Cytoreductive Nephrectomy In Clinical Practice
David Nicol is a Consultant Urological Surgeon at the Royal Marsden Hospital in London where he is also Chief of Surgery. His clinical work deals with complex kidney and testis cancer including surgery in patients with advanced and metastatic disease. Here, he explains the use of cytoreductive nephrectomy in metastatic kidney cancer.
David, can you explain what is meant by cytoreductive nephrectomy?
Cytoreductive nephrectomy refers to the removal of the primary kidney tumour in patients who have metastatic disease. Historically it had been noted that occasional patients experienced spontaneous regression of metastatic disease when this was performed. This however only occurred in a very small number of cases and general opinion was that cytoreductive nephrectomy as the overwhelming majority died within 12-18 months from metastatic disease. In the late 1980’s and early 1990’s, drugs which stimulated the immune system(immunotherapy) had an effect on metastatic kidney cancer.
Small trials with 2 agents interferon-alpha (IFN-a) and interleukin-2 (IL-2) showed response rates better than what had been observed with conventional cytotoxic chemotherapy. Analysis of these studies suggested that patients who had a nephrectomy performed prior to treatment resulted in a better response to both INF-a and IL-2. The basis for this was uncertain with possibilities including a selection bias with only fitter patients, who would otherwise expect to live longer, having nephrectomy. Alternatively it was also proposed that cytoreductive nephrectomy may exert some biological effect improving the effectiveness of immunotherapy and thus overall survival.
Which patients with metastatic kidney cancer are suitable for cytoreductive nephrectomy?
Cytoreductive nephrectomy is really only an appropriate option for patients who are otherwise well. Patients whose performance status is impaired are at high risk of complications from major surgery and also generally have poor survival that is not improved with cytoreductive nephrectomy. Therefore patients who have noted significant weight loss, are anemic or who feel tired and generally unwell are not considered candidates for cytoreductive nephrectomy. Some patients may present with significant symptoms including pain and bleeding for which nephrectomy is recommended. This is regarded as a palliative intervention to control symptoms rather than a cytoreductive nephrectomy which is performed with the expectation that it may improve survival.
Can you outline the evidence that cytoreductive nephrectomy can be beneficial in some patients?
There are 2 trials – one performed in Europe and another in the United States that have demonstrated a survival benefit with cytoreductive nephrectomy in patients who are subsequently treated with IFN-a. These were both randomised controlled trials - in which patients, who all received IFN-a were randomly allocated to either cytoreductive nephrectomy or no surgery. Comparing the 2 groups which were of equal size revealed that patients undergoing cytoreductive nephrectomy had a median survival of 14 months compared to 8 months without. These studies also reinforced the lack of benefit in patients with poor performance status.
This is obviously difficult surgery. Are complication rates much higher compared to other forms of kidney cancer surgery?
Patients with metastatic kidney cancer usually have quite large primary tumours with a rich blood supply being a common feature. Both of these factors can make surgery very difficult and associated with a higher risk of complications, particularly major bleeding, compared to other forms of kidney cancer surgery. Most patients with kidney cancer have relatively small tumours and are able to have surgery performed either laparoscopically or robotically with low risk of complications. In contrast cytoreductive nephrectomy, in almost all cases, requires major open surgery as minimally invasive procedures are usually neither feasible nor safe. Patients with metastatic cancer are also generally at higher risk of complications with major surgery. Deep venous thrombosis and pulmonary embolism are 2 specific examples of this.
A relatively new treatment for metastatic kidney cancer is a class of drugs called tyrosine kinase inhibitors (TKIs). Is there any evidence that cytoreductive nephrectomy followed with TKIs is beneficial for patient outcomes and survival?
The treatment of metastatic kidney cancer has rapidly changed and now IFN-a and IL-2 are rarely used. Both agents have been largely replaced by a new group of drugs – termed targeted therapies due to their effect as tyrosine kinase inhibitors (TKIs). These drugs have a completely different mechanism of action – rather than stimulating the immune system they target tumour blood vessels. Essentially they reduce the blood flow to tumours.
At this point in time it is unknown whether or not cytoreductive nephrectomy improves the outcome in patients treated with TKI’s. It is important to note that the previous studies on cytoreductive nephrectomy only addressed the question as to whether or not this improved survival when patients were treated with IFN-2. Accepting the lack of clear evidence at this time it can still be considered in some patients. For example a patient who is otherwise well presenting with a kidney cancer and small volume metastatic disease I would suggest a cytoreductive nephrectomy as their initial management. The patient would then be observed, avoiding drug treatment until they show clear evidence of substantial progression of their metastatic disease. The rationale behind this is that TKI’s can have significant toxicity and also that resistance to treatment inevitably develops. By removing the kidney and delaying drug therapy the patient avoids toxicity of treatment and also emergence of resistance at a time when their metastatic disease may be stable or only slowly progressing(ie reserving it for maximum effect when it is really needed).
A different approach to cytoreductive nephrectomy would be considered in the patient with high volume or symptomatic metastatic disease. In this scenario I would not recommend cytoreductive nephrectomy as an initial step. Rather the patient should consider commencing a TKI from the outset. Surgery could delay therapy during which time his disease may progress with an overall deterioration in his condition such that he is never suitable for a TKI (as again these drugs only appear of benefit in patients with good performance status).