Classic High Dose Interleukin-2
High dose IL-2 gives great benefit to a small percentage of patients, including well documented remissions that are ongoing after over a decade and which are almost certainly cures. [Fisher 2000]. These probable cures are the reason to try high dose IL-2. Another plus is that once the initial treatments are complete, those fortunate enough to gain a remission don’t need any maintenance therapy, although in some cases surgery to remove residual disease is important.
The downside is that most patients get no evident benefit at all and that everyone suffers significantly from the side effects. Fortunately in most cases, despite its misery, the treatment does no permanent damage.
The Basic Results
- Partial or complete responses in 15-20% of Patients. [Fisher 2000, Fyfe 1995, Kammula 1998]. Among the 255 patients whose treatment was the basis for FDA approval there were 7% complete responses and 8% partial responses.
- Excellent durability of many responses, particularly complete responses. Most patients with complete response haven’t relapsed after over a decade of follow-up and are probable cures. Most patients with partial response do relapse, though there are exceptions. Even with partial relapse, a few years of remission is common. [Fisher 2000].
- 10 year survival of 12-15% with pronounced flattening of the survival curves after a several years, again indicating probable cures[Fisher 2000] (see below!). While this long term survival rate may seem very poor to you (and it is), it’s an improvement, and represents a real chance for extended survival and even cure.
- To maximize the odds of cure it is absolutely essential to keep the appropriate use of surgery with immunotherapy in mind: Surgery for relapse after response to IL-2, or to remove residual disease after a partial response can cure some patients, including some who were inoperable before IL-2. For a detailed review, see my article on combining surgery with immunotherapy.
- Summary and Mechanism of Clinical Benefit: If a treatment can cure metastatic cancer then first it must eradicate all detectable tumors, which is to say it must create complete responses. Furthermore, in a cure, the response must last indefinitely, showing that for all practical purposes the cancer has actually been totally eliminated. For IL-2, the existence of 12-15 percent survivors at ten years, combined with the documented response durability, shows that some patients are being cured. As above, in some cases it takes a combination of surgery and IL-2 to produce a cure. This is all in distinct contrast with Interferon, where complete response is very uncommon, and responses only rarely last.
Below are the long term survival and response durability curves fromFisher 2000. They are the key results for high dose IL-2. The flat right tails of these curves extending out beyond ten years of follow-up show that patients are being cured by this treatment.
You can also see that most patients are not cured, so clearly better treatments are greatly needed. Despite this, many different drug treatments have been tried since high dose IL-2 started getting results in the mid 1980’s, and in my opinion, none have yet proven as successful as high dose IL-2. Therefore, I advise caution in deciding to substitute experimental or other drug treatments for IL-2 unless there are already very promising results. Experimental treatments are appropriate if IL-2 has been tried without success, or if you are ineligible for IL-2 treatment for some reason.
Note that survival duration will be greater than response duration, and may be significantly greater, given that patients who relapse can frequently be rescued surgically. See my article on Combining Surgery With Immunotherapy for the details on this.
The Skeptical Argument…
You should know that many conservative oncologists are skeptical that IL-2 is beneficial, or believe it has no advantage over Interferon, which has somewhat milder side effects, or at least believe any advantage isn’t worth the side-effects. I don’t agree at all, but here are some of the typical skeptical arguments:
These results are not from randomized trials, and the fact that they appear to be better than usual for metastatic kidney cancer in certain respects could just be due to bias in the selection of patients, or even just chance. In fact, there is an obvious source of bias. Selecting patients who are in good enough shape to withstand the rigors of high dose IL-2 treatment automatically selects against sicker patients who won’t do as well on average. Excluding these sicker patients surely improves the survival curves. The fact that IL-2 causes tumor shrinkage in some patients doesn’t prove it has actual benefit. In the world of chemotherapy, it’s well known that transient responses don’t necessarily improve survival, even if the responders live longer. Response may simply be a marker for being healthier to start with. Furthermore, renal cancer occasionally has spontaneous remissions and that could explain the “responses”. Finally, there’s no evidence from any of this that IL-2 improves median survival, something which really requires a randomized trial to demonstrate.
…And Why it is Wrong
The responses to IL-2 are frequently extremely durable, ongoing after well over a decade. These responses occurred in the context of progressive disease which was interrupted by IL-2 therapy. They were not spontaneous remissions. Although it’s indeed true that these patients were healthy enough to take the treatment, these patients still had progressive metastatic disease which would be expected to kill them within months to a few years in the absence of effective therapy. Instead, many years later some still show no sign of cancer and are apparently cured.
The durability of these immunotherapy responses makes them different from transient chemotherapy responses seen in some other cancers, which naturally have a trivial effect on survival, or even no effect. These long term immunotherapy responders clearly make up and explain a major proportion of the flat right tail of long term survivors on the survival curve, most of whom surely would not have survived had they not gotten a durable remission from IL-2. In my own case, extensive and rapidly progressing metastasis, accompanied by severe pain and debility, were sharply interrupted by IL-2 therapy. There is no question that the therapy gave me a dramatic response, and no question about what would have happened had I not responded.
Finally, with respect to median survival, extending the survival of a few by a lot doesn’t affect the median much, if at all. Therefore, one would not expect much change in median survival from a therapy whose major benefit is to confer long term survival on a few, but in no way does this detract from the value of this treatment, as any long term survivor will gladly tell you. For the last word on why the median isn’t the only measure of success, see Stephen Jay Gould’s wonderful essay, The Median Isn’t the Message, here on CancerGuide.
High dose IL-2 treatment stresses the heart and lungs, so you need to have good heart and lung function. Most patients get pulmonary function tests and a cardiac stress test to document this before treatment, depending on age and other factors. If you have serious heart or lung disease you won’t be able to take high dose IL-2. Normal, or close to normal, kidney and liver function is also a requirement. If you’ve had a kidney out, that absolutely isn’t a contraindication as long as the other kidney is functioning normally, as is almost always the case.
Eligibility for high dose IL-2 is sometimes pictured as requiring the perfect patient. This is far from true, as my own case well illustrates. Although my organ systems were all working OK, I was incredibly thin from the cancer, somewhat anemic, and in pretty severe pain from the metastases in my spine. My stress test was normal, but I lasted a whole three minutes before I maxed out my heart rate. My advice is that, unless the situation is very clear, you should not count yourself out, except on advice specifically from a doctor with extensive experience with high dose IL-2.
Giving high dose IL-2 is a specialized skill, and in the US, reimbursement from government insurance programs has been inadequate until a rules change in late 2003, so despite the fact that IL-2 was specifically approved for high dose, and the fact that high dose has the best documented chance for long term remission, it is available in only a few places.
Suggestions for finding doctors who do high dose IL-2:
- Call the Kidney Cancer Association 800-850-9132 and ask for referrals.
- Contact Chiron, the maker of IL-2. Check their Proleukin Site for contact info. The Sales and Marketing Dept will be your best bet.
This describes the basic treatment plan for classic high dose IL-2. Among other things, this should help you determine whether proposed treatment which is described to you as “high dose” is truly the classic high dose protocol.
- Inpatient: Treatment is usually in the Intensive Care Unit, but some doctors give high dose IL-2 in a regular ward with close monitoring. If you are in ICU it is for close monitoring, not because you need life support. You’re likely to be the “healthiest” patient there.
- Central Line: Before starting treatment you will have a minor surgical procedure to install a central line IV. This is usually done in your hospital room with local anesthetic. The procedure can be uncomfortable but isn’t excruciating. The central line allows drugs to be delivered to the great veins near the heart so they are dispersed very quickly throughout the body.
- Intravenous Bolus Doses: Each dose of IL-2 is given over 15 minutes via your central line. This is called a bolus dose and is in contrast to continuous dose.
- Dose Schedule: One treatment course consists of 5 treatment days in the hospital, 9 days of rest, mostly outside the hospital, and then 5 more days of treatment. During each 5 day treatment cycle you get a dose every eight hours for a maximum of 14 doses. When side effects reach a pre-determined level, individual doses are skipped. Few patients get all 14 doses, most get 8-12 doses in the first cycle and somewhat fewer in later cycles.
- Dose Level: Standard high dose is either 600,000 International Units per Kilogram of Body Weight per dose (written 600,000 IU/Kg/Dose) or 720,000 IU/Kg/Dose. Some intermediate dose IL-2 programs follow the same schedule as for high dose IL-2 but use a lower dose. To be sure you are getting true high dose, be sure you are getting one of these dose levels.
- Re-Treatment and Follow-Up: You will typically be scanned about a month after finishing treatment. If you have stable or responding disease, you’re likely to be offered a second course of treatment usually 6-12 weeks after finishing the first course. If the tumors are growing, this indicates the treatment isn’t working, and another course isn’t offered.
- Patients with a complete response after any course get one additional course.
- Patients with stable disease after the first course get one additional course, but no more, unless they have significant shrinkage with the second course.
- Patients with a partial response are offered additional courses of treatment as long as their tumors keep shrinking.
- In practice, more than three courses is very rare.
- These rules are always subject to physician judgment and patient preference.
These rules based on Lindsey 2000 as well as my observation of typical practice.
Side Effects and Recovery Period
My goal here is to give you an idea what it typically feels like to undergo high dose IL-2, rather than to enumerate every possible side effect or change in blood chemistry. This is based on my own experience with high dose IL-2, hearing the stories of others who’ve had it, and also reading the literature. Side effects do tend to be somewhat worse the second five day cycle of a treatment course, but not dramatically so.
Typical Side Effects During Treatment
- Vomiting, nausea, and diarrheaI found the nausea and vomiting to be one of the most constant side effects, and was able to eat very little. One problem was that if I felt like eating, by the time the hospital kitchen got me something, it was too late, and I no longer felt it. If at all possible, try to have your support person keep some snacks that might be easy to digest and that appeal in your room or in the floor refrigerator, but don’t panic if you aren’t able to eat much during the treatment.
- General fatigueThis increases and deepens over the course of the 5 day cycle and was one of the most difficult aspects of the treatment for me. Most patients don’t get as many doses as I did, but you may feel more exhausted than you ever have by the last day of the cycle.
- Difficulty sleepingI don’t see this reported in the official literature, but based on my experience and that of others, you may find that you are incredibly tired and yet you cannot sleep.
- Itching and peeling skinNot everyone has this. If you do, it won’t start right away, and may not start until after the cycle is complete, or even until after the treatment course is complete. I didn’t notice it until between the first and second 5 day cycles. It may take several weeks before it clears up completely. Although it was medically speaking very minor, to me the intense itching was a major side-effect.
- Flu like symptoms such as fever, chills, and muscle achesThese should subside very soon after treatment stops. Many patients experience great shaking chills called “rigors” a little while after some of the doses. This is treated with amazingly effectiveness with a little bit of IV demerol. Expect a brief head rush!
- Weight Gain/Fluid RetentionHigh dose IL-2 causes most patients to retain fluid and you may notice some puffiness. You will lose the fluid in the first few days after treatment.
- Low blood pressure and rapid heart rate.You likely won’t directly notice low blood pressure, but this will be closely monitored, and you may be given drugs or fluids to help support your blood pressure. You may notice that your heart rate increases, though it won’t feel like your heart is pounding. Your heart rate and blood pressure will probably be visible to you on monitors in your room, especially if you’re in ICU.
- After treatment ends, you’ll usually be discharged from the hospital after only 8-12 hours of rest from the last dose, but you may stay longer depending on your condition.
- You’re likely to feel very fatigued for the next two to three days with this getting better day by day. Any water weight you gained during your treatment will come off rapidly. Your appetite is likely to be poor as well at first, and nausea may alternate with hunger. I recommend keeping a variety of snacks easily available so that you can eat whenever hunger strikes. Expect this to be much better, though maybe not completely resolved, within in a few days
- You should feel much better overall within a week to ten days and you should be back to normal within a few weeks. If you have itching and peeling, this may be one of the last things to get better. It was for me, along with gradually fading fatigue.
A few doctors still tell prospective patients that high dose IL-2 is extremely dangerous, even too dangerous to try. If your doctor tells you high dose IL-2 is too risky and it’s not because something about your specific condition makes it inadvisable, my advice is: Run. Do not walk. You need an expert in kidney cancer who understands the significance of treatment risk in the context of metastatic renal cell carcinoma.
The truth is that while nothing is risk free, high dose IL-2 isn’t especially dangerous when given by experienced hands, and this is particularly true when you take the risk of the disease itself into account. When you do take that risk into account, the risks of treatment are by comparison utterly insignificant – as engineers say, “In the noise.”
The death rate in the initial series of trials which led to FDA approval was 4% [Fyfe 1995], however with more experience the treatment became much safer. In fact in 1998, doctors at the National Cancer Institute (where IL-2 treatment originated) reported zero deaths in their last 809 patients [Kammula 1998].
A variety of serious complications such as heart attack, fluid in the lungs and respiratory distress, and infection can occur but affect only a few percent of patients. The vast majority of patients who get high dose IL-2 from experienced doctors do not suffer serious permanent damage of any sort.
Fisher RI, Rosenberg SA, Fyfe G.
Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma.
Cancer J Sci Am. 2000 Feb;6 Suppl 1:S55-7. [PubMed Abstract (will open in new window)]
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC.
Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.
J Clin Oncol. 1995 Mar;13(3):688-96. [PubMed Abstract (will open in new window)]
Kammula US, White DE, Rosenberg SA.
Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer.
Cancer. 1998 Aug 15;83(4):797-805. [PubMed Abstract (will open in new window)]
Lee DS, White DE, Hurst R, Rosenberg SA, Yang JC.
Patterns of relapse and response to retreatment in patients with metastatic melanoma or renal cell carcinoma who responded to interleukin-2-based immunotherapy.
Cancer J Sci Am. 1998 Mar-Apr;4(2):86-93. [PubMed Abstract (will open in new window)]
Lindsey KR, Rosenberg SA, Sherry RM.
Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2.
J Clin Oncol. 2000 May;18(9):1954-9 [PubMed Abstract (will open in new window)]
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: February 10, 2003, Last Updated: Feburary 5, 2004