SUPPLEMENTS AND TKI DRUGS

As many of you know I am fortunate to have Hans Hammers, a nationally recognized expert in RCC,for my oncologist. Recently he responded to some questions from Susan Poteat on the ACOR KIDNEY-ONC site. While some may have already seen it (Neil) I know others not familiar with the site may have missed it. With Dr. Hammers blessing, I'm posting it here for the benefit of those who do not belong to ACOR.

From: Susan Poteat <gspshop@GMAIL.COM>

To: KIDNEY-ONC@LISTSERV.ACOR.ORG

Sent: Tuesday, March 12, 2013 9:29 AM

Subject: [KIDNEY-ONC] Supplements for RCC Patients: Hans Hammers answers questions for us

Dear all,

As the RCC drugs are fairly new and most of us see oncologists who are neither experts in the use of supplements nor experts in RCC, Neil and I after some private discussions decided to see if we could get opinions from experts in both fields.  Our main focus is on interactions with the VEGF suppressors-especially on whether a drug could reduce side effects without reducing the effectiveness.

We hope this will be the first in a series, but we do have an answer from Dr Hans Hammers at Johns Hopkins and permission to share it here with all.  I would have been happy with Yes No answers but I am amazed at his generosity in writing such a detailed response.

Thank you Dr Hammers!!

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Questions for Dr Hammers

1. If a list of supplements truly did suppress all TKI side effects, including the on-target side effects, would you have any concern that those supplements also be interfering with the therapeutic effects?

Principally yes, I would be worried if a dietary supplement or cocktail of dietary supplements rendered a patient completely free of any side effects including classic “on-target” side effects. I would be concerned that we have not achieved active drug levels, which we determine clinically by the presence of side effects.  Therefore, we might be underdosing the patient - probably because of the induced metabolism / breakdown in the liver.

It is well documented that the clinical benefit of most targeted therapies correlates with the drug levels and drug exposure which (unfortunately) correlates with side effects -  “on” and “off target” side effects.  In the case of the TKIs, “on target” side effects are those directly related to the inhibition of the VEGF receptor, the classic one being hypertension. “Off target” side effects are those related to the inhibition of non-VEGF receptor kinases such as bone marrow suppression, hand-foot-syndrome and hair discoloration. Older generation drugs such as sunitinib are less selective, hence exhibit more off-target side effects. In contrast, the next generation agents such as axitinib and tivozanib are more selective and potent inhibitors of the VEGF receptors. With these agents we generally see an improved off-target side effect profile and more pronounced on-target side effects, such as hypertension.

In principal, we do like to see “on-target” side effects because they do indicate active drug levels and predict improved benefit. An example of how this is currently applied is axitinib. If we don’t see an elevation in blood pressure or other side effects we typically increase to the next dose level until we do.

It is important to remember that there are two reasons why cancer therapies fail: a.) the cancer is simply resistant to the therapy or b.) we don’t achieve the appropriate drug levels.

With that said, all of the TKI are metabolized in the liver. Therefore, other medicines AND supplements can affect drug levels of the TKIs by either inhibiting their breakdown (e.g. antifungals, grapefruit juice > increased drug levels = more toxicity) or increasing their breakdown (e.g. omeprazole, St.John wort > decreased drug levels = less toxicity, loss of activity).

Therefore if a supplement or cocktail of supplements were able to (which I doubt they are) prevent all potential side effects then it would be critical to assure active drug levels by determining plasma concentrations.

Besides the potential effect on drug metabolism, supplements can affect drug levels in other ways. For example, in the list of supplements provided, you can see that excipients (helper agents) were used to increase absorption of the supplement (e.g. liposomal formulations). If consumed with the TKIs, increased drug levels could occur resulting in excessive toxicity. For example, pazopanib drug levels can double if taken with food or liposomal formulations.

In my opinion, using a large number of often not well characterized dietary supplements complicates things unnecessarily and might in fact cause harm by interfering with drug metabolism.

2. For patients on RCC therapy would you have any concern that supplements specifically intended to raise the nitric oxide levels (to reduce side effects) might interfere with VEGF suppression or other therapeutic effects?

The question is, why do we need to interfere with this pathway ? Nitric oxide release is downstream of VEGF signaling and the lack is held responsible for the subsequent increase in blood pressure. We have blood pressure medicines, which control this side effect very effectively. Although I am not theoretically opposed to it, I doubt that these supplements (often arginine based) can effectively control blood pressure. As a side note, nitric oxide inhibitors have shown tumor suppressive effects in some preclinical models, suggesting that maybe staying away from NO donors, especially if we don’t need them, is a better approach.

3. Can you think of any mechanism which might globally allow reduction of all "on-target" side effects of RCC TKI's without risking reduction of therapeutic effects?

Simply stated “no”. See discussion above.

4. The recommendation was made on the patient forum that patient should start supplements along with the TKI, and then stop the supplements if scans showed progression. Comments?

I would not recommend it – for a couple of reasons.

First, I think we have learned to manage side effects, either by prevention, symptomatic treatment, adjustment in schedule, treatment breaks or dose reductions fairly successfully. I would say for most patients we are able to achieve a reasonable balance between active drug levels on one side and side effects on the other. In other words, we do not need to expose every patient to supplements, which by themselves and especially in combination can interfere with targeted drugs.

Secondly, Let’s assume a cocktail of supplements was indeed able to prevent all potential side effects from TKIs. The problem then is that we don’t know if the patient has actually achieved active drug levels or not for the last 2 months. The continued treatment, then without supplement, is suggested to remedy this issue, but it risks that the patient is exposed to an ineffective drug for an additional 2 months if the disease is actually resistant to a TKI. While this approach may be of little consequence to patients with slow growing, indolent tumors, loosing an extra 2 months with ineffective therapy can be a problem for others.

I guess the question here is what do we want to use dietary supplements for? As a remedy for side effects ? I would argue that we can manage most of these sufficiently well already and at the same time can be assured of adequate dug exposure. If the use of dietary supplements is suggested by a healthcare provider on a systematic basis then the data should be collected in clinical trials so that we can all learn of their benefits or failures. At the same time I would suggest to determine plasma drug levels to avoid the risk of delivering ineffective treatment.

Are the dietary supplements used to potentially enhance treatment effects ? The largely unregulated dietary supplement industry makes a lot of claims and promises but rarely steps up to conduct clinical trials in our scared patient population. In a patient with aggressive disease I would not mess with drug / supplement combinations. Time can be precious for our patients and, unfortunately, almost 20-30% of patients don’t even make it to their second line drug! I think patients with low volume, slow progressing disease are better positioned to experiment with supplements. I have several such patients where we have held off targeted therapy for months and they tried various supplements in the meantime. I think in those situations it’s not unreasonable as long as it doesn’t cause them financial hardship. But again, the only way of identifying helpful supplements or combinations is through clinical trials.

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