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