Systemic treatment before surgery for kidney cancer prolongs patients’ survival

Renal cell carcinoma [2] (kidney cancer) is notoriously hard to treat, especially once it has started to spread to other sites in the body. If it has metastasised to the lymph nodes, five-year survival is between 5-15% and if it has spread to other organs the five-year survival is less than five per cent.

Studies have been carried out investigating the use of targeted therapies, such as bevacizumab and erlotinib, after surgery, but researchers at the University of Texas MD Anderson Cancer Center, USA, are conducting the first trial to investigate their use before surgery.

Assistant professor of medicine, Eric Jonasch, told a news briefing at the EORTC-NCI-AACR [3] Symposium on Molecular Targets and Cancer Therapeutics in Prague today (Thursday 9 November) that, as of June 2006, the 20 patients enrolled in the trial within the previous year were all still alive. One had complete remission in the primary tumour and stable disease in bone metastases, three patients were in partial remission, 13 patients had stable disease and three patients had progressive disease.

“Without this treatment I would have expected most of them to have progressive disease by now,” said Prof Jonasch. “The average time to progressive disease is usually about twelve weeks, and I would argue that our patients have more aggressive disease as they have not had the benefit of any previous treatment.

“These early data suggest pre-surgical treatment with bevacizumab and erlotinib is safe and efficacious in patients with previously unresected, untreated metastatic renal cell carcinoma, with shrinkage of both the metastatic disease and primary tumours.

“Our findings indicate that this treatment approach might be applicable to a wide range of patients with renal cell carcinoma, and that we might be able to use systemic treatment, before surgery, to treat many more people with metastatic disease successfully. It could become a new paradigm of treatment for the disease, instead of the current up-front surgery followed by systemic therapy.”

Prof Jonasch and his colleagues aim to enrol a total of 50 patients in the study, which they hope to complete by early 2007. So far they have 32 patients, and have evaluated tissue from 20. The patients were previously untreated, did not have brain metastases and had not undergone kidney surgery.

They gave the patients bevacizumab intravenously once every two weeks for four doses, and erlotinib orally every day for eight weeks. Two weeks after the last dose of erlotinib and four weeks after the last dose of bevacizumab, they surgically removed the kidney tumour (cytoreductive nephrectomy). Patients who had stable disease or a response one month after the surgery were restarted on the treatment, which was continued until the cancer started to progress.

When the researchers looked at the protein expression of key signalling molecules involved in controlling cell proliferation, survival and migration, they could not find any difference between tissues from treated patients and tissues from their tissue bank which had come from untreated patients. The one exception was a slight increase in the expression of AKT in the treated group, which meant that blocking the VEGF signalling pathway with bevacizumab might have resulted in feedback to the AKT pathway, which is known to be involved in cell signalling.

“At the moment, we don’t understand what mechanisms are operating to bring about the response we have observed in patients,” said Prof Jonasch. “We are looking at a number of other biomarkers to look for a ‘signal’ that can be associated with the response. We want to discover how these targeted therapies produce a response in renal cell carcinoma, what molecules and genes are controlling disease resistance and response, and, specifically, what role is played by the protein VHL, which is frequently mutated in patients with kidney cancer and which is known to be an important driver of angiogenesis.”

In addition, Prof Jonasch and his team are running similar trials with two other targeted therapies, sorafenib and sunitinib.

He said: “The main aim of this study was to look at the efficacy and safety of using these targeted therapies before surgery, and our results have shown that there were few side effects and that it prolonged the survival of our patients.”

1.Bevacizumab is a monoclonal antibody that inhibits angiogenesis; it is marketed as Avastin. Erlotinib targets EGF, blocking the signal that tells cells to divide; it is marketed as Tarceva.

2.Renal cell carcinoma is more common in men than in women, affecting an average of 4.7 men and 2.5 women in every 100,000 in the world (age standardised rate, world), and killing an average of 2.3 men and 1.2 women in every 100,000 (ASR, world). It is much more common in developed countries, with an average incidence of 10.4 per 100,000 in men, compared to 2.1 per 100,000 in less developed countries. (Source: Globocan 2002)

3.EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].