Thursday, January 01, 2009

The new adventures of old vincristine

And no, I won’t be having any more of that drug again.

Readers may recall that my doctor and I settled on R-CVP therapy (Rituxan + cyclophosphamide, vincristine, and prednisone) to treat CLL and AIHA during my hemolytic crisis of October 2007. In the research of those frantic days, I ran across all the usual warnings about chemotherapy
side effects.

I also ran a
cross what, it turns out, are disagreements among top doctors about which drugs are more disagreeable.

Dr. Clive Zent, CLL autoimmune expert at the Mayo Clinic, told me:

"Vincristine has very
good activity against AIHA and ITP in many patients -- acts against macrophages causing RBC and platelet destruction -- and is thus a useful component of treatment. Vincristine also has activity against CLL. The drug has very little other toxicity and in particular minimal bone marrow toxicity. In contrast both cyclophosphamide and corticosteroids have a wide spectrum of serious toxicities. Obviously patients need to be monitored carefully for vincristine neurotoxicity and the drug stopped early if this occurs. In most cases full recovery is likely.”

Dr. Terry Hamblin, the well-known UK researcher and clinician, had another view of vincristine:

“ . . .
It also has the added side effect of peripheral neuropathy. Experience can be dangerous here, too. Perhaps I am unfairly prejudiced against the drug after seeing an old lady confined to a wheelchair for the rest of her life after just one dose.”

Well, me, I’m not an old lady right? As my grandma from the Old Country might have said, “You are young and strong like bull.” What could go wrong?

* * *

Vincristine received FDA approval in 1963 under the trade name Oncovin, which is
the “O” in R-CHOP, another chemo regimen that node-heavy CLL and lymphoma patients sometimes find themselves experiencing. The drug is a derivative of the Madagascar periwinkle, formerly known as “Vinca rosea,” and had been used as a folk remedy before its refinement for cancer purposes.

I have provided pict
ures of this very pretty plant and I can almost see the lemurs of Madagascar swinging about by their tails and chomping on the inviting foliage -- until peripheral neuropathy sets in and they all come crashing down from the branches with a thud.

My doctor, Dr. Belle, made a good call on the first day of R-CVP therapy back in October ‘07. Because my heart was under extra stress (my hemoglobin was down to 6.8), she ordered what she called a “baby dose” of vincristine. I would norma
lly have received 1.4/mg per meter squared -- around 3 mg given my body weight. Instead I was given 1.4 mg total.

That's all the vincristine I have ever had because it turned out that I am highly sensitive to it. Within days, peripheral
neuropathy (numbness of the fingers) set in, which lasted a couple of months. My vision became blurred, which at first I blamed on all the steroids I had been taking to control the AIHA. But this was a marked blurring, which set in over a few days, hung around for several weeks, and then resolved. Given these symptoms, Dr. Belle deleted vincristine from my other two rounds of treatment, with my blessing.

* * *

Months later, in the Spring of ‘08, I began to notice what I called a “creakiness” in my legs. If I sat for awhile, my thighs would tend to fall halfway asleep and I would be very stiff when getting up. I’d walk like an old man -- weakly, unsteadily -- for a minute or so until I got “warmed up.” Even
then, when my steps were more or less normal, I experienced a subtle achiness and discomfort that I had never noticed before.

I was also having trouble being limber: Let’s say you’re laying on your back with your left knee bent. You want to raise yo
ur right leg up in the air and cross it over the left, resting it against that bent knee. I was having a lot of trouble doing that sort of thing. I would need to be using my arm to pull my right leg up and over. My leg wasn't dead weight, exactly, but it didn't want to move on its own very easily.

Getting down on my knees to look for something on the floor became an almost superhuman challenge. That's because getting back up was nearly impossible, with most of the effort having to come from my arms, grabbing hold of armchairs and tables and such to give me enough leverage to stand.

At night, I would toss and turn in bed. My hips would ache, especially where the thigh muscles seemed to attach. This achiness would generally stay with me throughout the day to one degree or another. I spent a lot of time grumbling at the mattress, which is made of pure latex rubber and had never given me such trouble before.

My primary care physician had no idea what might be causing these symptoms, and Google searches only led me to a host of scary-sounding websites that discussed in detail everything that can and will go wrong with the hips.

I eventually laid it at the feet of the steroids I had been on -- loss of muscle mass does indeed accompany steroid use. The thing is, that mass comes back as you use the muscles again. And no matter what I did -- which included several sessions of physical therapy last summer -- I did not get better. Things just stayed the same.

Until a few weeks ago when, like a storm lifting, my hips and legs went back to the way they used to be -- suddenly and unexpectedly -- over the course of no more than two days.

Which is when the light bulb went off and I realized that I had been experiencing del
ayed symptoms from that baby dose of vincristine. That the Madagascar periwinkle might have been the source of my trouble had occurred to me before; but compared to the finger numbness and blurred vision, the onset of the creakiness was delayed enough, and the effects lasted so long, that it didn't fit the pattern of what I expected, especially since I'd had such a small dose. So I blamed the steroids.

If you look at the dose-limiting side effects chart of this PDF on vincristine, you’ll see that symptoms are defined as immediate (onset hours to days), early (days to w
eeks), delayed (weeks to months), and late (months to years). Peripheral neuropathy gets an “early,” but in my case the leg part of the problem was definitely “delayed.”

And for the record, let me quote:

Neurotoxicity involves peripheral, autonomic and central neuropathy. I
t is the primary and dose-limiting toxicity of vincristine. Most side effects are dose related and reversible, but neurotoxicity can persist for months after discontinuation of therapy in some patients, and in rare cases may be disabling.

Peripheral neuropathy is the most common type of neuropathy and deve
lops in almost all patients. Loss of deep tendon reflexes, peripheral paresthesias, pain and tingling can occur. If therapy is prolonged or high doses are administered, wrist and foot drop, ataxia, a slapping gait and difficulty in walking can occur.

I'll close with a cautionary note. Your mileage may vary, of course, but as it turned out my experience with the drug was a little closer to Dr. Hamblin’s than to Dr. Zent’s. Which goes to show you again that when it comes to chemotherapy (and CLL in general), we are all individuals. Statistics are general; results are personal.

The good news is that I am hypersensitive to vincristine, which presumably means it works effectively in my case. The bad news is that I am so sensitive to it that I can never use it again. At least my experience with it did not involve regular or large doses and massive system shock and permanent damage. So in a backhanded way, I guess I was lucky.

Interesting what sometimes passes for luck when it comes to cancer.


Anonymous said...

Certainly it is easy to see why you've crossed Vincristine off of your Christmas List... What are you going to use?

Some patients have done well with the combination of immunosuppressives such as those used post allogrnic transplant and rituximab. There isn't good data, however, on how long to use such drugs. Because of side effects ( eg, hypertension, renal dysfunction, etc) great caution must be exercised with their use.

There never seem to be good answers with CLL.

Good luck,


Anonymous said...

And it is looking more and more like Tom is hypersensitive to Revlmid. Dr.Khan, from Roswell, emailed me stating that he didn't think tom would be a good candidate for Revlimid. We could restart at a lower dose, but personally, he said he wouldn't try it again. Khan said he had never seen a rash like the one Tom got within 3 days of Relimid before in any of his patient's. SJS jumps to mind. What next? We are willing to try Revlimid one more time and if even one small rash appears, it is over. we will wait and see.

jenny lou

David Arenson said...


The fallback is the RCD protocol developed by Dr. Rai's team. But we may be doing something different, or something more. I still think the underlying CLL is the cause that needs to be addressed. (For the moment, steroids appear to be working, but past experience tells me this won't last forever, so we'll definitely be doing more, and fairly soon.) Stay tuned.

Jenny Lou,

I am really sorry to hear about Tom's reaction to Revlimid and Dr. Khan's assessment. We want to be able to use every bullet in the arsenal, especially when some are closed off for particular reasons, such as vincristine in my case.

I imagine you are running the options past a larger pool of experts, as well as Tom's CLL doc. I'm hoping a good alternative emerges, maybe one that will give Tom a lucky break, instead of the other way around. You guys certainly deserve one about now. said...

Hi David,
What a bummer of a Christmas "present". I'm sure you were hoping to get a couple years of remission. When I Saw Dr Kipps in Aug, he recommended his R+HDMP for both my CLL & AIHA, but my local dr wouldn't do it, too dangerous he said. When I Saw Dr Zent in Nov, he said he was not in favor of Kipps' protocol, too immunosuppressive he said. When I said I was hoping to delay chemo-type txs, he suggested a very slow (over months) decrease in the prednisone I'd been on. I'd been on 10mg/day & he suggested decreasing the 10mg alternate day dose down to 0, over a 3-4 month time frame, & then maintain on the lowest dose until it no longer was effective. Yes, I realize I'm trading the side effects of steroids vs chemo, but with Fosamax & regular weight-bearing exercise, at least my bones & muscles should survive intact & I'll just hope the best for my adrenals. After this it will be time for RCP or RCD, but I'm off the fence for V after your experience! It's been so mentally relaxing to have a few months of NOT obsessing on a daily basis about my health, & I'm very sorry you're back in that emotional whirlpool.
My best wishes,
Marcia in Ca (Sta Cruz, actually)

Anonymous said...

Hi David,

Small world. I just finished 5 rounds of RFC at MD Anderson in November (they skipped round 6 because my counts would not recover). I started having the exact same leg and hip symptoms that you outline in your January 1st post. I am 45 with legs that feel as if they belong to a 65 year old. My doctors at MD Anderson were as perplexed as my local docs in Seattle. I also have some slight swelling but it's nothing compared to the "creakiness" that also recovers somewhat after I walk around for a while. I was thinking that this may be a Chronic problem (adding another one to the list) but it maybe mine will also go away over time. I did not get any Vincristine with my protocol so mine may have been caused by another drug or combination of drugs.

Thanks for the post,
James in Seattle.

David Arenson said...

Marcia, you saw a couple of big names there and got conflicting advice. Welcome to the club!

Kipps and UCSD like R+HDMP but there are a lot of docs out there who don't -- including Mayo's team and John Byrd (and my local oncologist) for what it's worth. Who's to say -- I know people who have been through R+HDMP and with proper management they seem to do well in terms of tolerance and side effects, although the remissions are not especially long-lived and usually require follow-up with Campath, which opens up another can of immunosuppressive worms.

The big question is whether your underlying CLL needs treatment or whether you can manage to control AIHA without taking on the CLL, and through the least invasive means, which is steroids. Low doses of steroids like Zent is talking about should not be a huge harm to the body, though I would advise getting a DEXA bone scan just to check up on any osteopenia/osteoporosis issues if you are going to be on steroids for a long time.

Enjoy the scenery in Santa Cruz. Even cancer can't put too much of a dent in the redwoods and the sea.

James, it's interesting that you report the creakiness following FCR. If it's chemo-related (and probably is), it should resolve over time. I think the lesson here is that none of us really know how drugs or a combination of drugs will affect us and we always take our chances. There are people who stay within the norm of experience and those who are outliers and it is usually impossible to judge where a person will fit.

The bottom line is that we are always taking chances with CLL, by not treating it and by treating it.

Anonymous said...

I certainly don't pretend to have any answers, but I would point out to you that the chronic use of steroids at any dosage can have devastating long term effects on the body, including alterations of muscle mass, bone density, glucose and fat metabolism, uncertain effects on immune function and changes in physiognomy.

The more horrific problems of aseptic necrosis of bone leading to the need for hip or knee joint replacement surgery, peptic ulcer disease, super-infections and onset of diabetes mellitus are not to be taken lightly.

If there is no choice, then chronic steroids must be used, but never with abandon!

A good DEXA scan doesn't preclude trouble down the road with osteoporosis, etc and a bad scan with the need for bisphosphonates opens up other cans of worms such as osteonecrosis and possible adenocarcinoma of the esophagus.

I don't mean to sound like the harbinger of doom, I just want to point out the potential pitfalls of chronic glucocorticoid use and remind everyone that "there is no free lunch".

I suspect that in your situation, David, you will ultimately have to deal more directly with the CLL anyway.

Certainly I wish you the best,


David Arenson said...


Thanks for those comments. There is definitely no free lunch with steroids. I hate using them at this point. (There is also no free lunch with things like Fosamax, which can have their own unwanted side effects, including osteonecrosis of the jaw.)

There is a reason that most CLL experts use steroids sparingly as part of an overall treatment program and not in the long term -- unless, of course, a patient is coping with AIHA or ITP.

One thing I might add is that CLLers, especially those on steroids, may want to make sure they are getting adequate levels of Vitamin D absorption, which helps to maintain healthy bones.

A blood test that can be ordered is Vitamin D 25-Hydroxy (Labcorp code 081950).

Over time, my D levels began to decline as they can in CLL and I have been on various supplements for it (sometimes prescription doses) to keep it in the normal range.

Anonymous said...

Hi Dave (all) -
Thanks for the posts on the creakiness. I've been lurking on this site for 2 years since diagnosis. 42 and on 2nd round of FCR. I was supposed to start my 3rd round on Monday and but somehow managed to get an inflamed liver the Friday previous. We don't know why that is, but it could be from the Bactrim. Right after that episode I woke up with the hip and leg pain you have described. I've been attributing it to the liver shenanigans, but to see the way you describe it is pretty much what I've been feeling. I feels like I'm doing 20 squats where I've only done one. Burns and aches. I'm relived to know it's not my liver shutting down and that it may resolve itself. If anyone has had a liver flare up, do share.
Misery loves company... so thanks!

aptosmax said...

Hi David,
Well, I never made it down to the lowest dose of maintenance prednisone, as my BM is telling me it's too full of cells & not making enough retics. So Dr Zent says tx time is here. Looks like it will be RC(V)P for me to clear out the marrow & hopefully control the AIHA. Zent said that some people still have to take maintenance pred after this tx & I'm wondering if that was/is the case for you? Also, how many cycles of chemo did you have? Still having, as you haven't blogged on it for awhile? Thanks, looking for some company-misery loves it, ya know!
Take care,
Marcia in SC

David Arenson said...


I had three rounds of chemo -- R-C(V)P -- the first with vincristine and the last two without. I continued on maintenance methylprednisolone for eight months after chemo. As explained elsewhere in the blog, I suffered an AIHA relapse just before Christmas 2008 and was treated with one round of R-CD in January 2009. I am going to do some further treatment soon.

May your treatment earn you a record-setting remission!