Controversy Revisited: The Role for Nephrectomy in Metastatic Renal-Cell Carcinoma

Abstract & Commentary

Synopsis: In an EORTC trial, good performance status patients presenting with metastatic renal cell carcinoma were treated with either nephrectomy plus interferon or interferon alone. Complete response rate and overall survival was better for the surgically treated group.

Source: Mickisch GHC, et al. Lancet. 2001;358: 966-970.

At the time of diagnosis, about 20% of pat-ients with renal carcinoma will have evidence for distant metastases and 25% have locally advanced disease. Of those with resectable lesions and no evidence for metastatic disease who are treated with nephrectomy, approximately one third will develop distant metastases.1,2 Treatment of metastatic disease with chemotherapy has not been satisfactory, and new immunotherapies, although only marginally better, are considered standard care.3

The role of nephrectomy for those who present with metastatic disease has been controversial.4 The purpose of this study was to establish whether radical nephrectomy done before interferon-based immunotherapy improved time to progression and overall survival compared with interferon alone for those who present with primary renal carcinoma and measurable metastatic disease.

The multi-site trial was conducted by the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group. Eighty-five patients were randomly assigned combined treatment (n = 42) or immunotherapy (n = 43) alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at the time of entry. In study patients, surgery was done within 4 weeks of randomization and interferon (5 ´ 106 IU/m2 subcutaneously 3 times per week) started 2-4 weeks later. In controls, interferon was started immediately after randomization.

Of the 42 assigned to the study group (surgery and immunotherapy), only 29 completed 16 weeks of immunotherapy. Six patients had perioperative complications that necessitated minor delays in the initiation of interferon treatments. Nevertheless, time to progression (5 vs 3 months, hazard ration of 0.60, 95% CI 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 1 to interferon alone. Dose modification was necessary in 32% of patients, most commonly because of nonhematological side effects.

Comment by William B. Ershler, MD

These results clearly demonstrate an increased complete response (CR) rate and a survival benefit for those that receive combined nephrectomy and immunotherapy compared to immunotherapy alone. Why would such occur? One possible explanation is that a surgical debulking could result in spontaneous regression, as has been reported now and again.5 However, the overall frequency has been calculated to be about 0.7%, which is actually less than operative mortality (1-5%). Nevertheless, previous nephrectomy may enhance response to systemic therapy, and the current data would support that contention.

Another reason to contemplate nephrectomy in patients presenting with metastatic disease relates to quality of life and reduction of morbidity. Removing the primary tumor would likely reduce tumor pain and hematuria, both of which can be a major cause of morbidity for renal cancer patients. Furthermore, the tumor wasting syndrome, felt to be paraneoplastic, at least in part, might be ameliorated after nephrectomy, although, in the presence of metastatic disease, this amelioration of systemic symptoms is likely to be of short duration.

This trial affords information regarding 2 critical questions with regard to nephrectomy for patients presenting with metastatic renal cancer: 1) do patients tolerate the procedure well enough to receive systemic therapy?; and, 2) does removal of the primary tumor increase the likelihood of an objective response to immunotherapy observed in the metastatic lesions? The data would indicate that both are true. However, the trial was relatively small and needs to be confirmed before such an approach becomes standard of care. In this regard, the findings from a similarly constructed SWOG trial (8949), will be very instructive. Early reports indicate a similar survival advantage has been observed for those receiving nephrectomy and immunotherapy.6

References

1. Godley PA, Taylor M. Curr Opin Oncol. 2001;13: 199-203.

2. Scheltema JMW, Mickisch GH. European Urology Update Series. 1997;6:27-33.

3. Bukowski RM. Semin Urol Oncol. 2001;19:148-154.

4. O’Connell JR, et al. Semin Urol Oncol. 1996;23:1728.

5. Van Poppel H, Baert L. Acta Urol Bélgica. 1996;64: 11-17.

6. Flanigan RC, et al. J Urol. 2000;163(Suppl):685.