Kidney Cancer

Dr. Tim Eisen provided an update on the sorafenib (Nexavar) phase III trial in patients with advanced renal cell carcinoma (RCC), or kidney cancer, during the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Atlanta. Dr. Eisen is the consultant medical oncologist at The Royal Marsden Hospital in London. The updated analysis confirmed that overall survival was longer for sorafenib than for placebo patients.

The introduction of newer classes of chemotherapeutic agents, with varying mechanisms of action by which they affect tumor growth and viability, has challenged the traditional norms of clinical trial design and drug approval in oncology. Most notably, the emergence of cytostatic biologic agents with antitumor efficacy has necessitated reassessment of appropriate primary endpoints for phase II and III trials in advanced disease from both a clinical and regulatory standpoint. Recent data in the field establishes an endpoint hierarchy, which places progression-free survival (PFS) between overall survival (OS) and response rate (RR) as appropriate primary endpoints for assessing the clinical efficacy of cytostatic and cytotoxic agents.

Although improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the US Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.

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.

The manuscripts that comprise this supplement "Defining Clinical Endpoints in Renal Cell Carcinoma" are presented by six leading international clinical and basic investigators, and are derived from their presentations at the roundtable discussion, "Defining Clinical Endpoints in Renal Cell Carcinoma," which took place in Chicago on October 21, 2005, sponsored by Bayer HealthCare.

Several novel targeted agents are being tested for the treatment of advanced renal cell carcinoma (RCC), and results of phase I and II trials have been encouraging. A recently completed phase III, placebo-controlled study showed that median progression-free survival doubled from 12 weeks to 24 weeks in patients treated with the multi-kinase inhibitor sorafenib (Nexavar) (hazard ratio [HR], 0.44; P < .00001), and approximately three-quarters of patients had some degree of tumor regression. Furthermore, interim analysis showed an estimated 39% improvement in overall survival in sorafenib-treated patients (HR, 0.72; P = .018) and an investigator-assessed response rate of 10%, indicating that many more patients had clinical benefit than had tumor regression qualifying as response by traditional criteria. These data and others have added to the evidence of lack of correlation between response rate and clinical benefit in RCC patients (as well as in other tumor types) treated with targeted therapies. Issues surrounding study endpoints and biologic efficacy markers for molecular targeted agents in RCC are discussed in this article, with a focus on results of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs).

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

The US Food and Drug Administration (FDA) recently approved sunitinib malate (Sutent) capsules for two types of cancer: advanced renal cell carcinoma and malignant gastrointestinal stromal tumor (GIST), after disease progression on or intolerance to the frontline drug imatinib mesylate (Gleevec).

For the first time, the US Food and Drug Administration (FDA) has granted a new oncologic drug product approval for indications for two different cancers simultaneously. The agency approved Sutent (suniti-nib, Pfizer) for the treatment of patients with gastrointestinal stromal tumors (GIST) whose disease has progressed on imatinib (Gleevec) or who are unable to tolerate imatinib. It also granted Sutent accelerated approval for treating advanced renal cell carcinoma (RCC).

The Food and Drug Administration (FDA) has approved Nexavar (sorafenib tosylate) tablets for the treatment of patients with advanced renal cell carcinoma. Nexavar, a multikinase inhibitor that has been shown to double progression-free survival in these patients, is the first FDA-approved treatment for this type of cancer in more than a decade, Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc.

Although resection currently remains the standard of care for renalcarcinoma, the search for less invasive treatments has led to alternativesurgical approaches. Even less invasive, and appropriate for manygroups of patients, is percutaneous radiofrequency ablation, which inducestumor necrosis via lethal hyperthermia. Multiple series of renaltumors treated with percutaneous ablation in vivo and left in situ havebeen published; these series reveal that for small renal tumors,radiofrequency ablation results in complete necrosis at imaging in 79%to 100% of cases. Because current results come from tumors left in situwith short postablation follow-up, long-term results are necessary tocompare outcomes to surgical standards. Complication rates are lowerthan those following partial nephrectomy. Future reports will shed lighton the long-term outcomes of percutaneous ablation and the relativeadvantages and disadvantages of various technologies for thermal ablation.

This supplement to Oncology News International includes more than 15 reportson presentations made at the 41st annual meeting of the American Society of Clinical Oncology.Reviews focus on the use of targeted agents in non–small-cell lung cancer and other solid tumors,evaluating the novel therapies bevacizumab, cetuximab, bortezomib, erlotinib, and gefitinib, aloneand/or in combination with other chemotherapy agents. Continuing medical education credit isavailable by completing a post-test and evaluation online at www.cancernetwork.com/cme.

This supplement to Oncology News International includes more than 15 reportson presentations made at the 41st annual meeting of the American Society of Clinical Oncology.Reviews focus on the use of targeted agents in non–small-cell lung cancer and other solid tumors,evaluating the novel therapies bevacizumab, cetuximab, bortezomib, erlotinib, and gefitinib, aloneand/or in combination with other chemotherapy agents. Continuing medical education credit isavailable by completing a post-test and evaluation online at www.cancernetwork.com/cme.

ASCO - In a large randomized double-blind phase III international trial in patients with previously treated metastatic renal cell cancer (RCC), the oral multikinase inhibitor sorafenib (BAY 43-9006) was well tolerated and doubled progression-free survival (PFS) vs placebo with best supportive care. Lead investigator Bernard Escudier, MD, presented interim results in 769 patients at the 41st Annual Meeting of the American Society of Clinical Oncology (LBA4510) on behalf of the BAY 43-9006 TARGETs Clinical Trial Group. The primary endpoint of the study, overall survival, has not yet been reached, he said, and will be reported at a later date.

Renal-cell carcinoma (RCC) is curable only in patients presenting with resectable, early-stage disease. Advanced local or metastatic disease carries an approximate 15% 5-year survival rate. However, the natural history of metastatic RCC is heterogeneous, and aggressive palliative treatment is recommended, especially for patients with a solitary metastatic site and good performance status.

This supplement to Oncology News International includes 17 reportson clinical trials of targeted therapies used alone, in combination with chemotherapy,or in combination with each other in the treatment of non–small-cell lung cancer (NSCLC),bronchoalveolar carcinoma, glioblastoma multiforme, and renal cell carcinoma.Included is a report on a novel targeted agent recently approved for treatment of NSCLC.

WASHINGTON-The 2004 US Surgeon General’s report on the health risks of smoking adds five cancers to the list of diseases caused by cigarettes-acute myeloid leukemia, and stomach, pancreatic, cervical, and kidney cancers. Other newly

SAN FRANCISCO-Renal cell carcinoma patients given a vaccine prepared from their own excised tumors experienced delayed time to progression (TTP) in a multicenter phase III trial, Christian Doehn, MD, of the University of Lübeck

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

Drs. Uzair Chaudhary and GeraldHull provide a comprehensivereview of the role ofcytoreductive surgery in metastaticrenal cell carcinoma. This controversialtopic has been debated for manyyears. Metastatic renal cell carcinomacontinues to be a chemotherapyresistanttumor with a poor prognosis.About 30% of newly diagnosedpatients present with metastatic disease.In the metastatic setting, themost recognized treatment modalitiesinvolve the biologic agents interferon-alpha and interleukin-2 (IL-2,Proleukin). They produce an objectiveresponse rate of about 10% to15%, with approximately 5% of patientsachieving a durable completeresponse.

In this issue of ONCOLOGY,Chaudhary and Hull succinctlysummarize historical trends andcurrent thinking regarding the role ofcytoreductive nephrectomy in patientswith metastatic kidney cancer.Before the era of immunotherapy,there was little evidence that the naturalhistory of metastatic renal cellcarcinoma was improved by cytoreductivenephrectomy.[1] Patientswith metastatic cancer generally diefrom complications related to theirsites of tumor spread and not fromthe primary tumor; thus, on face value,it seems illogical to surgicallyremove the primary tumor in thesepatients.

Metastatic renal cell carcinoma is a devastating disease associatedwith poor survival. Immunotherapy is the mainstay of treatment, butresponse rates are low. The role of cytoreductive surgery in thepresence of metastatic disease is evolving. From both retrospective andrecently published randomized clinical trials, it is now apparent thatamong patients with metastatic renal cell carcinoma and good performancestatus, cytoreductive surgery followed by immunotherapy improvessurvival. However, this approach is likely to be detrimental inpatients with poor performance status. Clinical trials of novel agentsremain a priority in this disease.

FRAMINGHAM, Massachusetts-Genzyme Molecular Oncology has launched a phase I/II vaccine trial in advanced kidney cancer. The vaccine is made by combining the patient’s own cancer cells with dendritic cells using an electrical fusion approach. Up to 20 patients will be enrolled at Beth Israel Deaconess Medical Center and the Dana-Farber Cancer Institute, Boston.

Women who received radiation therapy for Wilms’ Tumor are at increased risk of complications during pregnancy and, therefore, should be carefully assessed and monitored by their obstetricians. These conclusions were part of a National Wilms’

Despite significant advances in the treatment of a variety of malignancies, highly effective therapies for most patients with metastatic renal cell carcinoma or metastatic melanoma are rare. Traditional oncologic treatment methods, such as

Interleukin-2 (IL-2, Proleukin) is one of the most effective agents in the treatment of metastatic renal cell carcinoma and metastatic melanoma. High-dose IL-2 therapy produces overall response rates of 15% to 20%;

Although high-dose interleukin-2 (IL-2, Proleukin), a highly toxic agent used in the treatment of renal cell carcinoma and melanoma, was initially associated with treatment-related mortality, it can, in the appropriate

Flavopiridol [2-(2-chlorophenyl 5 ,7-dihydroxy-8-[cis-(3-hydroxy-1-methyl-4-piperidinyl)-4H-1-benzopyran-4-one, hydrochloride] is a semisynthetic flavone with a novel structure compared with that of polyhydroxylated flavones, such as quercetin and genistein.[1] It is derived from rohitukine, an alkaloid isolated from the stem bark of Dysoxylum binectariferum, a plant indigenous to India.[2] Originally synthesized and supplied by Hoechst India Limited, flavopiridol is provided to the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) by Aventis Pharmaceuticals, Inc.