Western Regional Blog – BC, YK, AB, NWT and Nunavut
“…chemotherapy-induced neuropathy is a big, big problem; it is one of the more prominent toxicities we have with a number of commonly used chemotherapy agents, such as the platinum agents and taxanes.”
PracticeUpdate: Dr. Loprinzi, please speak about the current treatment regimens for chemotherapy-induced peripheral neuropathy.
Dr. Loprinzi: First, I’ll say a couple of words about something that is obvious to many—chemotherapy-induced neuropathy is a big, big problem; it is one of the more prominent toxicities we have with a number of commonly used chemotherapy agents, such as the platinum agents and taxanes.
Although chemotherapy-induced neuropathy will often get better for many patients after stopping chemotherapy, it won’t for others and, for some, it can become a chronic problem that lasts for years. Mostly, we’re talking about peripheral neuropathy—stocking-and-glove numbness, tingling, with or without pain; occasionally patients can also develop some motor weakness.
We don’t have great ways of preventing the problem. Calcium and magnesium for FOLFOX neuropathy has been most actively used in clinical practice over the past decade; stay tuned for ASCO 2013, because a large trial studying this issue will be presented there, which may set the standard for whether or not this approach should continue to be used in practice.
In terms of treatment of patients with established neuropathy, the most common drugs used in clinical practice over the last decades have been the gabapentinoids—gabapentin and pregabalin. Nonetheless, only one reasonably sized, placebo-controlled, randomized controlled trial has evaluated either of these drugs—that being gabapentin—and results were convincingly negative.However, gabapentinoids are still commonly used in clinical practice. It’s possible that the negative results of the gabapentin trial were just by chance and that gabapentin really does work (since it works for other neuropathy syndromes), or it could be that gabapentin helps some patients and hurts others— resulting, on average, with the trial showing no benefit. It is also possible that pregabalin helps, but this has not been established by clinical trials.
Recently, however, Smith et al published a trial evaluating duloxetine for treatment of neuropathy that was substantial and persistent after completion of taxane or platinum therapy; this trial showed a statistically significant benefit for duloxetine vs a placebo. A subset analysis supported that the benefit was primarily in patients receiving oxaliplatin—those taking taxanes did not seem to benefit. The benefit from duloxetine, however, was not a home run; duloxetine decreased pain, more than was associated with the placebo, by 1 point on a 0-to-10 point scale. For some patients, though, it appeared that it helped quite a bit. Additionally, it was relatively well tolerated.
It is reasonable to ask “Are these results believable?” And the answer is, I think, yes—for several reasons. First, the trial was well designed (double-blind, placebo-controlled, etc). Additionally there are data regarding venlafaxine, a cousin drug, which show that it can be helpful in patients with chemotherapy neuropathy. A double-blind, placebo-controlled, relatively small (48 patients) trial by Durand et al, actually a combined prevention and treatment trial (patients entered on study if they had an episode of acute neuropathy with a dose of FOLFOX and were treated with each subsequent dose of FOLFOX), reported a statistically significant decrease in neuropathy in patients getting venlafaxine vs placebo. Additionally, both venlafaxine and duloxetine have been shown to be helpful in other pain syndromes, such as diabetic neuropathy. So, there is good reason to trust the results.
It is reasonable to ask what else is there to use to treat established neuropathy. A number of things have been proposed and seem promising, although none have, yet, been definitively proven to be of value. There is a topical mixture, consisting of baclofen, amitriptyline, and ketamine, which looked promising in a double-blind, placebo-controlled trial; but, ideally, further work should be done to substantiate this. There is scrambler therapy, which Tom Smith investigated in a pilot study, and which we have used at Mayo; it does appear, to me, to help some patients, more than I’d expect with placebo therapy. There is also some early information on a topical menthol preparation, which looks exciting but needs to be proven. And, then, there are a couple of other oral medications, such as alpha lipoic acid and acetyl-L-carnitine; but, again, there is not enough evidence to prove that they are beneficial.
PracticeUpdate: Given the cost of duloxetine, do you think we can extrapolate and use venlafaxine instead, since they have similar mechanisms of action?
Dr. Loprinzi: This is a great question. They are cousin medications, and the fact that they both seem to have some effect is good. Duloxetine is supposed to go off patent in June, 2013, and, conceivably, the price should go down. It might be tolerated a bit better than venlafaxine, per cross-study comparisons. So, if cost is not an issue, duloxetine wins right now. However, if cost is an issue, I think that venlafaxine is a reasonable thing to try.
On another note, one of the more exciting possibilities from the Smith et al trial is that duloxetine, since it works for treatment of established neuropathy, may work for prevention of the neuropathy.
As noted above, the benefit from duloxetine on established chemotherapy neuropathy is less than ideal. However, if this lead results in a trial that demonstrates that this drug can prevent the development of neuropathy, this might be a much more helpful approach.
I liken this potential scenario to the situation in which patients have type X metastatic cancer whereby drug Y causes some responses, and patients live a few weeks longer, on average, than those who received a placebo. While that might be nice, it’s not a wow sort of phenomenon. But, if you run with that and put it in the adjuvant setting and find out that we can now cure 15% more patients, that’s the sort of thing—this lead we have on duloxetine having a possible prevention effect— that might lead to substantially less neuropathy. Of course, again, that’s all speculative.
There are currently efforts underway to conduct such a trial to evaluate duloxetine in patients receiving FOLFOX to determine if it can prevent neuropathy. This is based also on the Durand data, whereby venlafaxine was given along with the FOLFOX.3 Patients had a cycle of FOLFOX therapy; once they experienced some acute neuropathy symptoms—cold sensitivity, cramps, and swallowing difficulty—they were placed on venlafaxine with each subsequent dose of FOLFOX. This point is that a decrease in peripheral neuropathy appeared to have occurred, and it could be either from treatment or prevention. I think it’s more prevention.
PracticeUpdate: When do you recommend starting the duloxetine, based on the Smith study?
Dr. Loprinzi: Well, keep in mind that the Smith trial involved patients who were finished with their chemotherapy—who were not receiving ongoing neurotoxic chemotherapy. In my mind, there are two separate situations. The first is what do you do if somebody develops neuropathy while you’re treating them? The standard approach is to evaluate how bad the neuropathy is and how beneficial you think the treatment is for the cancer, and then to decide whether or not to stop the therapy. If you’re treating the patient in an adjuvant setting and you’re trying to increase that person’s cure rate, you might be more inclined to continue the chemotherapy. On the other hand, the person in the adjuvant setting may live for a long, long time, and some people have chronic neuropathy that is really bothersome for years. So, you have to put all those things in perspective to make a clinically appropriate decision. One option for patients getting FOLFOX, based on the Durand data, would be to start a serotonin and norepinephrine re-uptake inhibitor (SNRI), like duloxetine or venlafaxine, and see if this helps allow the patient to continue the treatment. However, this really should be studied before being routinely utilized in clinical practice.
The other situation involves the patient who has completed chemotherapy. If the patient says, “You know, it’s really not bothering me too much; I’m living with it. It’s getting a bit better,” in this case, I would not favor starting a medication for the neuropathy. However, if it’s bothersome enough, and you ask, “Would you consider taking a medication to treat it even if the medication might have some side effects?” and the patient says, “Yes,” you have your answer. It’s a discussion with the patient as to whether he or she wants to take a medication to try to prevent toxicity from a different medication, knowing that the new medication might cause some side effects but, hopefully, only temporarily. Clinical judgment, again, is necessary.
I am less inclined to start duloxetine for taxane-induced neuropathy, given the subset analysis by Smith et al.
PracticeUpdate: What about neuropathy associated with other types of chemotherapy, such as vincristine? Would you expect duloxetine to work in vincristine neuropathy as well?
Dr. Loprinzi: The first answer is “We really don’t know.” A second answer is “It might.” Still another answer is “We have no proof.” So, we’re back to that clinical judgment thing.
PracticeUpdate: Will these results change your practice?
Dr. Loprinzi: If a patient has bothersome neuropathy after finishing chemotherapy, and it is oxaliplatin induced, I think, at this point and time, the first drug to go to is duloxetine. When I’ve spoken to many audiences about chemotherapy neuropathy, I’ve frequently asked, “Does your practice—and that’s not necessarily you, it might be somebody else in your practice—use gabapentin or pregabalin for treatment of established neuropathy that’s bothersome?” about 90% of the hands go up. And, then, when I ask the question in a little different way, “Do you use or recommend the use of gabapentin in your patients with bothersome neuropathy?” about 50% percent of the hands go up. So gabapentinoids have been commonly used despite the study that Wong et al published demonstrating that it did not provide benefit. As I now see things, duloxetine should be the first drug to choose in this situation.