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CancerGuide: Special Kidney Cancer Section

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+ Randomized Trials: High Dose vs. Outpatient
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Important Randomized Trials Involving High-Dose IL-2

Most patients who get IL-2 do not get high dose IL-2. Instead, they typically get any of a variety of outpatient IL-2 regimens. Although long term response to these treatments is definitely possible, a critically important question is whether it is as likely as with high dose IL-2. If you're going for the long term, and could tolerate high dose, that will probably determine your rational treatment choice.

By far the best way to tell if the outpatient regimens are as good as high dose is to conduct a randomized trial. Unfortunately, randomized trials are expensive and difficult to conduct and if what you really care about is long term benefit, they require both a large number of patients and very long term follow-up. As a result, there are very few randomized studies comparing high dose IL-2 to outpatient IL-2. In fact, I am aware of just two.

This article summarizes the data for those two trials and links to separate more detailed articles on each of them. Briefly, the results from these two trials are not completely definitive but unfortunately, they strongly suggest that high dose is probably more effective, and are certainly not strong enough to show the outpatient versions tested in these trials are just as good high dose.

The Trials

  • The NCI Randomized Trial

    This very long term trial compares three different IL-2 regimens:

    • Standard High-Dose IL-2 (720,000 IU/kg/Dose).
    • Inpatient IL-2 at 10% of the standard dose (72,000 IU/kg/Dose).
    • Outpatient Subcutaneous IL-2 at 250,000IU/kg/day for 1 week thereafter 125,000 IU/kg/day for five weeks

    Result: The high dose arm had nearly twice the response rate of the other arms along with more durable complete responses. The difference in overall response rate was statistically significant (but very close to the border). With this difference in response rates, surprisingly survival was not significantly different between the arms. It turns out this very likely misses the fact that high dose is more likely to give a long-term response, and behind this near paradox is an interesting tale.

  • The Cytokine Working Group Randomized Trial

    This two arm trial has much shorter follow-up. It compares:

    • Standard High-Dose IL-2 (600,000 IU/kg/Dose).
    • Outpatient IL-2 + Interferon (5 Million IU/m2 IL-2, five days a week + 5 Million IU/m 2 Interferon three times a week).
      Note: 5 Million IU/m2 is roughly equivalent to 125,000 IU/kg as in the NCI trial.

    Result: The high dose arm had nearly twice the response rate as the outpatient arm and this was statistically significant, but follow-up is too short to track long term survival.

My Conclusions

Assuming you qualify for high dose IL-2, the reasons for using these outpatient regimens instead are tactical and short term. That is to say the lesser intensity of the side effects and outpatient administration are short term advantages (the longer duration of typical outpatient IL-2 treatment is a disadvantage). Those looking to maximize their odds of long term survival ought not trade off long term efficacy for short term advantages. Unless the data is strong enough to establish it's likely that the outpatient regimens are at least as good long term those regimens, it doesn't make sense to take the risk of losing long term efficacy in trade for the short-term advantages.

The data we have from these two studies aren't completely conclusive, but they both favor the high dose regimen and certainly don't allow the conclusion that these outpatient regimens are very likely at least as good, and in fact they tend so show it's more likely they aren't as good. Both studies had about twice the objective response rate in the high dose arm ,and this difference was statistically significant or close. Given that the long term benefit of high dose IL-2 appears to accrue largely or entirely to long term responders, this suggests it's likely the high dose is better. It's clear to me that the outpatient regimes tested in these trials have not met their burden of proof.

Not all important outpatient regimens are covered by these two trials. In particular, the Atzpodien Regimen, which is frequently used in Europe isn't covered. For the details on that treatment, see my article, The Atzpodien Regimen and Beyond.

If a different, new, or experimental outpatient IL-2 regimen has advantages which appear to be more than just tactical, such as a greatly increased durable response rate, or a particularly excellent long term survival rate, then these randomized trials don't answer the question of whether to do high dose or gamble on the new regimen. For information on any promising IL-2 regimens, see The New And Experimental Page.

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