The Cytokine Working Group Randomized Trial of High Dose IL-2 vs. Outpatient IL-2 + Interferon

A Randomized Phase III Trial Of High-Dose Interleukin-2 (HD IL2) Versus Subcutaneous (SC) Il2/Interferon (IFN) In Patients With Metastatic Renal Cell Carcinoma (RCC).

David McDermott, Lawrence Flaherty, Joseph Clark, Geoffrey Weiss, Theodore Logan, Michael Gordon, Jeffrey Sosman, Marc Ernstoff, Walter Urba, Kim Margolin, Michael Atkins.

Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2001;Abstract 685
Background: High Dose (HD) IL-2 produces durable high-quality responses in approximately 10% of patients (pts) with RCC but is associated with significant toxicity and cost and is not universally available. A low dose outpatient IL-2/IFN produced a similar response rate (RR) and median survival in a phase II trial (Dutcher, Cancer J Sci Am 1997, pS73). We conducted a Phase III trial to determine the value of outpatient sub-cutaneous (sc) IL-2/IFN relative to HD IL-2.

Patients and Methods: Pts were randomized to receive either IL-2 (5 MIU/m2 sc, q8hours [h] x 3 doses on day [d] 1 then daily 5 d/week [wk] x 4 wks) and IFN-a 2B (5 MIU/m2 sc, TIW x 4 wks) every 6 wks or HD IL-2 (600,000 IU/kg/dose IV q8 h, d 1-5 and 15-19 [max 28 doses]) every 12 wks. Tumor responses were assessed at wks 6 and 12, then q12 weeks. Responding pts on IL2/IFN received up to 6 cycles; on HD IL2 up to 3 cycles.

Results: 193 pts (age: 21-75, (median 54), ECOG PS 0/1: 116/68, M/F: 128/56, IL2/IFN-94, HD IL2-99) were enrolled between April, 1997 and July, 2000. Pts were stratified for bone and liver metastases, primary in place and PS 0/1. Treatment arms were balanced for these characteristics. Overall, 25% of pts had primary in place; 19% and 32% had liver and bone metastases, respectively. Toxicities seen were typical for these regimens, including 1 treatment related death from capillary leak on HD IL2. Responses are described in the table below.

Conclusion: At this preliminary analysis, HD IL2 shows a trend toward improved quality responses. Data on progression free and overall survival (the planned study endpoints) is forthcoming.

Tumor Response Results by Treatment Arm

ARMNCRPRRR (95%CI)Median Duration (mo)Ongoing (mo)
IL2/IFN9421012% (6.8-21.2)76 (2,4,13,18,24,28)
HD IL29981725% (17.1-35.0)1011 (5,8,10,14,19,20,22,22,26,27,29)

Key: N = Number of Patients, CR = Complete Response, PR = Partial Response, RR = Response Rate, CI = Confidence Interval


This important study has so far only been reported at a meeting, and neither long term results or a full paper are yet available.

The meaning of the last column in the table was unclear to me at first. 6 and 11 are the number of patients who responded and who had not yet relapsed in the IL-2 + Interferon and High Dose IL-2 arms respectively. The numbers in parentheses are the durations of these ongoing responses. Durations of the responses which ended are simply not given. Some of the relapses may have been after a long remission and some of the ongoing responses are very short duration so far, due to short follow-up (two months in one case). I don’t think ongoing response is a good surrogate for quality response or meaningful response, so I question the way this abstract was reported. It would have been better to report the duration of both the ongoing and relapsed responses.

The results favor the high dose arm which had twice the response rate and twice the number responses ongoing after a year (8 vs 4). I calculate that the difference in the response rate is statistically significant (p=.03, Fisher’s Exact Test), but by the same test, the difference in responses ongoing after a year is not statistically significant (p=.37). This doesn’t mean there isn’t a difference. More likely it means there aren’t enough patients to see it reliably. The follow-up of only a year or two is still very, very short compared to the decade plus of follow-up for the original responders to high dose IL-2. We don’t how many true long term responders there will be ,but we do know it’s at most 8 and 4.

Based on the idea that most of the benefit from IL-2 treatment goes to patients who responded, the difference in response rates in favor of the high dose arm suggests to me that indeed high dose offers better long term odds of survival. Unfortunately, proving this with a randomized trial requires much longer follow-up and possibly a significantly bigger trial. Such trials are difficult to do with intensive therapies like high dose IL-2.

This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: February 10, 2003, Last Updated: February 3, 2004