Elsevier

The Lancet

Volume 358, Issue 9286, 22 September 2001, Pages 966-970
The Lancet

Articles
Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial

https://doi.org/10.1016/S0140-6736(01)06103-7Get rights and content

Summary

Background

Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone.

Methods

We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5×106 IU/m2 subcutaneously three times per week) started 2–4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat.

Findings

40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0·60, 95% Cl 0·36–0·97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0·54, 0·31–0·94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects.

Interpretation

Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status.

Introduction

At diagnosis, about 20% of patients with renal-cell carcinoma have disseminated disease, and another 25% have locally advanced disease. About a third of patients with tumour of the kidney at diagnosis will develop metastatic disease postoperatively. Thus, some 50% of all patients with renal-cell carcinoma will eventually present with disease that requires complex treatment decisions.1 Radical nephrectomy is the preferred treatment in organ-confined stages of disease.2 However, because curative surgery is almost impossible in disseminated disease, the benefits of surgery to a patient with metastatic renal-cell carcinoma have been disputed. With arrival of modern immunotherapies, albeit of restricted efficacy, we need to critically reassess surgical treatment of metastatic renal-cell carcinoma.3, 4

The effect of nephrectomy before immunotherapy in patients with renal-cell carcinoma has not been measured. The theoretical advantages include reduction in the number of cancerous cells, removal of a trap for trafficking lymphocytes, prevention of complications during systemic treatment, opportunity to harvest tumour-infiltrating lymphocytes and tumour cells for use in experimental treatments, and reduction of a large and potentially immunosuppressive tumour burden. Other potential advantages include improvement in performance status score of patients, better tolerance and higher probability of response to immunotherapy, elimination of the primary tumour as a possible source of haemorrhage, discomfort, or propagation of metastases, and the fact that responses to immunotherapy in the primary disease site have been rare. Potential disadvantages include growth of metastatic disease in the recovery period that could preclude treatment, and morbidity associated with any major operation.5, 6

We aimed to address the issues of whether combined treatment lengthens time to progression and confers a survival benefit, and, secondarily, whether nephrectomy before immunotherapy increases the response rate to immunotherapy. Two randomised trials were done with the same eligibility criteria, treatments, and design: European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group trial 30 947, and Southwest Oncology Group (SWOG) trial 8949. We report results for the patients in the EORTC study. Results for participants in the SWOG trial have been reported elsewhere.7

Section snippets

Participants

All patients had a diagnosis of metastatic renal-cell carcinoma that had been histologically confirmed (needle biopsy or needle aspiration biopsy of at least one metastatic lesion or of the primary tumour). Inclusion criteria were metastases that extended beyond regional lymphatics (ie, any tumour, node, or metastatic 1 disease), measurable or evaluable disease in a region that could not be resected with standard nephrectomy procedures, and a primary renal-cell carcinoma that could have been

Results

From June, 1995, to July, 1998, the EORTC randomised 85 patients. Two were ineligible, one from each treatment group. Of the remaining 83 patients, 42 were randomised to surgery plus immunotherapy (study group) and 43 to receive immunotherapy alone (controls). Figure 1 shows the trial profile. No data were available for one control patient. Both groups were similar with respect to age, sex, WHO- performance score (0 or 1), tumour type, venous invasion, lung metastases only (stratification

Discussion

Our results clearly show an important survival benefit for nephrectomised patients presenting with a good performance score, whose primary tumour has been assessed to be surgically operable, and who are good candidates for subsequent immunotherapy. Response rates did not differ between nephrectomised patients and those with the primary tumour in situ.

A nephrectomy in a patient with metastatic spread of a renal-cell carcinoma almost certainly will not cure the disease, and the patient will die

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