Clinical research priorities in Renal cell carcinoma (1997)

Chemoprevention refers to the prevention of cancer or reduction of risk in susceptible individuals by the administration of natural or synthetic drugs with minimal toxicity to suppress, delay, or reverse carcinogenesis.1 Chemoprevention is most effective in the early stages of cancer formation when reversibility may be feasible. High risk target populations for renal cell carcinoma include patients with an inherited predisposition for this disease (von Hippel-Lindau [VHL] disease, hereditary papillary renal carcinoma, familial renal cell carcinoma) and sporadic cases such as acquired cystic kidney disease (patients undergoing dialysis). These patients may be candidates for a preventive strategy. Patients who have undergone radical nephrectomy for renal cell carcinoma who are at high risk for recurrence because of locally advanced disease or the presence of lymph node metastases also are good candidates for a preventive approach. Experimental chemopreventive agents including nutritional supplements should be screened in animal models to determine their safety and efficacy for human use. For this goal the Eker rat model2 is a good animal model because it is a hereditary form of spontaneous renal cell carcinoma in Wistar rats due to a single gene mutation that shares similarities with VHL disease. Additional experimental models should be developed to simulate the VHL gene mutation3, 4 as well as other acquired and spontaneous variants of renal cell carcinoma. In addition to nutritional supplements, other agents could be used including cytokines, retinoids, or agents that inhibit angiogenesis including interferon (IFN)-α, IFN-β, and interleukin (IL)-12. Data obtained from these preclinical studies should be translated into the design of protocols for human clinical trials. Patients with VHL disease with multiple bilateral angiomas may be a suitable population in which to evaluate new chemopreventive agents, particularly those that inhibit angiogenesis. Metastatic renal cell carcinoma is refractory to conventional therapies including radiation, hormones, and chemotherapy, and has been more responsive to immunotherapy. Immunotherapy is a novel approach based on enhancement of the host immune response against the tumor and uses a variety of biologic response modifiers and activated immune cells. Immunotherapy clinical trials in metastatic renal cell carcinoma have been promising.5 There currently is a consensus that high dose bolus intravenous IL-2 therapy is more effective than low dose IL-2 or subcutaneous IL-2 and results in higher response rates (20% complete response and partial response) with a longer duration of responses.6 The combination of IL-2 with lymphokine-activated killer cells, generated in vitro by activation of peripheral blood lymphocytes with IL-2, has not shown an additional benefit compared with IL-2 alone.6 The administration of IL-2 combined with tumor-infiltrating lymphocyte (TIL) cells, isolated from tumor specimens and activated with IL-2 in vitro, has not resulted in antitumor responses in renal cell carcinoma unless TIL were obtained after in vivo cytokine priming.7 Combinations of cytokines, more specifically IL-2 and IFN-α have yielded interesting results but were not found to be more significant than high dose IL-2.8, 9 The addition of 5-fluorouracil to IL-2 and IFN-α has shown some improvement but variations in response rates were observed between institutions.9 The various clinical protocols used in different institutions make it difficult to draw conclusions regarding the efficacy of these protocols. Even when the same protocols were used, the response rates have not been consistently reproduced. There is a need to establish a national data base to determine the long term efficacy of immunotherapy. The failure of renal cell carcinoma patients to respond to immunotherapy may be due to the immunosuppression induced by these tumors10 or to the poor immunogenecity of these tumors. In contrast to melanoma, it has been difficult to isolate renal cell carcinoma tumor antigens. Recent developments in immunotherapy, which may help overcome these limitations and hopefully lead to more effective protocols, include the use of the newer and promising IL-2 cytokine,11 the use of dendritic cells for antigen presentation,12 and the transfection of tumor cells with viruses such as New castle disease to enhance immunogenicity.13 Recent advances in cellular and molecular biology have made gene and vaccine therapies potential therapeutic approaches for renal cell carcinoma.5 However, extensive investigations are still needed to develop the technology for crucial basic problems such as gene delivery systems or vectors, frequency of gene transduction, and gene expression. Recent preliminary clinical traits utilizing gene therapy include the use of intralesional injection of HLA-B7 Class 1 major histocompatibility complex antigen in lipid complex or tumor vaccines transfected with granulocyte-macrophage-colony stimulating factor for the treatment of renal cell carcinoma but have resulted in localized response and limited systemic response. Gene therapy as a single modality may not be sufficient to achieve a significant antitumor response as shown by preliminary trials. A multimodality approach comprised of tumor irradiation or chemotherapy combined with gene therapy and systemic administration of low doses of cytokines may enhance the effects of gene therapy. To explore the clinical utility of periodic routine ultrasound of the kidneys as a tool for the early diagnosis of renal cell carcinoma in both populations at high risk and in the general population. To develop a diagnostic test using urine or blood to detect early stage and occult renal carcinomas. Assays should be developed to detect the presence of tumor cells or free tumor DNA and test for loss of heterozygosity or VHL and MET gene mutations. For example, the screening of urine samples to detect VHL gene deletion and MET gene amplification can be performed by fluorescent in situ hybridization. To develop genetic assays to distinguish benign or malignant potential in kidney lesions. For example, the identification of a VHL mutation in a cystic lesion might indicate the need for follow-up. Microsatellite analysis recently has been used for the diagnosis of renal malignancies. There was a good correlation between histologic features of the renal neoplasm and the results of microsatellite DNA analysis. This technology is relatively simple, has the potential to establish prognosis, and could be adopted by clinical laboratories. To identify factors that will predict response to immunotherapy and gene therapy. Several genes that play a critical role in human renal carcinogenesis have been identified. These include the VHL gene, the MET proto-oncogene, and TFE3/PPRC genes. It is likely that there are additional genes that are involved critically in human kidney cancer. Finding these genes is dependent on obtaining additional clinical material with unusual presentations of renal carcinoma. Such presentations would include families with three or more members with renal carcinoma, twins with renal carcinoma, or patients with bilateral multifocal renal neoplasms (either papillary or oncocytoid in morphology). Multidrug resistance in renal cell carcinoma is believed to be caused by expression of the mdr-1 gene. Preliminary data suggest that resistance to chemotherapy may be reversed by chemosensitizers such as Dexverapamil®; further studies are warranted to confirm these preliminary findings.14 The working group recommends that a national or international renal cell carcinoma data base and working group, similar to the Wilms' Tumor Working Group, be established to coordinate research activities. This type of working group will promote interactions between clinicians and scientists, as well as allow the exchange of ideas, tissues, specimens, and other resources. Adequate funding will be required from national, international, and private sources. Although the incidence of renal cell carcinoma is lower than that of other malignancies, the working group believes that a collaborative approach to develop strategies to prevent, control, or treat renal cell carcinoma could yield findings applicable to other malignancies. Genetic research in renal carcinoma appears to be an exceedingly fertile area and already has resulted in the identification of four cancer genes that are involved in renal carcinoma and other malignancies. Its support should be strongly encouraged. Primary care physicians and the general public should be informed about the etiology symptoms, and risk factors (including family history) of renal cell carcinoma. * Workgroup participant.