Treatment of patients with metastatic renal cell ... - Wiley Online Library

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Treatment of Patients With Metastatic Renal Cell Cancer A RAND Appropriateness Panel

Ronald J. Halbert, MD, MPH1,2 Robert A. Figlin, MD3,4 Michael B. Atkins, MD5 Myriam Bernal, MD, MPH1 Thomas E. Hutson, DO, PharmD6 Robert G. Uzzo, MD7 Ronald M. Bukowski, MD8 Khuda Dad Khan, MD, PhD9 Christopher G. Wood, MD10 Robert W. Dubois, MD, PhD1 1

Cerner Life Sciences, Beverley Hills, California.

2

Department of Community Health Sciences, University of California-Los Angeles School of Public Health, Los Angeles, California. 3 Department of Medicine, University of Los Angeles School of Medicine, Los Angeles, California. 4

Department of Urology, University of Los Angeles School of Medicine, Los Angeles, California. 5 Department of Medicine, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, Massachusetts. 6 GU Oncology Program, Texas Oncology, PA/ Baylor Sammons Cancer Center, Dallas, Texas.

BACKGROUND. New developments in the treatment of patients with metastatic renal cell cancer (MRCC) have suggested a need to reevaluate the role of systemic therapies. The authors convened a panel of medical and urologic oncologists to rate the appropriateness of the main options. METHODS. The authors used the RAND/University of California-Los Angeles Appropriateness Method to evaluate systemic therapy options and cytoreductive nephrectomy. After a comprehensive literature review, an expert panel rated the appropriateness of systemic options (108 permutations) and cytoreductive nephrectomy (24 permutations) for patients with MRCC. RESULTS. The appropriateness evaluation indicated that 27.3% of permutations were rated ‘‘appropriate,’’ 46.9% were rated ‘‘inappropriate,’’ and 25.8% were rated ‘‘uncertain.’’ There was a high rate of agreement (95%). Sunitinib and sorafenib were rated appropriate for patients with low-to-moderate risk regardless of prior treatment. Temsirolimus was rated appropriate for first-line therapy for higher risk patients. Interferon-a and low-dose interleukin-2 were rated inappropriate or uncertain. In patients who received prior immunotherapy, cytokines were rated inappropriate. In all permutations for evaluating systemic therapy, enrollment into an investigational trial was considered appropriate, treatment with bevacizumab was uncertain, and thalidomide was inappropriate regardless of risk status or prior therapy. For good surgical risk patients with planned immunotherapy, nephrectomy was rated appropriate in patients who had limited metastatic burden regardless of tumor-related symptoms and in symptomatic patients regardless of metastatic burden. Only the most favorable combination of surgical risk, metastatic burden, and symptoms generated an ‘‘appropriate’’ rating for patients with planned targeted therapy.

7

Department of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 8 Department of Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio. 9

Department of Oncology/Hematology, American Health Network, Indianapolis, Indiana. 10

Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Supported by an unrestricted educational grant from Chiron Corporation. At the time this work was performed, Drs. Halbert, Bernal, and Dubois were employees of Cerner Corporation, which provides consulting services to the pharmaceutical industry.

Dr. Hutson has acted as a consultant and member of the Speakers Bureau for and has received support from Pfizer Inc. and Bayer Inc. Dr. Wood is a Medical Advisory Board member for Antigenics Inc. Consensus panel members included the following: Michael B. Atkins, MD (Beth Israel Deaconess/Harvard Medical School, Boston, MA); Ronald M. Bukowski, MD (The Cleveland Clinic Foundation, Cleveland, OH); Robert A. Figlin, MD (David Geffen School of Medicine, Los Angeles, CA); Bonni Lee Gearhart, MD (Overlook Hospital Cancer Center, Summit, NJ); Thomas E. Hutson, DO, PharmD (Texas Oncology, PA/Baylor Sammons Cancer Center,

ª 2006 American Cancer Society DOI 10.1002/cncr.22260 Published online 17 October 2006 in Wiley InterScience (www.interscience.wiley.com).

Dallas, TX); Khuda Dad Khan, MD, PhD (American Health Network Oncology/Hematology, Indianapolis, IN); Robert J. Motzer, MD (Memorial Sloan-Kettering Cancer Center, New York, NY); Robert G. Uzzo, MD (Fox Chase Cancer Center, Philadelphia, PA); and Christopher G Wood, MD (The University of Texas M. D. Anderson Cancer Center, Houston, TX). Address for reprints: Ronald J. Halbert, MD, MPH, University of California-Los Angeles School of Public Health, 3781 Wasatch Avenue, Los Angeles, CA 90066; Fax: (801) 340-5983; E-mail: halbert@ ucla.edu Received May 11, 2006; revision received July 25, 2006; accepted August 18, 2006.

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November 15, 2006 / Volume 107 / Number 10 CONCLUSIONS. The current results begin the process of defining an appropriate role for cytokines, newer targeted therapies, and surgery in the treatment of MRCC. Cancer 2006;107:2375–83.
2006 American Cancer Society.

KEYWORDS: renal cell carcinoma, neoplasm metastasis, immunotherapy, angiogenesis inhibitors, nephrectomy, practice guidelines.

R

enal cell carcinoma (RCC) is the most common malignancy of the kidney and accounts for approximately 3% of adult tumors. Annual RCC incidence estimates have increased steadily, and approximately 25% of patients present with advanced disease at the time of diagnosis.1 The management of metastatic RCC (MRCC) remains a significant challenge both for the medical oncologist and for the urologist. Treatment with standard cytotoxic chemotherapeutic agents and radiotherapy have produced disappointing outcomes, with low overall response rates (85%) Low expression (staining
85%) Expression not known Scenario 2: Patients with prior immunotherapyy MSKCC (Motzer et al., 200422) Favorable risk: 0 risk factors Intermediate risk: 1 risk factor Poor risk: 2–3 risk factors Type of prior therapy Prior therapy with IFN Prior therapy with IL-2 CAIX expression (for IL-2 treatment only) High expression (staining >85%) Low expression (staining
85%) Expression not known Scenario 3: Patients with primary tumor in place (no prior immunotherapy){ Surgical risk Good risk (good performance status, no major comorbid conditions) Poor risk (poor performance status, major comorbid conditions, and/or life expectancy 10 mg/dL) 5. Absence of nephrectomy Based on these defined risk factors, patients are classified into 3 risk groups: 1. Favorable risk: Patients with 0 risk factors 2. Intermediate risk: Patients with 1 or 2 risk factors 3. Poor risk: Patients with >3 risk factors III. MSKCC risk classification for survival in previously treated patients with MRCC (Motzer et al., 200422) Prognostic factors 1. Karnofsky performance status 50%), chills, nausea/emesis (3%), gastrointestinal abnormalities (10%), and electrolyte abnormalities (13%) Grade 1–2: Fever, chills, malaise, and anorexia (10%); nausea/emesis (8%); and oliguria (8%) Grade 2–3: Fatigue, fever, and diarrhea (4%); nausea/emesis; and hypotension (3%) Grade 3–4: Constitutional (fever, chills, fatigue) and gastrointestinal symptoms (14%), hypotension (1%), neurologic toxicity (3%), and electrolyte abnormalities (3%) Grade 1–2: Hand-foot skin reaction (21%), rash (31%), diarrhea (29%), fatigue (16%), and pruritus (14%) Grade 3–4: Hand-foot skin reaction (5%), fatigue (2%), and rash (1%) Grade 1–4: Diarrhea (53%), fatigue/asthenia (51%), nausea (44%), stomatitis (25%), and hypertension (25%) Grade 3–4: Neutropenia (13%), lymphopenia (12%), hypertension (8%), and fatigue/asthenia (7%) Grade 3–4: Anemia (21%), asthenia (12%), hyperglycemia (10%), and hyperlipidemia (7%) Fatigue, lethargy and constipation (>30%); neuropathy (with prolonged therapy; 25%); deep vein thrombosis (20%); and pulmonary embolism (15%)

IFN indicates interferon; IL, interleukin.

in the first round of ratings. Specific results for each scenario are described below. In Figures 1 through 3, green represents ‘‘appropriate’’ ratings, yellow represents an ‘‘uncertain’’ rating or disagreement among the panelists, and red represents an ‘‘inappropriate’’ rating.

Scenario 1 The first scenario involved the use of systemic therapy in patients who did not receive prior immunotherapy (Fig. 1). The panel considered high-dose IL-2 appropriate for patients with favorable risk status (no MSKCC risk factors) when the expression of CAIX is high or unknown and for patients with intermediate risk status (1 to 2 MSKCC risk factors) when the expression of CAIX is high. All other use of immunotherapy was considered uncertain or inappropriate. Among targeted therapies, both sunitinib and sorafenib were rated appropriate for favorable-

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FIGURE 1. Appropriateness ratings are shown for systemic therapy in patients with no prior immunotherapy. Green represents ‘‘appropriate’’ ratings, yellow represents an ‘‘uncertain’’ rating or disagreement among the panelists, and red represents an ‘‘inappropriate’’ rating. The enrollment of patients with metastatic renal cell cancer into an investigational trial always was considered appropriate. MSKCC indicates Memorial Sloan-Kettering Cancer Center; IL, interleukin; CAIX, carbonic anhydrase IX; IFN, interferon.

FIGURE 2. Appropriateness ratings are shown for systemic therapy in patients who received prior immunotherapy. Green represents ‘‘appropriate’’ ratings, yellow represents an ‘‘uncertain’’ rating or disagreement among the panelists, and red represents an ‘‘inappropriate’’ rating. The enrollment of patients with metastatic renal cell cancer into an investigational trial always was considered appropriate. MSKCC indicates Memorial Sloan-Kettering Cancer Center; IL, interleukin; CAIX, carbonic anhydrase IX; IFN, interferon.

FIGURE 3. Appropriateness ratings are shown for cytoreductive nephrectomy in patients with metastatic renal cell carcinoma with primary tumor in situ who did not receive prior immunotherapy. Green represents ‘‘appropriate’’ ratings, yellow represents an ‘‘uncertain’’ rating or disagreement among the panelists, and red represents an ‘‘inappropriate’’ rating.

risk and intermediate-risk patients, and temsirolimus was rated appropriate for poor-risk patients. All other use was considered uncertain.

Scenario 2 The second scenario involved the use of systemic therapy in patients who received prior immunotherapy (Fig. 2). Overall, immunotherapies were considered inappropriate for patients who already had failed other immunotherapy. However, there was uncertainty regarding the use of high-dose IL-2 for favorable-risk patients (0 MSKCC risk factors) and intermediate-risk patients (1 MSKCC risk factor) who had high CAIX expression and who previously had failed IFN-a treatment. Sunitinib and sorafenib were

considered appropriate for any patients with MRCC who had failed previous immunotherapy. Several systemic therapy options were consistent across Scenarios 1 and 2. Enrollment of MRCC patients into an investigational trial always was considered appropriate, treatment with bevacizumab always was rated uncertain, and treatment with thalidomide was rated inappropriate regardless of risk status or prior therapy.

Scenario 3 The third scenario addressed the use of cytoreductive nephrectomy in patients with primary tumor in situ who had received no prior immunotherapy (Fig. 3). Nephrectomy was rated appropriate for patients with good surgical risk, symptoms related to the primary tumor, and

Appropriateness of MRCC Treatment/Halbert et al.

limited metastatic burden. For patients with planned immunotherapy and good surgical risk status, the appropriate ratings also included 1) patients with limited metastatic burden and no primary tumor-related symptoms and 2) patients with extensive burden who had symptoms present. Nephrectomy was considered inappropriate for patients with poor surgical risk, no primary tumor-related symptoms, and extensive metastatic burden. For patients with planned targeted therapy, the inappropriate rating also included individuals with poor surgical risk, no symptoms, and limited metastatic burden. All other permutations were rated uncertain.

DISCUSSION The current results provide important insights for clinicians and investigators dealing with MRCC with clear cell histology. For clinicians, several trends emerge. First, our panel recognized that the therapeutic options available for MRCC still are imperfect. Therefore, enrollment on an investigational trial continues to be an appropriate option for all eligible patients. Second, empirically tested risk schema, such as those developed by the MSKCC, may be used to support both evidence-based and clinical decisionmaking. Third, the panel agreed that thalidomide, despite widespread use in clinical practice, has no role in the management of MRCC. Among the newer targeted therapies, the panel supported an ‘‘appropriate’’ rating for sunitinib and sorafenib in lower risk patients, whether or not they had received previous treatment. The most recent results for sunitinib were considered particularly encouraging, with a reported objective response rate of >30%.52 The uncertainty for these 2 agents as first-line therapy for poor-risk patients was based on the lack of data in this population. However, recent (2006) results for temsirolimus led to an ‘‘appropriate’’ rating for this difficult group of poor-risk patients.53 Temsirolimus was not considered a treatment option for second-line therapy. The situation with bevacizumab was more complex. Although some panelists considered that bevacizumab was a reasonable option in the second-line setting for immunotherapy-resistant patients, others considered this agent less appropriate, leading to a combined panel rating of ‘‘uncertain.’’ The panel did not believe that sufficient data were available at the time to make a recommendation with regard to the use of bevacizumab in previously untreated patients. Whether treatment with targeted therapies may limit downstream treatment options with immunotherapy was not addressed. These results help clarify the role of immunotherapy in relation to the newer available therapies. The most notable change involves the rating of IFN-a as

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inappropriate for the treatment of MRCC, a marked change from prior practice. These ratings resulted from head-to-head studies presented in 2006 that reported superior results with sunitinib in patients with better risk status and with temsirolimus in poorrisk patients.52,53 Low-dose IL-2 also was rated inappropriate for most patients, although there was some uncertainty regarding better risk patients with unknown or high expression of CAIX. Some panelists stated that high-dose IL-2 still offers the best chance for a durable response, albeit to a minority of patients. At experienced referral centers, treatment with highdose IL-2 can be administered safely, and adverse events can be predicted and managed.54 This is based on careful patient selection as well as appropriate monitoring and management. Despite these advances, immunotherapy generally is inappropriate for patients who have failed previous immunotherapy and those with poor risk status. Combination immunotherapy was not considered explicitly by the panel. The panel held that the available data on the use of CAIX expression as a biomarker for response to IL-2 were very promising, but more prospective validation is needed. Particularly, more information is needed to integrate CAIX status with other prognostic factors, such as histologic subtype and MSKCC score. Information on the appropriate treatment options for patients with low expression of CAIX and the role of CAIX in predicting benefit for other targeted therapies also is needed. Panelists noted that this test is not yet available routinely for clinical use; therefore, at the moment, these recommendations are speculative. The panel held that cytoreductive nephrectomy was most appropriate for patients with lower surgical risk, lower metastatic burden, and symptoms related to the primary tumor, especially in the context of planned immunotherapy. For good surgical risk patients with planned immunotherapy, nephrectomy was rated appropriate for patients with limited metastatic burden regardless of whether there were symptoms related to the primary tumor and for symptomatic patients regardless of their metastatic burden. Only the most favorable combination of good surgical risk, limited metastatic burden, and symptoms related to the primary generated an ‘‘appropriate’’ rating in patients with planned targeted therapy. These results suggest a need for additional studies to quantify the risks and benefits of cytoreductive nephrectomy better for patients with poor surgical risk and symptoms related to their primary tumor. In addition, clarification is needed regarding the role of nephrectomy in patients for whom targeted therapy is planned. The RAND/UCLA Appropriateness Method is a well studied approach that blends evidence from the

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literature with an expert consensus process. However, no panel can deduce the results of a definitive randomized controlled trial before it has been conducted. The scenarios rated by our panelists represent a simplification of the clinical decision-making process. Several variables—for example, tumor grade and the presence of specific comorbid conditions—were not addressed explicitly by this panel. These variables and others can and should influence the choice of therapy in particular circumstances. Nothing in these guidelines should be construed as contradicting the accepted use of any therapy, as indicated on the product labeling. The current results should be viewed in the context of a rapidly changing field. New agents currently are being tested, and new results may become available at any time, potentially altering the appropriateness of any given therapeutic option. Our results represent a single point in a changing process and should be treated as such. In conclusion, the emergence of newer therapies and biologic markers to enhance the use of existing therapies has created areas of uncertainty regarding the appropriate management of patients with MRCC. For clinicians, these results help begin the process of defining an appropriate role for cytokines, newer targeted therapies, and surgery in the treatment of this challenging disease. For investigators, these results highlight the gaps between currently available data and the evidence needed for clinical decision making. Future trials should be designed to address these needs.

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