzyme, raf kinase. A phase III trial of sorafenib randomized 900 treatment-refractory metastatic RCC patients to sorafenib at 400 mg twice daily or placebo. A PFS advantage in the treatment arm was observed (5.5 vs 2.8 months, 

< .000001; Table 1).[23] Although overall survival was similar between the two arms (17.8 vs 15.2 months, 

= .15), a preplanned analysis demonstrated improved survival with sorafenib after the censoring of placebo patients who crossed over to the sorafenib arm (17.8 vs 14.3 months, 

It is likely for this trial and other phase III trials that patient crossover to active therapy may obscure the overall survival benefit of targeted therapy in a single trial. The phase III data contrast somewhat with the results of a smaller, randomized phase II study of sorafenib vs IFN-alpha in 189 previously untreated metastatic RCC patients. In this smaller trial, median PFS was 5.7 months with sorafenib vs 5.6 months with IFN-alpha.[25] The reason for the lack of significant effect vs IFN-alpha in the front-line setting is not entirely clear but may result from weaker inhibition of VEGFR compared to sunitinib. Although there may be patients in whom sorafenib would be the preferred initial agent, for example, due to toxicity profile, sorafenib use has moved toward second-line and later therapy. Investigators need to identify the phenotype of patients in whom sorafenib is the preferred initial treatment.

Bevacizumab is a monoclonal antibody that binds and neutralizes circulating VEGF protein. The activity of this agent in RCC was initially identified by small randomized trials.[26,27] More recently, two multicenter international studies have established bevacizumab-based therapy as robust in the front-line setting.[28,29]

The AVOREN trial randomized 649 untreated patients with metastatic RCC to treatment with IFN alfa-2a (Roferon-A) plus placebo infusion or to IFN alfa-2a with bevacizumab at 10 mg/kg IV every 2 weeks. This trial demonstrated a significant difference in favor of the bevacizumab-containing arm for objective response rate (31% vs 13%, 

The second trial, conducted through the Cancer and Leukemia Group B (CALGB), was nearly identical in design, with the exception of using IFN alfa-2b (Intron A) instead of IFN alfa-2a, lacking a placebo infusion, and not requiring prior nephrectomy. This trial also demonstrated a significant difference in favor of the bevacizumab-containing arm for objective response rate (25% vs 13%, 

< .0001). The contribution of IFN-alpha to the antitumor effect of this regimen, especially when balanced against increased toxicity, is unclear, although preliminary results indicate a longer PFS and higher response rate than expected with bevacizumab monotherapy.[27]

Based on these findings, regulatory approval of bevacizumab-based therapy in advanced RCC has been granted in Europe and is expected in the United States, and it is likely that bevacizumab-based therapy will join sunitinib as a front-line standard of care. Although the response rate is lower than that seen with sunitinib, bevacizumab is very well tolerated day-to-day and is familiar to community oncologists given its common use in colorectal and lung cancers.

Temsirolimus is an inhibitor of mTOR, a molecule implicated in multiple tumor-promoting intracellular signaling pathways. Regulation of mTOR pathway activation is mediated through a series of complex signaling interactions linking growth factor receptor signaling and other cell stimuli, phosphatidylinositol 3-kinase (PI3K) activation, and activation of the Akt/PKB pathway.

mTOR phosphorylates and activates p70 S6 kinase (p70S6K), leading to enhanced translation of certain ribosomal proteins and elongation factors. This process leads to-among other effects-the production of HIF-1 alpha, which regulates the transcription of genes that stimulate cell growth and angiogenesis, including VEGF. The second major mTOR effect is on the 4E binding protein-1 (4E-BP1) and eukaryotic initiation factor-4 subunit E (eIF-4E) complex, promoting dissociation of this complex and allowing eIF-4E to stimulate an increase in the translation of mRNAs that encode cell-cycle regulators such as c-myc, cyclin D1, and ornithine decarboxylase.

Retrospective analysis of a prior phase II trial in treatment-refractory metastatic RCC suggested that antitumor activity was more pronounced in a poor-risk subset.[30] A randomized phase III trial was subsequently conducted in patients with metastatic RCC and three or more adverse risk features as defined by the following: Karnofsky performance status < 80%, lactate dehydrogenase > 1.5 × laboratory upper limit of normal, hemoglobin < laboratory lower limit of normal, serum calcium corrected for albumin > 10 mg/dL, time from first diagnosis of RCC to start of therapy < 1 year, plus a sixth factor, ie, three or more metastatic sites identified as prognostic in a separate analysis.[31,32] A total of 626 patients were randomized to temsirolimus at 25 mg IV weekly vs IFN-alpha at 18 MU three times per week vs temsirolimus at 15 mg IV weekly plus IFN-alpha at 6 MU three times per week.

Patients treated with temsirolimus had a statistically longer overall survival than IFN-alpha monotherapy patients (10.9 vs 7.3 months, 

= .0069; Table 1).[33] The investigators also found a progression-free survival benefit from temsirolimus monotherapy vs IFN-alpha (median = 3.8 vs 1.9 months, 

< .0001). There was no survival advantage to the combination-therapy arm over IFN-alpha monotherapy, perhaps due to the lower dose of temsirolimus, which may have been inadequate for mTOR inhibition.

These data led to US Food and Drug Administration approval of temsirolimus for advanced RCC on May 31, 2007, and validated mTOR as a relevant therapeutic target in RCC, at least in the subset of patients with multiple adverse-risk features. This agent is being used frequently in patients who have failed prior therapy, including prior VEGF-targeted therapy, for whom no safety or efficacy data is yet available. The utility of this agent in patients who do not meet the poor-risk criteria of the phase III trial awaits further study.

Management Strategies for Metastatic RCC Patients

Given the availability of multiple treatment options, each with a slightly different profile of risk and benefit, there are currently several options for initial therapy. The choice of treatment requires appreciation of the risks and benefits of the agents discussed as well as knowledge of the limitations of the current data. The goal for every metastatic RCC patient upon presentation is to maximize overall therapeutic benefit, delaying for as long possible a life-threatening burden of disease while maximizing quality of life and patient convenience. This translates into selecting the treatment with the optimal risk-benefit ratio for a given patient, while realizing that limited criteria exist to predict response to a given agent and that multiple sequential treatments are ultimately likely to be pursued for most patients.

Although several active agents are now available for metastatic RCC, their inability to produce durable complete responses necessitates chronic therapy in the majority of patients. Therefore, benefits must be weighed against the overall burden of treatment, including toxicity, time commitment, and cost. A subset of metastatic RCC patients has low-volume, slow-growing disease. For these patients, the overall goal of controlling tumor burden and maximizing quality of life may be achieved more successfully by not initiating immediate systemic therapy.

Evidence suggests that treatment benefit is preserved even if therapy is delayed. For example, Ratain et al reported on 28 patients who were randomized to placebo on the sorafenib randomized discontinuation trial, where sorafenib was readministered upon disease progression.[34] These patients continued on sorafenib until further progression for a median of 24 weeks, identical to the PFS for patients initially randomized to continue sorafenib. These data suggest that some asymptomatic patients can have treatment delayed without compromising the ability to achieve subsequent clinical benefit to therapy.

This critical question of whether a given agent offers identical clinical benefit after a period of observation will require prospective study. This treatment delay could also provide a window for exploring investigational therapy with low toxicity.

All the targeted therapies noted above have demonstrated benefit in a phase III setting vs either interferon monotherapy or placebo. None of these agents have been directly compared to one another, and thus definitive answers to this question are not readily available. As noted above, patients are likely to be treated with multiple agents in the course of their disease, and therefore a careful assessment of risk and benefit for each patient is warranted in choosing the most appropriate therapy.

Sunitinib is distinguished by the highest objective response rate. For most patients, control of overall disease burden over the long term is more important than objective response. Nevertheless, a subset of RCC patients have bulky, symptomatic disease, and these patients may require a greater degree of tumor burden reduction in the short term. In this context, sunitinib is the most appropriate choice.

Temsirolimus is the only agent to date to demonstrate an overall survival benefit, albeit restricted to a poor-risk subset of patients. The utility of this agent in an unselected, better-risk population awaits further study.

Bevacizumab-based therapy is noteworthy for a favorable toxicity profile. However, this agent requires infusion therapy and subcutaneous injections if interferon is added.

Sorafenib has not yet demonstrated effects in the front-line setting that are as robust as those of the other agents. Still, its oral availability and favorable toxicity profile may make it a reasonable initial choice in a subset of patients.

As noted below, investigation into sequential therapy may help identify which agent is preferred initially, as exposure of RCC tumors to certain agents may affect tumor biology and response to subsequent therapy. We are also missing tools with which to predict benefit in individual patients from individual drugs. While characteristics such as normal hemoglobin may predict for better response to a single agent (eg, to sunitinib), such general clinical features may not distinguish among the multiple available agents. Translational investigation to identify the molecular phenotype of response and resistance to each of the agents is needed.

Ongoing Clinical Investigations in Metastatic RCC

An orally bioavailable derivative of the immunosuppressant macrolide rapamycin that targets mTOR kinase, everolimus (RAD-001, Certican) has shown activity in preclinical models of the cancer. In a phase II study, the clinical efficacy of everolimus in patients with metastatic RCC was evaluated.[35] A total of 25 patients with progressive metastatic RCC were treated with everolimus at a dose of 10 mg daily with continuous dosing. The primary endpoint of the study was time to progression and the secondary endpoint included response rate and toxicity. The median time to progression was 6+ months. A total of 7 patients had partial responses and 11 had stable disease. Treatment-related adverse events included mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, and anemia. A large phase III trial of RAD-001 vs placebo in treatment-refractory RCC has completed accrual, and results are highly anticipated.

Pazopanib is an oral multitarget receptor tyrosine kinase inhibitor with potent effects against VEGFR-1, -2, -3, PDGF receptor (PDGFR)-alpha, -beta, and c-kit. A randomized discontinuation trial of pazopanib at 800 mg daily in treatment-refractory RCC patients was preliminarily reported and demonstrated an objective partial response rate of 40%.[36] Toxicity was generally similar to that observed with other small-molecule VEGFR inhibitors, with the notable lower incidence of hand-foot syndrome. A phase III randomized trial of pazopanib vs placebo in cytokine-refractory patients has completed accrual, and results are anticipated.

Axitinib (AG-013736) is a substituted imidazole derivative that inhibits the tyrosine kinase portion of all VEGF receptors and PDGFR-beta at low nanomolar concentrations. A phase II trial of axitinib was conducted in cytokine-refractory RCC patients, demonstrating a 44% objective response rate and a median time to progression of 15.7 months.[37] Treatment-related adverse events included diarrhea, hypertension, fatigue, nausea, and hoarseness.

Articles

Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease.

Targeted Therapy for Metastatic Renal Cell Carcinoma: A Home Run or a Work in Progress?

The management of invasive bladder cancer represents a challenge for medical and urologic oncologists. The unique bladder anatomy and the biologic characteristics of bladder cancer have permitted investigators to develop postoperative adjuvant therapy as well as preoperative neoadjuvant therapy. Additionally, bladder cancer poses a significant economic burden to the US health-care system in view of the frequent surveillance procedures required and the often long natural history of superficial bladder tumors.[1] In view of these issues, the article by Sonpavde and Lerner is timely, discussing in detail the rationale and evidence for use of various types of therapy in patients with bladder cancer.

In the 1980s it became clear that advanced urothelial cancers were sensitive to a variety of chemotherapeutic agents, and that cisplatin combinations such as MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) were associated with the best outcomes.[2] A series of randomized trials were then conducted to determine which single agent or regimen was superior. Sonpavde et al clearly discuss the regimens investigated, and those now considered as standards of care: MVAC, dose-dense-MVAC, and GC (gemcitabine [Gemzar]/cisplatin). The use of these approaches in patients with earlier-stage disease but at significant risk for recurrence was the next logical step.

Table 1 lists the varied options considered as adjunctive therapy in this patient population. These approaches involve multimodality care utilizing both local and systemic therapy. The rationale behind the use of neoadjuvant therapy prior to either surgery or radiation is to target micrometastatic disease that may be present at the time of diagnosis. Neoadjuvant chemotherapy is intended for patients with operable clinical stage T2–T4a muscle-invasive disease. As has been adequately described in the review, neoadjuvant therapy holds several benefits. It allows assessment of tumor response, and complete pathologic response may be used as a surrogate marker for overall survival.[3]

Chemotherapy is better tolerated prior to cystectomy or radiation therapy, and delay due to postoperative morbidity is avoided. The dose of cisplatin-one of the most active agents in bladder cancer-may be affected if the cystectomy results in urinary diversion and compromised renal function. Additionally, drug delivery may be theoretically enhanced as a result of an intact vascular bed. Downstaging with neoadjuvant therapy may allow for better surgical resection and, in some cases, bladder preservation.

Administration of neoadjuvant therapy doesn't seem to increase perioperative morbidity,[4] but there is a risk of overtreating patients. The frequency of clinical staging errors was found to be as high as 38% in a pilot study comparing clinical and pathologic staging.[5] Also, it is important to realize that chemotherapy may delay a potentially curative cystectomy for patients whose tumors were biologically destined to fail chemotherapy.

The review describes the various neoadjuvant trials. The latest is the Southwest Oncology Group (SWOG) Intergroup trial, which showed a trend toward improved survival in the MVAC-treated arm.[6] The meta-analysis reported in 2003 demonstrated a 5% reduction in death rate at 5 years, with 5-year survival improving from 45% to 50% with platinum-based therapy.[7] This analysis included patients mostly from the European Organisation for Research and Treatment of Canacer (EORTC)/Medical Research Council (MRC) trial, and hence, the results were comparable to that trial.

A similar Canadian meta-analysis of 16 eligible trials was reported in 2004.[8] Eight trials used cisplatin-based combination chemotherapy, and the absolute overall survival benefit was described to be 6.5%. A major pathologic response was associated with improved overall survival in four trials, and it was concluded that neoadjuvant cisplatin-based chemotherapy improved overall survival in muscle-invasive urothelial carcinoma, though with only a modest effect. Overall there seemed to be more benefit for higher-risk patients (cT3 vs cT2) with neoadjuvant therapy.

The authors also discuss in detail the rationale and trials utilizing postoperative adjuvant chemotherapy. Unfortunately, current adjuvant data are limited, and attempts to prospectively study this question have met with poor patient accrual. Although postoperative adjuvant therapy may be common practice for high-risk patients, this approach is not based on level 1 evidence.

As mentioned in the review, transitional cell carcinoma is an aggressive disease, for which cystectomy is considered the gold standard of treatment. A review by Stein et al demonstrated that aggressive surgical treatment can achieve good long-term results.[9] Operating techniques have improved with the development of continent urinary diversions, leading to greater patient satisfaction.

The goal of bladder preservation is to achieve survival equivalent to that associated with radical cystectomy while maintaining the patient's quality of life. Hence, a multimodality approach including neoadjuvant chemotherapy with or without radiation therapy is undertaken. The review describes the data available in this setting, none of which are robust. No randomized trials have compared transurethral resection of the bladder tumor (TURBT) with cystectomy, nor does the addition of radiation to chemotherapy seem to provide a survival advantage.

The take-home message is that patients who undergo bladder preservation need to be a highly selected group of patients who are willing to undergo close routine follow-up with multiple cystoscopies and understand the possibility that cystectomy may be required in the course of the disease.

Finally, a discussion of biologic markers that may predict outcomes and/or tumor response and facilitate patient selection for adjuvant treatment is important. Takata et al characterized gene-expression profiles of 27 invasive bladder cancer specimens prior to administration of preoperative MVAC. They were able to identify 14 genes that were differentially expressed in responding vs nonresponding tumors.

The authors proposed a numerical prediction scoring system for chemotherapy response.[10] Whether such approaches will allow clinicians to tailor therapy will depend upon further studies. In addition, p53 gene expression has been studied as a tool with which to identify poor-prognosis patients. A trial comparing MVAC to observation in cystectomy patients with mutant p53 has completed accrual.

In summary, substantial evidence supports the use of neoadjuvant chemotherapy for clinical stage T2–T4a muscle-invasive bladder cancer. The development of additional markers will improve our understanding of the disease, be useful for prognostication, and aid in selection of appropriate treatment modalities.

-Ila Tamaskar, MD
-Ronald M. Bukowski, MD

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

1. Riley GF, Potosky AL, Lubitz JD, et al: Medicare payments from diagnosis to death for elderly cancer patients by stage at diagnosis. Med Care 33:828-841, 1995.

2. Sawhney R, Bourgeois D, Chaudhary UB: Neo-adjuvant chemotherapy for muscle-invasive bladder cancer: A look ahead. Ann Oncol 17:1360-1369, 2006. 

3. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 133:403-407, 1985.

4. Millikan R, Dinney C, Swanson D, et al: Integrated therapy for locally advanced bladder cancer: Final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 19:4005-4013, 2001.

5. Scher HI, Yagoda A, Herr HW, et al: Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) effect on the primary bladder lesion. J Urol 139:470-474, 1988.

6. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003.

7. Advanced Bladder Cancer Meta-analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 361:1927-1934, 2003.

8. Winquist E, Kirchner TS, Segal R, et al, for the Genitourinary Cancer Disease Site Group, Cancer Care Ontario Program in Evidence-Based Care Practise Guidelines Initiative: Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: A systematic review and meta-analysis. J Urol 171:561-569, 2004.

9. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001.

10. Takata R, Katagiri T, Kanehira M, et al: Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling. Clin Cancer Res 11:2625-2636, 2005.

Occult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.

Bladder Cancer and Current Evidence for Treatment

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Paralleling the increasing use of multikinase inhibitors in the field of cancer therapy, patients and clinicians are confronted with frequently occurring cutaneous side effects associated with the use of these new drugs. Two such targeted agents, sunitinib (Sutent) and sorafenib (Nexavar), were recently approved by the US Food and Drug Administration to treat patients with metastatic renal cell cancer (RCC). Cutaneous adverse effects associated with these drugs are sometimes distressing, partly because of their chronicity given the long-term duration of treatments, and can result in treatment interruption. Active collaboration between dermatologists and medical oncologists or urologists is urgently needed to characterize and treat these dermatologic side effects.

 gene products (serine-threonine kinases), including mutated B-Raf, as well as platelet-derived growth factor-beta (PDGFR-β), FLT

, and vascular endothelial growth factor receptor-2 and -3 (VEGFR-2 and -3). Sunitinib blocks VEGFR-1, -2, and -3, PDGFR-α and -β, Ret, Kit, and FLT

. Both drugs were recently approved by the US Food and Drug Administration (FDA) to treat patients with metastatic RCC,

 and sunitinib has also been approved for patients with imatinib (Gleevec)-resistant gastrointestinal stromal tumors.

 Furthermore, both drugs are currently being tested in various tumors (such as sorafenib for hepatocarcinoma) as single agents and in combination with chemotherapy, with promising preliminary results in several tumors. Numerous cutaneous side effects have been observed with these two molecules.

 Some side effects are common to the two drugs, such as hand-foot skin reaction (HFSR), xerosis, and subungual splinter hemorrhages (SSH), whereas others, like hair modifications, keratotic papules, and facial erythema, seem to be associated with the use of one or another of these targeted agents. Table 1 shows the association between the targeted receptors and the skin symptoms observed.

HFSR occurs in 30%−60% of patients receiving sorafenib and 15%−20% of patients treated with sunitinib,

 often appearing after 2 to 4 weeks of treatment. It seems to be dose dependent and rapidly disappears after treatment discontinuation.

HFSR usually presents as painful symmetric erythematous and edematous areas on the palms and soles, often preceded or accompanied by paresthesia (tingling sensations and intolerance to contact with hot objects); these sensations seem to be aggravated by a warm environment. HFSR can also affect the lateral sides of fingers or the periungual zones. Hyperkeratosis and desquamation are often associated. Painful hyperkeratotic areas on pressure points, surrounded by rings of erythematous and edematous lesions, are classically observed (Figure 1), and painful bullous lesions may be seen (Figure 2). Sole involvement can result in walking impairment. Preexistent sole hyperkeratosis seems to confer a predisposition to painful sole involvement and functional consequences. Although this syndrome can sometimes clinically resemble the more classic chemotherapy-induced acral erythema (AE), kinase inhibitor-induced HFSR has more localized and hyperkeratotic lesions, distinct from classic AE.

Histologic examination of HFSR shows epidermal changes suggestive of keratinocyte differentiation modifications. The granular layer is thinner or absent in several specimens, and some areas of parakeratosis are seen. Epidermal cells are swollen in the superficial stratum spinosum. Numerous mitoses are seen in the basal layers and also above the basal and suprabasal layers, where normally they should not be found physiologically. Dyskeratotic keratinocytes suggestive of apoptotic cells are observed.

As a preventive measure, patients with plantar hyperkeratosis are advised to have a pedicure prior to treatment. During treatment, however, shock absorbers can be used to relieve painful pressure points, and sandals seem to be helpful in some cases. Symptomatic treatment with over-the-counter emollient and keratolytic ointments (containing salicylic acid or urea) can be used. When grade 3 HFSR occurs (pain interfering with function), a dose reduction (to 50% of the dose) or treatment interruption for 1−2 weeks is recommended until symptoms return to grade 1. When treatment is resumed, the dose should be decreased by one level; the full dose should be returned after 3−4 weeks. As is the case with most of the other side effects occurring with kinase inhibitors, resuming treatment is not always associated with similar side effects, in our experience.

In our experience, multiple, painless distal SSH are frequently seen (in 40%−65% of patients) under fingernails (Figure 3) and less often under toenails of patients receiving multikinase inhibitors. First described in patients with infective endocarditis, SSH appear as linear black or red lines that actually look like wood splinters under the nails. They are formed and confined within the epidermis of the nailbed and consist of a mass of blood in a layer of squamous cells adhering to the undersurface of the nail. They are carried forward with nail growth and can be scraped away once they attain the free margin of the nail.

SSH are considered to be thrombotic or embolic in origin. Initially thought to be a typical sign of bacterial endocarditis, they have subsequently been reported to occur with various conditions,

 such as antiphospholipid syndrome, severe rheumatoid arthritis, thromboangiitis obliterans, and mitral stenosis; they also may occur at a high altitude or when arterial catheters are used. In addition, they may be seen in healthy patients, where they are more often confined to a single digit, and trauma seems to be the most common cause.

 Such traumatic SSH occur in the region where the nail plate separates from the nailbed, beneath which delicate, specialized, spiral capillaries are located and can easily rupture. Toxiderma is not usually an etiologic factor in SSH. SSH are rarely observed with imatinib and have not been reported with epidermal growth factor receptor (EGFR) inhibitors in the literature.

SSH may result from elective VEGFR blocking, which might prevent the physiologic repair of traumatized nailbed capillaries and facilitate the emergence of SSH.

 The hypothesis that nailbeds could offer a clinical monitoring window into the antiangiogenic effects of drugs that target VEGFR is being prospectively evaluated.

No therapeutic measure is needed for SSH, which are totally asymptomatic.

Skin dryness is a frequent complaint of patients treated with sorafenib and sunitinib. In our experience, skin dryness is reported in approximately 20%−30% of treated patients and is usually easy to treat symptomatically with skin emollient or body oil.

A face and scalp rash is seen in more than 50% of patients after 1 or 2 weeks of treatment with sorafenib, in our experience. It appears as an erythematous and squamous rash involving the mediofacial area and the scalp skin, sparing the periocular areas. Reminiscent of classic moderate seborrheic dermatitis, it is frequently preceded by or associated with scalp dysesthesia. This rash frequently fades or disappears after several weeks of treatment and usually does not require treatment; however, if patients request therapy, a topical emollient, 2% ketoconazole, or level 2 or 3 topical steroids can be prescribed for a short time, depending on the severity of symptoms.

In our patients, the texture of scalp hair is frequently modified with sorafenib treatment: hair becomes more brittle, finer, and curly, sometimes resembling hair modification associated with the use of EGFR inhibitors. Some patients have reported darkening of hair color.

Alopecia may occur in some patients treated with sorafenib or sunitinib, but it is rarely severe (Figure 4). As opposed to EGFR inhibitor-induced alopecia, it is not located on the frontotemporal areas but rather as diffuse hair loss. Spontaneous resolution of alopecia usually occurs despite continued sorafenib treatment, and interestingly, regrowing hair is often curlier than it was prior to sorafenib treatment (Figure 5).

Sunitinib frequently gives rise to hair depigmentation after 5−6 weeks of treatment. It is reversible as early as 2−3 weeks after treatment discontinuation. Successive depigmented and normally pigmented bands that are correlated respectively with periods on and off treatment can be observed.

 Sunitinib-induced hair depigmentation is probably due to the blockade of Kit signalling, which modulates the expression of the melanogenesis enzymes via the microphthalmia transcription factor.

Keratotic Papules, Kystic Lesions, and Keratoacanthomas

The prevalence of this side effect is not yet known; however, we and others have observed several cases of multiple keratotic papules, cystic cutaneous lesions (from milia cysts to more inflammatory lesions), and keratoacanthomas in patients receiving sorafenib.

 Keratoacanthomas are autoinvolutive epidermal tumors with borderline frontiers with squamous cell carcinomas. One case of squamous cell carcinoma in a patient treated with sorafenib has been reported.

 Further studies are ongoing to understand the mechanisms leading to these cystic lesions and keratoacanthomas. Cystic noninflammatory lesions do not require treatment, unless they become inflammatory and/or infected. Topical antibiotic treatments, such as topical clindamycin, metronidazole, or erythomycin, are then indicated.

Lesions suggestive of keratoacanthomas should be surgically removed.

Sunitinib is bright yellow, which may account for the yellowish skin coloration of patients treated with this drug. In our experience, yellowish skin is reported in about 30% of cases and is more visible in fair-skinned patients.

Periocular edema can be seen in sunitinib-treated patients. The preferential periocular location of the edema might be due to the high distension capacity of this skin area. Imatinib, which also targets PDGF and Kit receptors, is also known to be associated with edema, more frequently and severely than is sunitinib.

 Although the prevalent hypothesis explaining this symptom is the effect of PDGFR inhibition on interstitial fluid homeostasis, the exact mechanism leading to edema is not yet known. Moderate sunitinib periorbital edema does not usually require any treatment.

Inhibition of multikinase receptors results in a wide range of new and chronic cutaneous side effects. Some of these effects, like multiple subungual hemorrhages, facial erythema, moderate periocular edema, or hair modifications, are usually well tolerated. Nevertheless, physicians should be aware of them and should provide detailed information to their patients before introducing these drugs. Preventive measures can be taken for some of the skin effects, such as treatment of preexisting plantar hyperkeratosis to prevent HFSR.

Physicians also have to adapt the management of these cutaneous side effects in the context of long-term prescription of kinase inhibitors in renal cell cancer. Indeed, patients sometimes find it even more difficult to accept such chronic cutaneous side effects than acute and more severe effects. The study of these hitherto unknown side effects will provide useful information on skin, hair, and pigment cell physiology. Therefore, besides the mechanistic information generated as a result of their study, early recognition and symptomatic treatment of these associated cutaneous events should be critical aspects of the medical management of patients treated with kinase inhibitors. Synergistic collaboration between oncologists or urologists who treat patients with renal cell cancer and dermatologists is critical.

Paralleling the increasing use of multikinase inhibitors in the field of cancer therapy, patients and clinicians are confronted with frequently occurring cutaneous side effects associated with the use of these new drugs. Two such targeted agents, sunitinib (Sutent) and sorafenib (Nexavar), were recently approved by the US Food and Drug Administration to treat patients with metastatic renal cell cancer (RCC).

Cutaneous Side Effects of Multikinase Inhibitors Used in Renal Cell Cancer

This report of a case of cytokine-refractory metastatic, clear-cell renal cell carcinoma (RCC) presents some current issues related to use of targeted therapy in the community. Due to the different mechanisms of cytostatic vs cytotoxic agents, traditional response assessments may not always apply in deciding when to either continue or stop treatment. While community physicians may increasingly focus more on duration of response, symptom relief, and how well patients tolerate treatment, there is a clear need for validated surrogate markers of biologic activity and response, as well as randomized trials that directly compare some of the targeted therapies being applied in advanced RCC.

This article presents the case of a 59-year-old male with metastatic renal cell carcinoma (RCC) initially treated with interleukin-2 (IL-2, Aldesleukin, Proleukin) plus pegylated interferon-alfa (PEG IFNÎ±), who then developed disease progression requiring further therapy. Since identification in 1993 of the Von Hippel-Lindau (VHL) gene, which is involved in the majority of genetic alterations in clear cell RCC, several agents targeting key molecular pathways active in RCC tumorigenesis (eg, vascular endothelial growth factor receptor [VEGF], epidermal growth factor receptor [EGFR], platelet-derived growth factor B [PDGF-B] receptor, and others) have been developed and are being evaluated in clinical trials, including the recently approved targeted agent sorafenib (Nexavar; formerly known as BAY 43-9006) (Table 1).[1,2]

These biologic agents are generally more tolerable than cytotoxic or immunotherapeutic therapies, and offer an alternate approach to improve outcome in patients with advanced RCC. At the same time, new issues surrounding evaluation of targeted therapies have been raised, including optimal trial design, the utility of traditional response criteria, and identification of molecular markers of drug activity and clinical response. While answers to these issues may help establish standard therapies and treatment guidelines through large randomized trials, physicians in daily practice also need practical evaluation tools that, when combined with other considerations regarding the patient's status, will aid in making treatment decisions in the clinic that are appropriate for each patient.

Case Report: Metastatic Renal Cell Carcinoma

A 59-year-old man underwent routine physical examination by his medical doctor in March 2002. He had no significant complaints, but physical examination revealed a mass in the left upper quadrant of the abdomen. Abdominal computed tomography (CT) scan showed a 10-cm renal mass on the right side and a normal left kidney. He also had enlarged mediastinal and hilar lymph nodes on chest CT scan and a negative bone scan. Results of laboratory assessments were within normal limits, including hemoglobin of 14.9 g/dL, creatinine of 1.0 mg/dL, calcium of 9.5 mg/dL, white blood cell (WBC) count of 8,950/µL, and lactate dehydrogenase (LDH) level of 150 IU/L. Results of transbronchial biopsy revealed a malignancy.

In April 2002 he was referred to a urologist because of the large renal mass, and subsequently underwent a right nephrectomy. The excised tumor was an RCC of clear cell histology, Furhman grade 3, and was 10.5 cm in size (T4). Recovery from surgery was uneventful.

The patient was referred to the Cleveland Clinic Foundation (CCF) Taussig Cancer Center in May 2002 for an opinion regarding additional therapy. He was asymptomatic with excellent Eastern Cooperative Oncology Group (ECOG) performance status (PS = 0). CT scans showed enlarged mediastinal and hilar lymph nodes, a 4-cm mass in the infrahilar region, and a 3-cm retroperitoneal lymph node. Brain CT and bone scans showed no metastases. Biochemical parameters remained relatively within normal ranges: hemoglobin, 13.9 g/dL; LDH, 188 IU/L; creatinine, 1.6 mg/dL, WBC count 8,670/µL; platelet count 267,000/µL; Ca+2, 9.6 mg/dL.

In June 2002, the patient was enrolled in a phase I trial of IL-2 15 mIU/m2 administered subcutaneously (SC) on days 1, 3, and 5 (weekly × 6), plus PEG IFNÎ± 3.0 µg/kg on day 1 (weekly × 6). He received nine treatment courses through August 2003. Toxicity was moderate. His disease was stable with no changes in the sizes of affected lymph nodes and no new disease sites. (The best response observed was stable disease [SD]). At that point, the treatment regimen was discontinued.

The patient was seen every 3 months for laboratory assessments and CT scans. He remained asymptomatic, but follow-up CT scans in February 2004 showed evidence of progressive disease. The infrahilar mass had increased to 4.5 cm, there was a 3.1-cm mediastinal lymph node, and the retroperitoneal lymph node measured 5.7 cm. Laboratory values remained relatively normal: hemoglobin, 14.9 g/dL; hematocrit, 46.7%; WBC count 4,890/µL; platelet count, 408,000/µL; LDH, 190 IU/L; Ca+2, 10.9 mg/dL; creatinine, 1.0 mg/dL; total bilirubin, 0.4 mg/dL.

Treatment options were discussed with the patient, including supportive care and clinical trials including the ongoing Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs).

The patient was entered into TARGETs, and therapy was initiated in March 2004. He had some toxicity, grade 1 diarrhea and grade 1 hand/foot syndrome, which suggested he was receiving active drug. The patient had a partial response (PR) of approximately 12 months' duration and then developed progressive disease. With unblinding, it was determined that the patient had received sorafenib 400 mg bid. Therapeutic options discussed with the patient at this point included a period of observation, a phase I trial of IMOxine plus IFNÎ± with or without MG98, or continuing sorafenib treatment. The TARGETs protocol allowed for continuing therapy in the presence of progressive disease, if the patient seemed to benefit clinically from treatment.

The patient elected to continue sorafenib. At the time of this writing, treatment has continued for another 10 months. He continues with SD, with no new disease sites, and adverse effects have been acceptable. On December 20, 2005, the US Food and Drug Administration (FDA) approved sorafenib for the treatment of adults with advanced RCC, the most common type of kidney cancer.

This case is a typical presentation of a patient with RCC and synchronous disease. He was asymptomatic, and scans revealed enlarged lymph nodes and a negative bone scan. Several groups have proposed models to predict survival based on risk factors.[3,4] The Memorial Sloan-Kettering Cancer Center criteria identified five prognostic factors associated with shorter survival in stage IV RCC patients, including poor performance status (Karnofsky < 80%), high serum LDH level (> 1.5 times the upper limit of normal), low hemoglobin (< lower limit of normal), high "corrected" serum calcium (> 10 mg/dL), and no previous nephrectomy. Multivariate analysis of these factors in 670 patients was used to develop a model to stratify patients into low-, intermediate-, or high-risk categories.[3] With none of the five risk factors, this case falls into the low-risk group, wherein the model predicts a median survival of 20 months, and 1-, 2-, and 3-year overall survivals (OS) of 71%, 45%, and 31%, respectively. The median survival (MS) duration decreases to 10 months in the intermediate-risk group (1-2 risk factors), and to 4 months in the poor-risk group (3-5 risk factors).[3]

When this patient received first-line treatment in 2002, our group was involved in trials of cytokines, and he was entered on a phase I trial of SC IL-2 and PEG IFNÎ±. High-dose IL-2 is a standard treatment for patients with advanced RCC and the only FDA-approved cytokine in this setting, but it is associated with significant toxicities. In a recent study in 400 metastatic RCC patients, Yang et al reported response rates (RRs) of 21% in patients receiving high-dose intravenous (IV) IL-2 (720,000 U/kg and 13% in those receiving low-dose IV IL-2 (72,000 U/kg) (

 = .048), with no significant survival differences in the two arms.[5] A third arm of this trial was SC IL-2, which resulted in a 10% RR-similar to that in the low-dose IV IL-2 group but lower than in the high-dose group (

 = .033). Response durations varied widely (2 to 130+ months) and tended to be longer with high-dose IL-2, particularly in patients achieving complete response. Toxicity was also markedly increased in the high-dose vs the low-dose group. IFNÎ± is associated with an approximately 15% RR in patients with metastatic RCC, and the side-effect profile allows its use combined with other agents. Previous trials administering SC IL-2 (either high- or low-dose) and IFNÎ± at varying doses have yielded mixed results.[6-9]

The patient in our case ultimately accrued onto the TARGETs trial investigating sorafenib, a novel bio logic targeting multiple kinases that are involved in pathways reported to be active in renal cell tumor growth and angiogenesis, including Raf kinase and VEGF receptor tyrosine kinases; sorafenib had demonstrated activity in previous phase I and phase II trials.[10,11] While the patient was on study, progression-free survival (PFS) data from TARGETs became available, with 769 patients enrolled and 342 PFS events reported.[12] PFS significantly improved from 12 weeks with placebo to 24 weeks with sorafenib treatment, a highly statistically significant difference (

 < .00001). The 12-week PFS rates were 50% and 79% for the two treatment groups, respectively.

Moreover, a benefit of sorafenib was seen among all patient subgroups regardless of age, previous treatments, or disease duration. Seventy-eight percent of sorafenib patients had SD, and 2% had PRs by initial independent review (55% and 0%, respectively, in the placebo group), underscoring the apparent importance of disease control (SD + PR) in achieving clinical benefit in advanced RCC. (These data also indicate that randomized PFS may be a better predictor of OS and clinical benefit or disease control than objective tumor response.) Furthermore, 74% of sorafenib patients (20% of placebo patients) had some degree of tumor regression.[12] In a subsequent interim analysis, there was an estimated 39% significant improvement in OS (the primary study endpoint) for patients receiving sorafenib vs placebo (hazard ratio [HR], .72; 

 = .018), with a corresponding RR of 10% by investigator assessment.[13] Tolerability of sorafenib was good: grades 3 and 4 drug-related effects included rash (1% of patients), diarrhea (1%), hand-foot skin reaction (5%), fatigue (2%), and hypertension (1%).[12,13]

After receiving sorafenib on study, the patient in our case achieved a PR that lasted for 12 months, with SD maintained for a further 6 months and continuing at the time of this report (Figure 1).

In this lesion, development of a cystic or necrotic center was noted. This has been seen after therapy with other TKIs, and it is most common in soft tissue and similar lesions, but can be seen in almost any site. The etiology is presumed to be an effect similar to that seen in patients with gastrointestinal stromal tumors (GIST) treated with imatinib (Gleevec).[14] The possibility of obscuring a response because of this type of development, and over producing with an expanding cystic lesion exists. The importance of a surrogate PFS demonstrating clinical benefit is again illustrated. Tumor necrosis may be an important indicator of anticancer activity and may mask RR.

Interestingly, when the patient initiated treatment, we assumed he was receiving sorafenib because of the mild toxicities exhibited (eg, grade 1 diarrhea and hand-foot skin reaction). Notably, however, when the study was unblinded, we found that our assumptions regarding the probable treatment arm to which patients were assigned were often incorrect. For example, several placebo-treated patients in the trial had diarrhea or hand-foot skin reaction.

A primary question raised by this case in terms of treatment in the community relates to duration of treatment and subsequent-line therapies. The TARGETs protocol specified that patients with disease progression could continue therapy based on potential for clinical benefit. This may mirror what will happen in the community, given the good tolerability of sorafenib and other novel molecular therapies. Experience in the community with combinations of conventional chemotherapy with the VEGF inhibitor bevacizumab (Avastin) indicates that targeted therapy is often continued when disease progresses, whereas the cytotoxic agent might be changed or another targeted agent added. Thus, the ability to combine targeted therapies with cytotoxic chemotherapy or cytostatic agents, which will depend on side effects, will become key as clinicians move forward in using these agents.

Another consideration regarding use of targeted agents in the community relates to evaluating response in individual patients. Defining disease progression based on an increase in tumor size at a specified time point may have different implications in the community, compared with assessments that have to meet response criteria in clinical trials (eg, Response Evaluation Criteria in Solid Tumors [RECIST]). Physicians in the community may focus more on relief of symptoms and on toxicities (or lack thereof) to decide when to make a change in treatment. In patients with indolent disease, continuation of therapy in the presence of progressive disease may be reasonable, if a patient's symptoms are controlled. In the case presented herein, the patient on sorafenib was continued following disease progression, and then did well with long-duration SD. Subjective experience from TARGETs revealed that some patients "seemed to feel better," even though tumor size may have increased. Changes in tumor size may occur over a prolonged period, and on the other hand, stability of disease may also provide significant patient benefit even in the absence of an objective response, as illustrated in the pivotal, phase III, placebo-controlled trial of bevacizumab in 813 patients with metastatic colorectal cancer receiving up-front irinotecan (Camptosar)/fluorouracil/leucovorin (IFL) ± bevacizumab. Even in patients who failed to achieve an objective response ("nonresponders" based on RECIST criteria), PFS and MS increased significantly (

 < .001 and < .05, respectively).[15,16] These and other findings support the current focus on re-evaluation of response criteria in patients treated with targeted therapies. Perhaps, the rate of tumor growth or the occurrence of any tumor shrinkage, regardless of the amount, may be important clinical response clues in patients treated with targeted therapies.

Surrogate markers of biologic effect and response are also needed, and will aid in application of these treatments in the clinic. No reliable pharmacodynamic markers are currently available for targeted agents in RCC. One area of interest in this regard is to measure tumor blood flow as a surrogate for VEGF inhibitor-induced antiangiogenic effects. For example, in the TARGETs trial, color Doppler ultrasound was used to track changes in tumor blood flow.[17] Preliminary data in a 30-patient subset showed that reductions in tumor blood flow were evident as early as 3 weeks after treatment initiation, and correlated with improved PFS.

Dr. Bukowski acknowledges research funding, a consultant/advisory role, and membership on a speaker's bureau for Bayer, Genentech, and Pfizer.

1. Favaro JP, George DJ: Targeted therapy in renal cell carcinoma. 

2. Cohen HT, McGovern FJ: Renal cell carcinoma. 

3. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. 

4. Zisman A, Pantuck AJ, Said JW, et al: Improved prognostication of renal cell carcinoma using an integrated staging system.

5. Yang JC, Sherry RM, Steinberg SM, et al: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. 

6. Dutcher J, Fisher R, Weiss G, et al: Outpatient subcutaneous (SC) interleukin-2 (IL-2) plus Î±-interferon (IFN) in metastatic renal cell cancer (RCC): 3-year follow-up of the cytokine working group study (abstract). 

7. Vogelzang NJ, Lipton A, Figlin RA: Subcutaneous interleukin-2 plus interferon Î±-2a in metastatic renal cancer: An outpatient multicenter trial. 

8. Atzpodien J, HÃ¤nninen EL, Kirchner H, et al: Multi-institutional home-therapy trial of recombinant human interleukin-2 and interferon Î±-2 in progressive metastatic renal cell carcinoma. 

9. Clark JI, Gaynor ER, Martone B, et al: Daily subcutaneous ultra-low-dose interleukin 2 with daily low-dose interferon-Î± in patients with advanced renal cell carcinoma. 

10. Ratain MJ, Eisen T, Stadler WM, et al: Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) (abstract 4544). 

11. Strumberg D, Awada A, Piccart M, et al: Final report of the phase I clinical program of the novel raf kinase inhibitor BAY 43-9006 in patients with refractory solid tumors (abstract 813). 

12. Escudier B, Szczylik C, Eisen T, et al: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (abstract 4510). 

13. Escudier B, Szczylik C, Eisen T, et al: Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) (abstract 794). 

14. Ryu M-H, Lee J-L, Chang, HM, et al: Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. 

15. Mass RD, Sarkar S, Holden SN, et al: Clinical benefit from bevacizumab (BV) in responding (R) and non-responding (NR) patients (pts) with metastatic colorectal cancer (mCRC) (abstract 3514). 

17. Lamuraglia M, Lassau N, Chami L, et al: Doppler ultrasonography with perfusion software and contrast agent injection as a tool for early evaluation of metastatic renal cancers treated with the Raf kinase and VEGFR inhibitor: A prospective study (abstract 3069). 

Targeted Therapy for Cytokine-Refractory Metastatic Renal Cell Carcinoma, and Treatment in the Community

ABSTRACT: Patients with metastatic renal cell carcinoma continue to present a therapeutic challenge. Current therapeutic approaches involve surgery and various types of immunotherapy. The rationale for this latter form of therapy include the observations of spontaneous tumor regression, the presence of a T-cell–mediated immune response, and the tumor responses observed in patients receiving cytokine therapy. Analysis of prognostic factors in these patients demonstrates that clinical responses occur most frequently in individuals with good performance status. The cytokines interleukin-2 (IL-2, aldesleukin [Proleukin], interferon-alfa (Intron A, Roferon-A) , or the combination produce responses in 15% to 20% of patients. Randomized trials suggest that administration of interferon-alfa may result in a modest improvement in median survival. Investigation of the molecular genetics of renal cell carcinoma and the presence of T-lymphocyte immune dysregulation have suggested new therapeutic strategies. Further preclinical and clinical studies investigating inhibitors of angiogenesis or pharmacologic methods to reverse immune dysregulation are ongoing. Therapeutic results in patients with renal cell carcinoma remain limited, and investigational approaches are warranted. [ONCOLOGY 13(6):801-810, 1999]

Renal cell carcinoma is an epithelial malignancy that appears to be slowly increasing in incidence. It is estimated that 30,600 new cases of kidney cancer are diagnosed annually in the United States,[1] and 12,000 deaths result from this tumor each year. Since 1935, the rate of increase of renal cell carcinoma has slowed somewhat but approximates 2% per annum.[2]

Histologically, renal cancer encompasses a heterogeneous group of diseases.[3] The most common histologic type is clear cell cancer (Figure 1a), which accounts for approximately 75% of renal carcinomas. Papillary tumors (Figure 1b) occur in only 15% of patients, and other malignancies, such as sarcomatoid, collecting duct, and medullary tumors, develop in fewer than 5%.

Recent molecular genetic studies have identified mutations of the von Hippel Lindau (VHL) gene in patients with clear cell carcinoma.[4] It appears that vascular endothelial growth factor (VEGF) may be under the regulation of the VHL protein product. Mutant forms of this protein, such as are found in clear cell cancer, may be associated with enhanced expression of VEGF.[5] The vascular nature of renal tumors, together with these observations, suggest that methods to inhibit VEGF expression may be of therapeutic interest.

.[6] This proto-oncogene codes for a protein that functions as a receptor for hepatocyte growth factor.

These kinds of studies have provided insights into the genetic defects occurring in renal cancer and may lead to new treatment approaches. Current therapeutic approaches in patients with advanced disease continue to involve surgery and various forms of immunotherapy, however.

Figure 2 shows the distribution by stage of patients with newly diagnosed renal cell carcinoma. Close to half of patients (45%) have localized disease at diagnosis. However, approximately 30% of individuals have metastatic disease, and another 25% have locally advanced tumors with lymph node and/or local organ involvement.

In patients with metastatic renal cell carcinoma, 3- to 5-year survival rates are less than 5%.[7] Outcomes differ in subsets of individuals with advanced disease, however. In patients who have synchronous metastatic disease or who develop metastases within 12 months of surgery, the 2-year survival rate approaches 0%.[8] In contrast, patients in whom metastatic disease develops more than 2 years from diagnosis have a 5-year survival rate of over 20%.[8] In addition, various prognostic factors play an important role in determining therapeutic outcomes in patients with metastatic renal cancer. The most important factor identified to date is performance status.[9]

The possibility that the immune response may control the progression of cancer was suggested over 40 years ago. In patients with renal cancer, three observations have provided a rationale for the use of immunotherapy.

The first observation, spontaneous regression, was recognized originally in patients in whom synchronous metastatic disease regressed after removal of the primary tumor. Recent reviews suggest that this phenomenon is very uncommon.[10]

In addition, it has been observed that pulmonary metastases may undergo regression in a subset of patients with metastatic renal cancer. In two trials, one conducted by Oliver and colleagues[11] and the second by the Canadian Urologic Group,[12] approximately 5% to 7% of patients had transient partial regressions of pulmonary nodules that were unrelated to therapy.

The second observation is the presence of a T-lymphocyte–mediated immune response in patients with renal cancer. Immunohistologic examination of renal tumors demonstrates infiltration by T-lymphocytes (Figure 3), as well as macrophages.[13] In approximately 25% of patients, these tumor-infiltrating lymphocytes are cytolytic and/or produce cytokines in response to autologous tumor in a major histocompatibility complex (MHC)–restricted fashion.[14] Recent studies have attempted to define the antigens recognized by these T-lymphocytes.[15]

The last observation is the occurrence of clinical responses in patients receiving biological agents, such as the cytokines. The cytokines used have included the interleukin and interferon families, as well as the colony-stimulating factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim- [Leukine, Prokine]), and macrophage colony-stimulating factor (M-CSF).

Of the interleukin family, recombinant human interleukin-2 (rHu-IL-2, aldesleukin [Proleukin]) is the predominant agent used in patients with renal cell carcinoma. This protein is a growth factor that enhances the proliferation and function of T-lymphocytes.[16]

In view of the T-lymphocyte population found in renal tumors, this cytokine was studied in kidney cancer patients. A recent review of clinical results in over 1,700 patients (Table 1) suggests that regression rates in individuals receiving rHu-IL-2 are approximately 15% to 16%.[17]

Three schedules have been used: a high-dose intravenous bolus approach, continuous IV infusion, and subcutaneous administration. In patients receiving high-dose intravenous rHu-IL-2, the complete regression rate was approximately 5%, whereas in those given the other regimens, this frequency tended to be somewhat lower (approximately 2% to 3%). In addition, the complete responses in patients receiving high-dose rHu-IL-2 appeared to be durable in many instances. Overall, however, clinical results did not appear to differ significantly with different methods or schedules of administering rHu-IL-2.

In order to compare these approaches, randomized clinical trials are necessary, since prognostic factors can significantly influence the outcome in renal cancer patients. A recent National Cancer Institute (NCI) randomized trial compared high-dose, intravenous-bolus rHu-IL-2 (720,000 IU/kg every 8 hours for 15 doses) with a lower-dose bolus (72,000 IU/kg every 8 hours for 15 doses) schedule in over 200 patients.[18] The overall response rates were 19% and 10% in the high- and low-dose groups, respectively, with no differences in median response duration or median survival between the two groups. Currently, the NCI is conducting a second trial to compare high-dose intravenous rHu-IL-2, a low-dose intravenous regimen, and subcutaneous rHu-IL-2.

A second cytokine that is widely used for the treatment of renal cancer is interferon-alfa (Intron A, Roferon-A). This pleiotropic protein has antiviral, immunomodulatory, and antiproliferative activities.

A recent review of over 1,500 patients (Table 2) suggested that tumor regression occurs in 12% to 15% of patients following administration of interferon alfa.[3] However, response rates may vary somewhat between the interferon preparations,[3] ranging from 12% to 18%. Complete responses occur in 2% to 5% of patients and are generally seen in individuals with pulmonary metastases.

The optimal therapeutic dose of interferon is not well defined, but appears to be between 5 and 10 MU/m² administered as a subcutaneous injection 3 to 5 days weekly.[19]

Randomized Trials-Unlike rHu-IL-2, randomized trials have been conducted in which interferon-alfa has been compared with other approaches. These include comparisons with non-cytokine–containing regimens and/or regimens containing other cytokines.

The studies of greatest interest (Table 3) are those reported in a preliminary fashion by PyrhÃ¶nen et al[20] and Ritchie et al.[21] PyrhÃ¶nen et al[20] conducted a trial in approximately 160 patients with metastatic disease who received either interferon-alfa and vinblastine or vinblastine alone. This trial detected significant differences in response rates in patients treated with interferon-alfa plus vinblastine compared with vinblastine alone (16.5% vs 2.5%). Median survival durations also differed significantly between the two groups (15.8 vs 8.8 months). These results suggest that interferon as a single agent may enhance survival since the clinical activity of vinblastine is minimal.[22]

Ritchie et al[21] compared renal cancer patients receiving interferon-alfa (10 MU subcutaneously three times weekly) with those receiving methoxyprogesterone (300 mg/d). This study, which involved over 330 patients, was closed early because of differences in median, 1-, and 2-year survival rates. Clinical results in patients treated with interferon-alfa were significantly better than results in patients given methoxyprogesterone. In patients with measurable disease, interferon-alfa produced responses in 13% and methoxyprogesterone in 7%. This study concluded that interferon-alfa significantly enhances survival in patients with metastatic renal cell carcinoma.

A third trial that was somewhat smaller than the latter two studies did not demonstrate a significant improvement in survival but the trends were suggestive.[23] Thus, the findings of these trials suggest that interferon-alfa may enhance survival in patients with metastatic renal cell cancer, although the effect appears to be modest.

A second interferon subtype is interferon-gamma-1b (Actimmune). This protein, referred to as immune interferon, is produced by T-cells.[24] Phase I and II studies suggested that responses to interferon-gamma occur in over 15% of patients with renal cancer.[3,25,26]

Recently, the Canadian Urologic Group conducted a randomized, double-blind, placebo-controlled trial of this interferon in over 180 patients with metastatic renal cell carcinoma.[12] Interferon-gamma produced a response rate of 4%, and placebo, a rate of 6%. This trial did not confirm the activity of interferon-gamma in patients with metastatic renal cell carcinoma. It also demonstrates the importance of a randomized trial design when assessing the value of any therapy for patients with metastatic renal cell carcinoma.

The single-agent activity of interferon-alfa and rHu-IL-2 noted in patients with metastatic renal cell carcinoma, and preclinical observations[27] indicating that these two cytokines may have synergistic antitumor activity, led to a series of studies examining the combination of these two proteins. A recent review[16] of over 1,400 patients receiving interferon-alfa and rHu-IL-2 (Table 4) suggests that the overall response rate to the combination is 20%, and that approximately 3% to 5% of patients have complete responses. These results do not appear to depend on the schedule of rHu-IL-2, and occur with either subcutaneous, continuous intravenous infusion, or intravenous boluses.

The clinical effects of this combination have been examined in randomized trials by two groups of investigators. Negrier et al[28] performed a three-arm study in 425 patients with renal cancer. The treatments included: (1) a continuous IV infusion of rHu-IL-2 (18 MIU/m²/d) alone, (2) the combination of rHu-IL-2 (at the same dose as in the single-agent arm) and interferon-alfa (6 MU three times weekly), and (3) interferon-alfa (18 MU three times weekly) alone.

Response rates with the cytokine combination were significantly higher than with rHu-IL-2 or interferon-alfa alone (18.6% vs 6.5% and 7.5%, respectively), as was event-free survival at 1 year. Toxicity was substantial, however, with high therapy-related mortality in the rHu-IL-2 and rHu-IL-2–interferon-alfa arms. Finally, there were no differences in overall survival among the three treatment arms. However, upon failure of their assigned therapy, patients were permitted to switch to another treatment arm, thus obscuring possible differences.

Recently, Henriksson et al[29] reported a study in which 128 patients with renal cell carcinoma were randomized to receive tamoxifen (Nolvadex) or the combination of subcutaneous rHu-IL-2, natural leukocyte interferon-alfa, and tamoxifen. No significant difference in median survival between the two treatment groups was detected. Response evaluation was not a primary end point of this trial; however, the authors noted five complete responses in the rHu-IL-2–interferon-alfa group and two in the patients receiving tamoxifen. Based on these results, it appears that the combination of rHu-IL-2 and interferon-alfa may increase response rates. However, it is unclear whether this therapy improves overall survival.

Finally, investigators have been intrigued by the potential synergism of biological agents with chemotherapeutic drugs. Specifically, the combination of interferon-alfa and fluorouracil has been widely investigated in other disease states, and recent data suggest that the combination of rHu-IL-2, interferon-alfa, and fluorouracil may enhance response rates in patients with renal cell carcinoma. In a review of 433 patients receiving various schedules of these three agents, an overall response rate of ~ 27%[30] was found. Response rates varied considerably among studies.

Kirchner et al summarized their experience with 246 patients who received these three agents in a phase II trial.[31] The response rate was 33%, with 11% of patients achieving a complete response. Patient response correlated with prognostic factors.

Finally, a randomized trial has been published in preliminary form[32] in which 131 patients were randomized to subcutaenous rHu-IL-2 and interferon-alfa, or the combination of rHu-IL-2, interferon-alfa, and fluorouracil. Low response rates (< 10%) were observed in both arms, with no enhancement by fluorouracil.

Available data suggest that there may be a slight increase in response rates when fluorouracil is administered with rHu-IL-2 and interferon-alfa. However, current results are conflicting, and additional randomized trials of chemoimmunotherapy are necessary.

The optimal therapy for patients with metastatic renal cell carcinoma depends on their disease and performance status. For individuals with a solitary metastatic site or surgically approachable disease, resection of metastatic disease is reasonable. Also, individuals with two to four pulmonary metastases may benefit from this approach.[33]

Among patients with unresectable metastatic disease, the groups who stand to benefit most from cytokine therapy are those who are asymptomatic and those who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Alternative approaches for these individuals include observation until disease progresses, or use of a cytokine, such as rHu-IL-2, interferon-alfa, or the two agents in combination.

In patients who are symptomatic (ECOG performance status of 3), symptomatic care may be most appropriate. For a more complete discussion of clinical approaches to these patients, readers are referred to a recent review.[3]

In view of the limited efficacy of currently available therapy for metastatic renal cell carcinoma, investigation of novel approaches is of paramount importance. Recent studies have focused on continued exploration of adoptive immune approaches, the use of post-surgical adjuvant therapy, and the role of immunosuppression.

Adoptive therapy has been extensively investigated in renal cell carcinoma in the past using lymphokine-activated killer cells[34] and tumor-infiltrating lymphocytes.[35,36] These studies suggested that selected patients responded to the adoptive transfer of cells. However, the role of the lymphocyte effectors in these studies was unclear, since concomitant IL-2 was also administered in most trials.