Nephrectomy Before Interferon Improves Survival in Patients with Renal Cancer

MAYWOOD, Ill—Removing the cancerous kidney before administering interferon alfa-2b (Intron A) improves survival in advanced renal cancer, according to results of Southwest Oncology Group (SWOG) Trial 8949. The role of interferon treatment, however, remains controversial.

In a plenary presentation at the ASCO Annual Meeting, Robert Charles Flanigan, MD, of Loyola University Stritch School of Medicine, Maywood, Illinois, said that overall survival and 1-year survival in the SWOG trial were both significantly longer in patients who received nephrectomy before interferon than in those treated with interferon alone.

Acting as discussant for this paper, Ian Tannock, MD, PhD, of Princess Margaret Hospital, Toronto, agreed that the increase in overall survival from 8.1 to 11.1 months was statistically significant. He added, however, that interferon should not be considered standard therapy in metastatic renal cancer.

"Although there are two trials showing survival benefit from use of high-dose interferon for metastatic disease, the treatment has a major negative impact on quality of life, and there are three large, unpublished trials that have found no benefit to interferon when used as an adjuvant to surgery for locally advanced renal cancer," Dr. Tannock stated.

Impetus for SWOG Trial

The SWOG trial was undertaken, according to Dr. Flanigan, because a potential benefit of nephrectomy in metastatic renal cancer patients had been reported from case series data. A SWOG review of cases found median survival of 11.4 months with nephrectomy followed by biologic response modifier treatment vs 5.9 months without prior nephrectomy.

SWOG 8949 randomized 121 patients to interferon alfa-2b treatment with no nephrectomy and 120 to interferon alfa-2b preceded by radical nephrectomy. Type of nephrectomy was not controlled, but surgery had to occur within 4 weeks of study entry.

Interferon was given weekly at 5 million IU/m² on Monday, Wednesday, and Friday until disease progression occurred.

The primary study endpoint was survival, and the secondary endpoint was clinical response. The trial was designed with an 85% power to detect a 50% difference in survival and a 15% difference in clinical response.

Varying Survival Rates

Dr. Flanigan reported that median overall survival was 8.1 months with interferon alone vs 12.5 months with nephrectomy plus interferon (P = .006). In patients with performance status (PS) 0, median overall survival was 12.8 months with interferon vs 17.4 months with surgery plus interferon. In PS 1 patients, overall survival was 4.8 months with interferon vs 11.1 months with surgery plus interferon.

Dr. Tannock pointed out that there was a chance imbalance in the distribution of patients between the two arms, with better performance status patients assigned to the surgery arm. This could explain some of the apparent benefits of surgery. However, there was still a difference when the subgroups of patients with PS 0 and PS 1 were compared between the two arms.

In patients with measurable disease, overall survival was 11.2 months with interferon vs 16.4 months with surgery plus interferon. In patients with evaluable but unmeasurable disease, overall survival was 7.7 months with interferon vs 10.3 months with surgery plus interferon (P = .0005).

One-year actuarial survival was also significantly better in patients who received surgery before interferon than in those receiving interferon alone .

Dr. Flanigan said that response rates were low in this trial: 3% in the nephrectomy/interferon arm (3 partial responses) and 4% in the interferon-only arm (1 complete response, 2 partial responses).

Eighty percent of patients had no complications associated with surgery, and there was only one surgical death. One patient (0.5%) died of interferon-related cardiovascular toxicity. Grade 4 toxicities affected 10 of 121 patients (8.3%) in the nonnephrectomy arm and 13 of 120 patients (10.8%) in the nephrectomy arm.

New Standard of Care?

“The survival advantage was only 4 to 5 months, but it does represent a 50% increase with treatment that would not now be considered standard therapy,” Dr. Flanigan said. “This is the first randomized, prospective trial of cytoreduction nephrectomy in advanced renal cancer. It shows that this should probably be the new standard of care, but only select patients, such as those with good performance status, may benefit substantially.”

Dr. Tannock said that the SWOG results showing that nephrectomy before interferon improved survival in all of the stratified patient groups were confirmed by a smaller study—European Organization for Research and Treatment of Cancer (EORTC) 30947—presented at the American Urological Association meeting.

“This study, with 83 patients randomized, was small but confirmatory,” Dr. Tannock said. There was a significant survival advantage in favor of nephrectomy.

Where Controversy Lies

“Surgery can be recommended to patients with higher performance status,” Dr. Tannock added, but noted that the results of the SWOG and EORTC studies should not be generalized to patients with lower performance status.

Dr. Tannock challenged the use of interferon as standard treatment in advanced renal cancer. Although a Medical Research Council study showed a survival advantage from use of interferon, it also showed high rates of side effects (particularly depression) and decreased quality of life.

“Three trials have shown no benefit to adjuvant therapy with interferon. One suggested there is a benefit. Although the negative studies were large trials, none have been published, apparently due to publication bias,” Dr. Tannock said. “The small gains in survival come at the cost of a significant decrement in quality of life.”