Principles of therapy
Chemotherapy
Cytotoxic chemotherapy remains the mainstay of systemic treatment for most solid cancers. Renal cell carcinoma however is a characteristically unresponsive tumour and at present, these agents are not routinely used.
A comprehensive review of chemotherapy in Renal cell carcinoma, performed by Yagoda etal., included 4093 patients in 83 trials between 1983 and 1993. The trials included every class of anticancer agent. The overall RR was 6% (1.3% complete response (CR); 4.7% partial response (PR)). Similarly, a review of published literature between 1990 and 1998 showed no survival benefit for any single-agent chemotherapy drug.
Vinblastine is a cytotoxic drug with some activity in Renal cell carcinoma. For a time it was regarded as the best available agent. However, it is clear that response rates are low, typically between 2% and 7%, and Vinblastine is no longer routinely used in the treatment of Renal cell carcinoma.
5-Fluorouracil is a cytotoxic drug that has some single-agent activity (approximately 10% RR) in Renal cell carcinoma. Introduced in the 1950s, it represents one of the first rationally designed anti-tumour agents. 5-Fluorouracil is a fluorinated analogue of uracil, a pyrimidine base essential for nucleic acid metabolism. Through a number of mechanisms it interferes with DNA, RNA and protein synthesis. Myelosuppression and gastrointestinal (gastrointestinal) toxicity are the predominant side-effects. The role of 5-Fluorouracil, in combination with IFN-a and IL-2, is currently being investigated.
Renal cancer cells have an intrinsic resistance to chemotherapy. Classical multi-drug resistance is associated with a membrane-bound protein, P-glycoprotein, that functions as a drug efflux pump. P-glycoprotein, and its encoding gene, multi-drug resistance-1, have been shown to be overexpressed in many tumours, including Renal cell carcinoma.
This is one of a number of mechanisms of drug resistance that has been described although several others have also been implicated. Until our understanding of these pathways improves, standard chemotherapy drugs are likely to remain largely obsolete in the treatment of renal cancer.
Scientists have long suspected that there is considerable interaction between tumour cells and the host’s immune system. The small but significant number of spontaneous regressions of tumours, the increased incidence of malignancy in immunosuppressed patients and the presence of lymphoid infiltrates in solid tumours lent early support to this notion.
In recent years, greater understanding of basic immunology and of the host tumour relationship has lead to the development of immunotherapeu-tic approaches to cancer treatment. Biotherapy can be broadly defined as the use of natural substances that, by modifying the host’s biological response to tumour cells, leads to therapeutic benefit. The term immunotherapy can be encompassed within this and relates specifically to approaches aimed at stimulating immune defence mechanisms.
The ability to differentiate tumour cells from normal cells is based on the ability of the immune system to detect tumour cells expressing abnormal proteins or abnormally expressed normal proteins (tumour antigens). Tumour antigens expressed on the cell surface can be detected by antibodies. Expression of intracellular tumour antigens is detected by T cells. Intracel-lular proteins are proteolytically degraded into small peptides, and a proportion of these are assembled into the groove of human leucocyte antigen molecules. This human leucocyte antigen molecule/peptide complex is transported to the cell surface where it can be recognized by the T cell receptor of cytotoxic T cells. The binding of the T cell receptor to the major histocompatibility complex (MHC)/peptide complex triggers T cell activation and release of cytotoxic factors that induce death of the target cell. T cells however require other signals to give full activation, including cytokines and costimulatory signals from specialized antigen-presenting cells such as dendritic cells. Indeed, effective T cell activation involves several steps.
Antigens shed by dying tumour cells are picked up by dendritic cells and processed into human leucocyte antigen molecules. dendritic cells migrate to the lymph nodes where the antigens are presented to T cells along with the appropriate costimulatory signals. These
partially activated T cells can then circulate and when they encounter tumour cells expressing these antigens they are fully activated and kill the tumour cell. This whole process is controlled by a network of cytokines. Cytokines are a broad class of soluble proteins produced primarily by T cells, antigen-presenting cells, mono-cytes and macrophages and act as signals between cells of the immune system.
Tumour antigens have now been identified in many cancers and cytotoxic T cells specific for these can be isolated from patients with cancer. Unfortunately, in the majority of cancer patients there are defects in this immune response, and to date many different mechanisms of immune evasion have been identified. The aim of immunotherapy is to overcome these to allow effective immune stimulation.
Several approaches have been tried. These include specific and non-specific immunotherapies. Non-specific immunotherapies include cytokines such as IFN and IL-2 that enhance the immune response by a range of different mechanisms. Immunotherapies that enhance the immune response to specific antigens include vaccination with antigens in the form of whole cell vaccines, specific protein or specific peptides. Although many approaches have been tried in renal cancer the current mainstay of immunotherapy in renal cancer is the cytokines IFN-a and IL-2.
Surgery
The role of surgery in the management of localized Renal cell carcinoma is well established. Radical nephrectomy is potentially curative for many patients with early stage disease. For patients with metastatic disease, decisions regarding surgery are more complicated.
At one time, nephrectomy was carried out in the hope of inducing a spontaneous regression of metastases. In fact, the frequency of this phenomenon is less than 1% [8] whilst the surgery itself carries a mortality of between 1% and 5%. There is therefore no justification for nephrectomy based solely on this assumption.
More recently however, data from two randomized trials have been published suggesting that nephrectomy in patients with metastatic disease can increase the likelihood of an objective response to immunotherapy at metastatic sites.
The European Organization for Research and Treatment of Cancer (EORTC) 30 947 trial randomized 83 patients with mRCC to either radical nephrectomy plus IFN-based immunotherapy versus IFN-a alone. Time to progression (5 vs 3 months) and median duration of survival (17 vs 7 months) were significantly better in the study patients than in the controls.
The results of a trial by the Southwest Oncology Group (SWOG) were similar. In that study of 245 patients, median survival was 12.5 months in the combined treatment arm compared with 8.1 months in patients who had interferon only and no nephrectomy.
It is important to note that only patients with a WHO performance status of 0-1 were eligible for these trials. In addition, both studies recruited relatively small numbers of patients over a very long time period.
Nevertheless, the current weight of evidence is in favour of nephrectomy before commencing immunotherapy for patients of good performance status. However, this approach is not appropriate or feasible in all cases and requires careful patient selection.
Adjuvant treatment
Adequate surgical excision is the only effective means of curing Renal cell carcinoma. Approximately 70% of patients have nonmetastatic disease at the time of first presentation. However, of those who undergo tumour nephrectomy 2-14% relapse locally and 31-36% develop distant metastatic disease.
The concept of adjuvant therapy is well established in several tumours, such as of the breast and colon. In Renal cell carcinoma however, chemotherapy, hormone therapy and radiotherapy have all failed to show a survival benefit when used in this setting. It remains unclear whether immunotherapy can make an impact in patients with Renal cell carcinoma at high risk of relapse.
Pizzocaro et al. randomized 247 patients with Robson stage II and III Renal cell carcinoma to 6 months of thrice-weekly IFN-a versus observation after radical nephrectomy. Overall, no advantage for adjuvant interferon was demonstrated in terms of overall and event-free survival. Other similar studies using single-agent interferon in this setting have failed to demonstrate a survival advantage.
The EORTC 30955 trial is currently open and is using combination therapy in an adjuvant setting. Eligible patients should have a pT3b, pT3c or pT4 stage tumour; any pT stage and nodal status pNlor 2; or any pT stage and microscopic positive margins or evidence of microscopic vascular invasion. Patients are randomized either to an 8-week regimen of triple therapy with IFN-a, IL-2 and 5-Fluorouracil or to observation.
There is currently no evidence to support the routine use of adjuvant therapies in Renal cell carcinoma and observation remains the standard of care. Suitable patients should however be considered for participation in clinical trials.