Overview

This article mostly covers interferon by itself. I cover combinations involving both Interferon and Interleukin-2 in the IL-2 Section. Any promising especially combinations of Interferon with other drugs or variants on Interferon itself will be covered here, or at least I'll include a pointer to further information here.

If you want to see the details and data read the whole article, but to start here's the short version of the story (The very short version is: I think Interferon is inferior to IL-2 based treatment and should be avoided by anyone who wants a chance at a cure.)

Long Story Short

• Interferon Benefits: Interferon has been shown to increase median survival by a few months in randomized trials. Interferon has a similar response rate to many IL-2 regimens, including high dose IL-2, however responses are much less likely to be either complete or lasting with one major proponent characterizing response duration of more than two years as rare[Motzer 2000]. In addition, when one of the randomized trials with the best results was re-analyzed excluding the responders that didn't change the results [Pyrhonen 1999], suggesting its benefits are unrelated to the transient responses, so that unlike high dose IL-2, response does not translate to long-term benefit. I can find no real evidence that Interferon creates long term survivals. I think any benefit from Interferon is most likely due to a modest slowing of tumor growth in many patients. Interferon has direct effects on the proliferation rate of cancer cells, and also has anti-angiogenic effects which could account for this kind of benefit.
  
  
• I think that Interferon is inferior to high dose IL-2, and likely to other IL-2 therapies, because it does not create truly durable complete remissions - apparent cures - the way high dose IL-2 does. Unlike with IL-2, responses to Interferon are almost always just temporary. Comparing the early IL-2 data to Interferon back in 1989, I thought the decision was a truly no-brainer. To me the small but real chance of a cure is what makes immunotherapy worthwhile, and if you want that chance you need IL-2, not Interferon.
  
  
• Interferon is a popular first line therapy for metastatic RCC and many conservative oncologists prefer Interferon to IL-2 based therapy, perhaps because of its milder side effects. This includes doctors at some of the very best cancer hospitals and also in many countries with cost conscious nationalized health care systems (see Getting IL-2 in Canada, the UK and Australia for details).
  
  
• If you choose Interferon anyway...
  
  
  • If your kidney tumor is still in place, consider having the tumor removed before Interferon. Two randomized studies testing the effect of adding this surgery to Interferon alone showed benefits which arguably exceed the benefits of the Interferon itself! See my article on Combinations of Surgery and Immunotherapy for more detail.
    
    
  • If you achieve a partial response or even just stable disease with Interferon, surgery may be very beneficial if all detectable residual tumor can be removed. In fact, I think this is the most likely way of achieving long term survival with Interferon. See my article on Combinations of Surgery and Immunotherapy for more detail.
    
    
  • Consider combining Interferon with the chemotherapy drug Vinblastine. The best results with Interferon that don't include IL-2 have been with this combination. Vinblastine is an old-line cytotoxic drug which should be available from even conservative oncologists or in countries with conservative policies on cancer treatment.
    
    

Short Story Long: The Details

At bottom, this is a short and simple story which isn't hard to grasp, but there is still plenty of detail to sift through.

What is Interferon?

Like Interleukin-2, Interferon is a cytokine - a natural messenger molecule of the immune system. Like IL-2, Interferon is a protein and is manufactured as a drug through genetic engineering techniques.

There are actually several different classes of interferon and several of them are used as drugs for various purposes, however only Interferon-Alpha is commonly used to treat kidney cancer. There are two slightly different alpha- interferons used to treat kidney cancer, Interferon-Alpha-2a, trade name Roferon, and Interferon-Alpha-2b, trade name Intron-A. There is no major difference between these drugs. Neither are formally approved for use in kidney cancer in the US ("Off-label" use of drugs is very common in oncology), but interferon is in very common use for kidney cancer in the US, and in many countries it is the only standard therapy or close to that.

Interferon works differently than IL-2. It acts to make tumor cells more susceptible to immune attack by increasing the degree to which they present antigen on their surface. If the immune system recognizes these antigens as abnormal it may be able to attach and destroy the cells. It also has a modest direct effect on growth of the cancer cells themselves. It can apparently also stimulate some immune cells such as Natural Killer Cells.

Interestingly, Interferon also has anti-angiogenic effects, and in fact Interferon is now a standard treatment for certain blood vessel tumors called hemangiomas. Hemangioma is a benign tumor but it can also be serious, even life threatening in some cases. When interferon is used for it's anti-angiogenic effect more frequent lower doses are used. Whether the anti-angiogenic effects of Interferon can be useful in kidney cancer or are even part of its known effects is unclear. Protocols which use low doses of Interferon may be targeting this effect. I think the longer acting Pegylated Interferons (see Promising Variants Below) - considered experimental in kidney cancer - may have potential here.

Treatment

This is an outpatient treatment. Although a variety of injection routes have been tried over the years, these days, interferon is usually given by injection under the skin (subcutaneously) in a variety of doses and schedules. Patients learn to give themselves the injections just as diabetics learn to inject themselves with insulin. The typical treatment schedule is one injection a day 3 to 5 times per week. The dose per injection varies. A typical medium dose protocol is 18 million units by subcutaneous injection three times a week. Because side effects of interferon are usually worst at first and then moderate, many protocols use a lower dose initial dose and escalate to the final dose over a week to a few weeks.

Treatment is often continued indefinitely until the disease gets worse. This means that those fortunate enough to have a response can expect to remain on treatment indefinitely - unlike IL-2 where responding patients are only treated for at most a limited additional time once the point of maximum response had been reached.

Side Effects

Many of the side effects of Interferon are similar those of outpatient Interleukin-2 but are generally milder. Unlike IL-2, or most drugs for that matter, Interferon side effects often actually decrease over time. If you have a hard time with Interferon therapy early on, try to stick it out rather than give up.

Some of the more typical side effects are:

• Flu-like symptoms such as fever and muscle aches
• Fatigue
• Loss of appetite
• Nausea and vomiting
• Depression

Depression from Interferon treatment can occasionally be a serious problem and it may not announce itself as depression. If find you're apathetic or withdrawn it could be you're depressed. Depression caused by Interferon responds to modern Selective Seratonin Uptake Inhibitors like Prozac. If you have depression, be sure to bring it to the attention of your doctor and ask for treatment.

Results

Some Review Articles

Motzer and Berg's Book Chapter

Doctors Motzer and Berg from Sloan Kettering are prominent proponents of Interferon for metastatic kidney cancer and have typically used Interferon in preference to IL-2. Their review [Motzer 2000] summarizes much of the data from single arm trials using interferon alone. There were 648 The overall response rate was 14.5% among a total of 648 patients in these studies. This isn't much different from IL-2, but only 13 patients out of the 648 (2%) had a complete response. They say the median duration of response is six months and that it "rarely" exceeds two years though occasional long term survivors are seen. If you look at the response durations for high dose IL-2, the adjective that comes to mind to describe the chance of a response lasting more than two years is "likely". Their summary does cover a variety of injection methods (IV, IM, and SC), doses and schedules, and it's possible things would look a little brighter if the best dose and schedule were known, though complete response is always rare.

Cochrane Review of Immunotherapy for Advanced RCC

Evidence Based Medicine A Rant The Cochrane Evidence Based review simply refuses to consider evidence about IL-2, because there aren't randomized trials of IL-2 versus control or Interferon. Instead, because they claim to be able to see what is a very marginal benefit of Interferon from randomized trials (and which benefit does not include long term survival) they just stop there, entirely ignoring the actual clear evidence that IL-2 treatment can produce long term survivals because the evidence for that doesn't come from randomized trials. They ignore it even though it doesn't appear that Interferon produces long term survival more than very rarely. Metastatic renal cancer is a desperate disease. Those who want to have a chance to live a long time had better ignore Evidence Based Medicine and pay attention to the evidence instead. All of it. The phrase "Evidence Based Medicine" is perhaps the most brilliant rhetorical stroke in medical history. It sucks you right in. After all, if your decisions aren't "Evidence Based" then they must not be based on "evidence". And we all want our medicine to be based on evidence. But Evidence Based Medicine is actually a very particular and limited view of the evidence. It emphasizes data from randomized controlled trials to the point of excluding other evidence, and claims to insist on outcomes which really matter to patients like survival and quality of life. But here they ignore a chance for an actual cure (even if small) as if that outcome isn't one which actually matters. Evidence Based Medicine may well have its place - ultimately what they're shooting for - the greatest possible certainty conclusions are true, combined with evidence the intervention really helps - is the right thing. Evidence Based Medicine makes particular sense when trying to decide about interventions for large numbers of people who are basically healthy, a situation where conservatism is very justified. That same conservatism becomes lethally misguided when it thoughtlessly throws away a chance for long term survival in a disease where such chances are far and few between indeed.

The Cochrane Collaboration is a primary source for what is called "Evidence Based Medicine" and doctors who favor Interferon not infrequently cite their review of Immunotherapy for Advanced Renal Cell Cancer[Cochrane 2000]. This is a formal meta-analysis, which means they've pooled data from many different studies as a way to use all the evidence to get to the truth. Importantly, they've restricted their analysis to randomized controlled trials.

Their Key Findings on Interferon:

• Interferon increases the median survival compared to control by a very modest 2.6 months. This gave a median of 11.6 months.
• Interferon reduces the risk of death at one year by about 27% and by 22% at two years compared to control. Since the risk of death is very high, these are still small benefits.

"Control" here is treatment like hormone therapy or chemotherapy which is now known to be ineffective. Roughly it's what you'd expect with no treatment.

Problems

• IL-2 Excluded: Although this purports to be a general review of immunotherapy for RCC, not just interferon, they simply don't address the question of whether IL-2 produces long term survivals because they are only willing to consider the results from randomized studies. There are almost no randomized studies of IL-2 versus Interferon, and I know of none of IL-2 versus control where the IL-2 arm doesn't also include interferon. However their refusal to even consider long term survival with IL-2 doesn't change the evidence for long term response. It makes no sense to me to trade this very modest improvement in median survival for a shot at a cure.
  
  
• Short Term Analysis: For statistical reasons they only consider results out to two years, but this is inadequate for those of us who are interested in long term survival.
  
  
• Lumping Together Widely Varying Protocols Blurs Their Results: They combine a wide range of studies, including studies with very different Interferon doses and schedules. Not only that, but they lump together studies which used a variety of drugs in combination with Interferon in the experimental arm, including chemotherapy drugs, and even including IL-2. They justify the inclusion of IL-2 by showing that their results don't change much if the studies combining IL-2 with the Interferon are excluded, but remember they aren't looking at long term results. They also include trials with a wide variety of control arm treatments including hormone therapy with Provera or Tamoxifen, as well as cytotoxic chemotherapy. This, I think, is less of a problem since these treatments are almost surely without any significant survival benefit. Their lumping all of these variations together blurs any differences between them. It may be that some of these treatments are entirely ineffective while others are more effective than the modest results they show. They make little effort to try to dig deeper and find out if any particular Interferon combination or dose offers a more promise. It's a bit like saying exercise is good for you without saying a thing about what kind of exercise and how much! It turns out I think there is evidence one Interferon combination may be more promising than most Interferon alone.
  
  
• Questioning Their Study Inclusion Criteria: Their inclusion of one study [Steineck 1990] makes me seriously question their inclusion criteria. This small randomized study compared Interferon to hormone therapy and was just a disaster. Problems with side effects forced several modifications of the Interferon dose, but that's far from the worst of it. The big problem is that fully half of the hormone therapy patients were switched to Interferon when their disease progressed (which usually happened very quickly). Obviously, you can't hope to make a meaningful comparison of survival when half the hormone therapy patients also got Interferon. You can compare progression-free survival but that's not what this review actually did. Admittedly this study couldn't have contributed much to the results of this review because it was so small, but it makes me question their methodology.

Some Individual Studies

MRCCC Randomized Trial of Interferon versus Hormone Therapy

This 1999 paper [MRCRCC 1999] reports "preliminary" results (I haven't found any more recent report) of a British randomized study which compared single agent Interferon therapy with hormone therapy. This relatively large study had almost 170 people in each arm, and that alone makes it important. They used 10 million units three times a week by sub-cutaneous injection with a little less the first week. The key results were:

• A statistically significant, but very modest, 2.5 month improvement in median survival from 6 to 8.5 months.
  
  
• A statistically significant, and again modest, increase in the chance of living a year from 31% with hormone therapy to 43% with Interferon.
  
  
• Two year survival of about 20% for the Interferon group compared to about 12% for the control group. I estimated this from the survival curve and don't know if the difference was statistically significant. The data is not shown past two years, so I can't estimate five year survival.

If you actually look at the survival curves, you can see that while the Interferon group did consistently better, the difference was always small. It turns out though that the median point (look at where the curves intersect 50% survival) came at a point when the curves had about their maximum separation, suggesting a lesser benefit overall. I've marked this up on the survival curve below so you can see just what I'm talking about.

The progression free survival shows that almost every patient experienced worsening of their cancer by two years. Only 5 of the 167 Interferon patients were progression free at two years, compared to two of 168 hormone therapy patients. The response rates to Interferon were typical - 12% partial responses but only 2% complete response. Little information is given on duration of response but judging from the progression free survival it could not have been long.

Oddly, they treated patients for only 12 weeks. Motzer from Sloan Kettering[Motzer 2000] says that response typically takes 3-4 months to develop and sometimes longer, so this is barely long enough to be a fair trial. They do say they gave 14% of patients more than 12 weeks of treatment, but don't say how they decided when to continue treatment. Interferon treatment is often continued until there is clear progression of disease - they may have given a less than optimal amount of treatment to some.

A surprisingly large proportion of their patients still had the affected kidney in place (42%). There is evidence that nephrectomy improves survival in patients being treated with Interferon (For details, see my article on Combinations of Surgery and Immunotherapy). It's very possible they could have achieved better survival if they'd integrated nephrectomy into the treatment program. This doesn't mean the difference between the two arms would have been any greater though.

Almost a fourth of these patients were very symptomatic (Performance status 2) so you would expect survival here to be worse than the typical IL-2 study where almost all the patients are in better shape, although there is nothing to suggest long term benefit in any appreciable number of patients.

The Sloan Kettering Experience (Minasian 1993)

This summary of Sloan Kettering's experience with Interferon[Minasian 1993] is important because it includes a relatively large number of patients (159) with good follow-up, and because it is from Sloan Kettering, which is perhaps the most well respected cancer hospital in the world, and which has been a proponent of Interferon for metastatic RCC.

This paper actually summarizes three different trials using different doses and schedules of Interferon - so it's just a little "blurred", but all three were higher dose regimens. Of note, 28 of the 159 got Vinblastine with the Interferon and at a higher then usual dose which proved too toxic. Overall, their patients had bad prognostic factors similar to the MRCRCC trials with 28% of patients with the kidney in place and 37% with performance status 2.

Key Results:

• Median survival 11.4 months, five year survival 3%.
• 10% response rate, only 1% complete. The median duration of response was 12.2 months.

Minasian 1993, Figure 1: Overall Survival

Of note, both of their complete responses were long-term durable. While 2 of 159 is a tiny number, it does hint that CR to Interferon might be a major benefit in the very rare cases when it happens. Three other patients survived at least five years. One had a partial response and then surgery to remove the remaining tumor, one had a partial response and then switched to IL-2 and achieved a durable CR, and one had long term stable disease.

Conclusion: Though median survival was reasonably consistent with the other studies, long term benefit was quite rare. Still, this is ugly. Does not make me want to run out and get Interferon. This was published in 1993. To my knowledge, a full decade later, Sloan Kettering still prefers Interferon to IL-2. I find that difficult to understand.

Interferon + Vinblastine

Vinblastine is an old-line cytotoxic chemotherapy drug and for many years was considered the most active cytotoxic drug in RCC, although this amounted to less than a 10% chance of getting a brief response. While this is unimpressive, Vinblastine combined with Interferon is more interesting, although it's far from clear this improves on Interferon alone.

As you will see, despite a number of studies showing greater than expected median survival, the best randomized study showed no survival benefit despite an increased response rate. An increased response rate could translate to increased opportunities for complete resection of residual metastases though that isn't specifically proven for this treatment. The case for adding Vinblastine is far from strong, but there also seems to be very little to lose, since adding a modest dose of Vinblastine adds very little in the way of side effects. Finally, this old-line drug would be available from any oncologist who wants to give it. I think it's worth considering if you will definitely be getting Interferon treatment. I certainly don't recommend either Interferon or the combination as the best possible treatment.

Pyrhonen 1999 Interferon + Vinblastine versus Vinblastine Alone

Pyrhonen 1999 is a study comparing Interferon + Vinblastine to Vinblastine alone [Pyrhonen 1999] and it has the most promising result I've found for an Interferon trial. It was medium sized with around 80 patients in each arm, the Interferon dose was 18 million units three times per week by subcutaneous injection, and the Vinblastine arm got 0.1/mg/kg body weight IV once every three weeks.

As with the MRCRCC trial [MRCRCC 1999], an appreciable number of patients were very symptomatic (Performance Status 2) - here it was about 20%, but unlike that trial, here nearly 90% had had a nephrectomy. The median survival for the control arm was longer then for the MRCRCC trial - 10 months versus 6 - and this may in part be due to the higher proportion who'd had a nephrectomy. They treated patients for 12 months in the absence of progression of disease (compare to 12 weeks in the MRCRCC trial), and again for longer in selected patients who were stable or responding. Although only about a quarter of the combination patients got a year of treatment, at least here you know that was standard in the absence of progression or unacceptable side effects.

Key results:

• Median survival was 67.6 weeks in the combination group and only 37.8 weeks in the Vinblastine group. This almost seven months increase was statistically significant. Five year survival was about 10% for the combination arm and about half of that and maybe less for the control arm (the plot for that arm doesn't quite go out to five years).
• Response rate was 16.5% for the combination (8.9% complete), compared to a dismal 2.5% response rate for Vinblastine alone. The 8.9% CR rate is unusual for an interferon trial, but the median duration of these complete responses was short at 27 weeks, only slightly more than the 24 weeks for their 6 partial responders.
• As you can see from the survival curve below, there were a limited number of long term survivors out beyond five years, but it appears that almost all patients eventually experienced progressive disease (as also seen by the limited response durations), and most patients progressed very early on.
• Adding Vinblastine did not seriously increase side effects, although there was a modestly increased incidence of low white blood count. This is a side effect oncologists are very well equipped to handle.

Interestingly, they determined that their results would have been similar even if responding patients were excluded from the analysis. It seems the major benefit here is not in creating durable remissions but slowing the course of the disease.

Importantly, they briefly review a series of earlier arm studies of Interferon + Vinblastine which were fairly consistent as to dose and schedule. The median survivals in these studies were 55, 39, 96, 70, 65 and 70 weeks which is very consistent with the combined arm in this study (68 weeks).

Conclusion: Despite the fact that the combination arm recorded some of the best results I've ever seen with Interferon, this is the wrong study to prove adding Vinblastine to Interferon improves on Interferon alone. To prove that you'd need to compare the combination to Interferon alone rather than to Vinblastine alone. Unfortunately two randomized studies that did compare to Interferon Alone [Fossa 1992, Neidhart 1991] failed to prove that adding Vinblastine was helpful, leaving the unusually long median survivals in a number of different studies of Vinblastine + Interferon, this one included, as the best evidence. This is shaky considering that two of the cited studies were the combination arms of the above randomized trials.

Fossa 1992 Interferon + Vinblastine versus Interferon Alone

If Pyrhonen [Pyrhonen 1999] was the "wrong" study, then this is the "right" one because it compares to Interferon rather than Vinblastine. It used the same dose for the combination as Pyrhonen alone, and the standard 18 million units three times a week subcutaneously for the Interferon only arm. As with Pyrhonen, the only significant increase in side-effects from the combination was a modest increase in the incidence of depressed white blood cell count. Unfortunately, the results were that adding Vinblastine didn't improve survival. As you can see from the survival curves below, the combination arm did have a very slight edge which persisted until towards the end of the curve when the two curves converge, but this edge wasn't statistically significant - it could easily have been due to chance alone. The median survival was about 10 months for Interferon alone and 12 months for the combination, with a 9% five year survival for both arms.

Interestingly, the combination arm had twice the response rate (24%) as the Interferon only arm (11%) but almost all of the responses were partial with only a single complete response in each arm. Unfortunately, all of the partial responders relapsed with a median duration of 6 months duration and a maximum of 18 months. The two complete responders each had very short follow-up so it's unknown if these turned out to be durable. Once again this demonstrates that responses to Interferon tend to be short lived and do not translate into long term survival. If the partial responses could have enabled surgical resection of residual disease perhaps they could have converted some of them into long term benefit and this could be a benefit of the combination they didn't reap, especially since much less was known about the benefits of aggressive surgery at the time these patients started treatment (1985-6).

Fossa 1992 Fig. 1a.: Overall Survival

Neidhart 1991 Interferon + Vinblastine versus Interferon Alone

This is another study comparing the combination to Interferon alone, and it also showed no survival benefit for the combination. I include it mainly just to note that while it's the "right" general design, the details of the treatment differ enough that I don't think it's really comparable, so I don't think this is a strong blow against the combination.

There were differences in both the Vinblastine portion and the Interferon. Compared to the other studies, they gave about twice as much Vinblastine in their first 29 patients but then reduced it to about the same for the remaining 136 patients. For the first 12 weeks, interferon given 5 times a week rather then three times per week, starting with low doses for the first 4 weeks, and then escalating to 20 million/m² for the remaining eight weeks. Given an average body surface area of about 2 meters this would be about twice as much as the other studies gave per day - and again for five rather than three days. But after 12 weeks of this high dose treatment, their protocol then lowered the dose to 5 million units / m² three times a week, which would be about half the dose of the other studies.

Furthermore, they used a different and unusual Interferon preparation. Interferon given as a drug is usually a pure single alpha-interferon made through genetic engineering techniques, but this was a mix of various natural interferons derived from human cells stimulated to produce it.

Promising Variants

Pegylated Interferon is a form of Interferon which as been chemically modified to make it long acting. Two forms of PEG-Interferon have been researched in kidney cancer, and active research is ongoing. While not spectacular, I find the results so far somewhat promising.

For a detailed review of a Pegylated Interferon trial, including a detailed literature review, see Phase II Study of PEG-Interferon alfa-2b in Patients With Metastatic Renal Cell Carcinoma in the Renal Cell Cancer Evaluated Trials Database.

References

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This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: August 31, 2003, Last Updated: February 2, 2004

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