Melanoma|December 10, 2011 12:32 am

Today’s Thought: What matters in treatment choices?

At many melanoma meetings, the issue of treatment of metastatic disease with Interleukin-2 comes up. The room quickly divides into two sides, the true-believers and not-in-my-cancer-centers. The two groups both mean well and are both completely versed in the pros and cons, but just like in politics (?) both sides can look at the same data and draw diametrically opposed conclusions.

But what do the patients think?

Here are the known facts:

Interleukin-2 (IL2)is a highly toxic immunotherapy drug with proven efficacy:
1. It is dosed to toxicity, in other words, 100% of patients get significant if not life threatening side effects, which may not always be reversible.
2. About 7-8% of patients seem to have have complete responses, which means all tumir deposits go away with treatment. These responses are often indefinite, seeming “cures.”
3. However the other 92-93% of treated patients get short lived if any tumor shrinkage–usually the tumor grows unhindered by the IL2, even with maximal dosing and toxicity.
4. IL2 has never been shown to statistically extend survival in a large group of people, almost certainly because so few people respond, not to mention the risk of treatment toxicity/mortality.

IL2 was approved in 1998 and the data really haven’t changed since then.

What has changed is the approval in 2011 of Ipilimumab (Yervoy) and Vemurafenib (Zelboraf), both of which DO significantly extend survival, at much much less toxicity. Yes, there are toxic side effects, but they really are much less in scope and severity.

So here is the question:

What matters? Is IL2 toxicity (ie risk) worth the benefit? What if you can’t tolerate any other therapy after IL2? Is the 7% “cure” rate worth it? Does your opinion change based on BRAF mutation status, ie Zelboraf eligibility? Would you rather get a drug like this first? Second? Third?

Thanks for listening, reading and commenting. As always not looking for answers, just perspectives…

Eric D.Whitmns, MD
Senior Editor,

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  • I’m presently on 6miu’s 5/7 of interferon. Took 9 miu’s for 3 weeks but blood results were not good so reduced back. I’ll be on this till Sept 2012 but wonder do side effects out weigh the benefits & also will I be left with any long term side effects

    • The potential for long term side effects is always scary, particularly when you are just beginning treatment and have a long road ahead. Interferon does not usually cause long term side effects.

  • As a 32 year old Mom of two, the potential benefits outweigh the risks in my mind. I am BRAF+, but the 6-18 months of benefit isn’t enough for me yet. That is the last resort. For now, we try everything to get me NED or limit my disease to give those researchers as much time as possible to make advances!

    Interferons odds were bad, too. And it didn’t work for me. But it was worth the toss of the dice.

  • I am in the minority group. In 2006 I had Biochemotherapy along with IL-2. It completely shrunk my lung tumor away. This was the only treatment that was offered to me. I did this for 18 long months and was in good health as a 46 year old at the time. I have had no recurrence since that time. It saved me.

    • Biochemo was very commonly used for several years although less so now with the newly approved drugs. Congratulations on your response to treatment, which always makes the side effects worth it in retrospect.

  • My husband did two treatments of IL-2 and got through more treatments then most people, do. However, it basically did nothing and he’s dead.

    I spent hours on the phone begging for somebody to take him in for a compassionate Ipilimumab study, but ironically only otherwise healthy people are accepted into studies.

    He was going to be treated at NIH, but tumors in his intestines put an end to that :-(

    • I’m very sorry for your loss, and for the frustration you felt pushing against the system. The time between proof of concept and actual approval can be very difficult to tolerate.

  • I’ve done interferon, braf inhibitor, TIL Study along with 8 doses of IL-2, and countless surgeries. Just found out tumor in my lungs is still growing. Thus far nothing has worked. My drs are thinking next to do Yervoy, braf/mek inhibitor, and or surgery. The IL-2 almost killed me twice! It was the hardest treatment EVER!! I was diagnosed hypothyroid recently from the IL-2.

  • Great comments, all! It’s so hard to know what to do, even in retrospect. I still struggle with the thought of risk vs benefit in this setting, and I look forward to more comments and insights.

  • I’ve had 6 weeks IL2 , 50 nodes removed and 25 rounds radiation. I would do the IL2 again if my DR said it was the best option. 4 1/2 survivor 3 yrs ned. I believe who administers IL2 and where you get it makes a world of difference. I made it through after starting w/ 14 tumors, even ripping out my pic line in my neck the first week! I NEVER was afraid to go back I trusted my DR & nurses!

    • You have certainly been through alot and I am glad that it has worked out for you. It is good to hear the attitude of people who have benefited from IL2 and were willing to do it again.
      The issue of where to get the treatment actually is less of an issue because most physicians do not treat people with IL2 at all, limiting the choices. The data seems to be the same everywhere.

  • Such thought-provoking questions! IL-2 is, as you have noted, a brutal treatment that often leaves permanent damage in its wake! And even knowing that, melanoma patients will continue to cling to it as a ray of hope.

    I imagine that the answer to whether the toxicity is worth it correlates with whether you are a responder or nonresponder. If IL-2 worked for you, then absolutely it was worth it; if it didn’t, then you probably feel differently. For my daughter’s treatment plan, we decided (under the wise guidance of her melanoma doc!) to keep the IL-2 in our back pocket to be used as a last resort. In hindsight, I would do it that way again, especially with the newly approved drugs (patients now need a road map to know what to try in what order), but I have struggled for years with the question of should we have given it to her at the beginning when she was strong enough to handle it or at the end, giving the less toxic drugs a chance to work first … or even should she have gotten it at all. In the end, none of it mattered because the IL-2 didn’t work for her … unless the success of IL-2 has something to do with the timing???

    The questions I have are: Has any research been done on why IL-2 works for the small percentage that it does? Did it matter whether it was a first-line treatment or second, third, etc? Was there a common thread among responders for anything like previous treatments, etc?

    Thank you, Dr. Whitman, for caring what the patients/members of the melanoma community think about this issue.

    • Thanks for your note Donna. Unfortunately, nobody has ever been able to identify who would be more likely to respond to IL2 beforehand. That would be ideal, to spare those unlikely to respond from the toxicity. There is a suggestion that has never been scientifically tested that people with lymph node and skin metastases only (“M1a”) are more likely to respond but that is anecdotal.

      First, second or third line therapy doesn’t seem to matter. There have been studies looking at that. Earlier treatment may matter but only from the perspective of being better able to tolerate the drug.

      Even after all these years (IL2 was approved in 1998 but tested for years before that with essentially no change in the results) the key to identifying who will benefit is elusive. It is great to hear from people who have done well but I wonder if those who failed to respond have regrets?

  • My husband has been through every therapy. In my opinion IL2 and Biochemotherapy was pure torture and did not work. We were not in the lucky 7%. However, Zelboraf was a success for 7 months first time, and 2 months second time. You have to be BRAF positive and we were lucky. Yervoy was not successful first time, but we are hoping it works 2nd time around. Bottom line, my husband was strong as a bull and made it through 16 of 24 rounds of IL2, but it took a long time to recover and no benefit was derived from this. Biochemotherapy was also not worth the side effects. The future is in combining Zelboraf with either Yervoy or another cocktail.

    • Thanks, I am leaning that way as well and I think in general melanoma specialists are getting very excited about more targeted and proven (and hopefully less toxic) therapies. Hoping for the best for your husband.

  • My Melanoma Oncologist started working with IL-2 in the early 1980′s. He has a great staff trained for working on the side effects. He is personally involved with every bag that is administered and works with each patient several times a day. I went to him when I went to stage IV because when I talked with other people who’s spouses had tried other treatments first, I was told that their Oncologists had recommended that IL-2 be put off to be used as a last resort. i was then told by most of the spouses that their significant other failed to recover from the chemo treatments that were recommended in time to be able to try the il-2. I wanted to try the roughest treatment when I was at the strongest part of my battle.
    i disagree with the statement that 92-93% of patients get a short lived response to IL-2. What I have read says that 12-15% get a partial response and that roughly 75-80% get no positive response to il-2. What I liked about the readings was that in the huge majority of patients the recovery was extremely fast and one could then go quickly to another treatment if they did not respond to the IL-2. (These numbers seem to be in about the same range as the positive responses to Ipi.) The IL-2 worked to hold me essentially stable for 20 months. During this time there was one peer reviewed article published on the off-label usage of an approved cancer drug for for my C-kit melanoma. When my melanoma went wild after the 20 months, I discussed the new (old?) drug with my Oncologist). I have been on the unapproved (for melanoma) drug for three years now. My tumors have been stable since 30 days after starting the new treatment.
    i have known people that have had IL-2 as their only stage IV treatment and have been melanoma free for over 20 years now. I have known others that after being either a partial responder or failing to respond directly to IL-2 have gone on to other treatments with success. I suspect that IL-2 primes the system so that other treatments are more likely to have positive results. i have also known Ipi patients that have had to spend a month or more in hospitals to recover from the sometimes extreme side effects of Ipi.
    I credit IL-2 and my Oncologist’s being able to step outside his normal box of treatments with my still enjoying life five years after being found at stage IV melanoma (still have tumors, OH where is NED?) But still enjoying life. Was told by a general Oncologist that he would recommend chemo, not IL-2 and to expect to die within 3-6 months of the stage IV diagnosis. Have known others that reached the NED level for years and sometimes many years (and still going on with life) thanks to IL-2

    • Thanks for your thoughtful reply. I include partial responses in the “93%” group because IL2 partial responses are not durable ie do not generally last long. I do that because the approval of IL2 is based really on the complete responses and how durable they are, acknowledging that the overall group will not show an improvement in survival. Although Gleevec is not approved for melanoma, its use for the relatively rare c-kit mutation patient is generally accepted I think among people who treat many patients with metastatic melanoma.
      I have not found Ipi to be more toxic than IL2, quite the contrary. And unlike IL2 Ipi may show a delayed response with tumor shrinkage seen several months later–with IL2 if nothing happens after the first 2 cycle course of treatment, it never will.
      I have also suspected that IL2 can prime the immune system, but to what end and how best to take advantage of it? Determining this would only increase the use of IL2 in the USA.
      I am happy for you that your melanoma has been able to be treated with some success over a long period of time.

      Eric Whitman, MD
      Senior Editor

    • Hi Jerry! Glad you found your way over here … your daughter thought you would be interested in commenting. Jane from Maine would have lots to add to this discussion as well. Please let her know we are talking about her favorite subject.

  • There doing clinical trials with targeted radiation & Il-2 at the hospital I was treated at and have had over a 50% success rate of durable responses. This was in a small group (12), but there expanding the study so hopefully they can continue and keep improving on the success rate. I am obliously bias having had success with IL-2 myself. I will say this about side effects I started IL-2 with in 6 weeks of being DX. I never had any symptoms and was in fairly good condition. My Dr. was VERY clear about side effects, including that many of them would go away after time and at least for me they have. Some took 2 years but I have far more problems from the surgery than the IL-2

    • I am glad that you have had personal success with your IL2 treatment; the fact remains that most people do not, and no large scale study has identified a way to improve those results (12 patient studies are nice but preliminary).
      It is interesting how long the side effects can take to go away. Which ones took the longest?

  • My husband David did 57 doses of IL-2. If I would have known what he was going to go through I would not of supported him in his decision for this treatment. I personally beleive that his quality of life was horribly altered due to the IL-2 treatment. His cancer was 13 months long. He passed away December 15, 2008.

    • I am very sorry for your loss. Hindsight is always difficult. I can however understand your perspective and wonder how common it is ?

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