The cure versus control debate

February 18, 2009 / / 7 Comments

S. Vincent Rajkumar, MD, of the Mayo Clinic, wrote a very interesting article last fall about the cure/control issue (see: http://tinyurl.com/aham3e). Two fundamental questions: Should we treat patients with myeloma with multidrug, multitransplant combinations with the goal of potentially curing a subset of patients, recognizing that the risk of adverse events and effect on quality of life will be substantial? Or should we address myeloma as a chronic incurable condition with the goal of disease control, using the least toxic regimens, emphasizing a balance between efficacy and quality of life, and reserving more aggressive therapy for later?

The ensuing paragraph confirms that there is no cure for myeloma. Ok, we already knew that. What we have instead is what is called “complete response” or CR. Now, I should note that quite a few studies have demonstrated that CR is not relevant for the vast majority of myeloma patients in terms of overall survival (see, for instance: http://tinyurl.com/bbjkuh). And Dr. Rajkumar essentially seems to agree: Cure vs control is debated because the strategies currently being tested are not truly curative but rather are intended to maximize response rates in the hope that they will translate into an operational cure for a subset of patients. Not very encouraging…

Dr. Rajkumar then provides a history of myeloma’s conventional treatments. CR was rare before the 1990s. Back then, Cure was never a goal of therapy because it was assumed to be unattainable. The goal was instead to control myeloma and keep the patient alive for as long as possible with a minimum of toxic side effects.

Then, in the 1990s, he writes, high-dose therapy with autologous stem cell transplant (ASCT) became part of standard practice when it was found to prolong survival compared with conventional chemotherapy. There follows a list of the conventional drugs that we myeloma folks know well, from thalidomide to bortezomib. Dr. Rajkumar states that the results have been remarkable and that curing rather than controlling myeloma has become the goal of many specialists.

He adds, though, that it is not uncommon to find that well-meaning investigators interpret the same clinical trial data in opposite ways because they ascribe to different philosophies (cure vs control). Hmmm, so the same data can be interpreted in more than one way…this statement makes a good case for getting a second opinion, if not a third and fourth, before making any decision regarding treatment. Eh.

Then we get to the first important statement (from my point of view): It is far from clear whether increasing or intensifying therapy for patients without CR until such status is achieved actually prolongs overall survival. In other words, although the achievement of CR is a favorable prognostic factor, modifying therapeutic strategy with the sole purpose of achieving CR in a patient who is otherwise responding well to therapy is of unproven value. Precisely.

Dr. Rajkumar then makes a series of very good points, which you can go read for yourself. I will simply highlight a few:

in clinical trials, CR is often but not consistently associated with better overall survival.
trying to achieve the highest CR rate may cause harm […]. High CR rates frequently require more aggressive, more toxic therapy.
a small monoclonal protein (minimal residual disease) is not in itself clinically important and is commonly present in the general population in the form of monoclonal gammopathy of undetermined significance. In many patients, reduction of myeloma to a state similar to monoclonal gammopathy of undetermined significance (near-CR or very good partial response) may be all that is required for best long-term survival.
CR in myeloma, unlike CR in large cell lymphoma, reflects profound tumor reduction but not elimination of the clone and thus is not a true surrogate for cure.
achievement of a CR seems particularly important in the 15% of patients with high-risk myeloma, whereas survival is similar in patients without high-risk features who have and have not achieved CR.

A question popped into my head as I was reading this article: how many patients do poorly for the rest of their lives or die as a result of the harsh CR-type therapies compared to those who actually achieve CR? Dr. Rajkumar makes no mention of this…yet there must be statistics…

There follows a discussion on stem cell transplants, both autologous (using one’s own stem cells) or allogeneic (using a donor’s stem cells). Interesting.

I was curious to know Dr. Rajkumar’s personal opinion. Outside of a clinical trial setting, he prefers the more cautious approach, the “control” one…except in a few high-risk cases. He implies that this approach gives more decisional power to the patient (I am so glad to know that Dr. Rajkumar does not follow the “Dr. House” approach to treating patients! P.S. I watch “Dr. House” even though sometimes it makes my blood pressure soar…).

Well, I am with Dr. Rajkumar. My motto is “primum non nocere.” Since the more toxic approach is not curative…why subject your body and spirit to it? It just doesn’t make any sense, that is, unless your myeloma is aggressive, unless you are a high-risk patient, unless nothing else works…

And, while we are at it: why in the world would you choose to have chemotherapy if you are MGUS or stable SMM, without any CRAB symptoms? Does it make sense to get your myeloma cells all worked up and possibly more aggressive? Especially given that, and I repeat Dr. Rajkumar’s words (see above list), In many patients, reduction of myeloma to a state similar to monoclonal gammopathy of undetermined significance (near-CR or very good partial response) may be all that is required for best long-term survival. Indeed.

Unless we have a stubborn and aggressive type of myeloma, there are heaps of things we can do to delay or even stop (hey, why not shoot for the moon? 😉 ) the progression from inactive to active myeloma. I have suggested many scientifically-backed approaches right here. So have a few blog readers. Whatever works…

Just my opinion…as usual.

Sherlock

February 16, 2009 / / 9 Comments

I haven’t mentioned my good friend Sherlock (I’m Watson, of course!) in a while. Well, the reason is simple. Back in November (2008), she decided to see what would happen if she stopped taking curcumin for a few months, whereas I decided to test feverfew.

[Note: I still haven’t had my blood tests done, for a variety of reasons. A lot of folks here have the flu, which means that the hospital lab is filled with dreadful coughers…and why do they always end up sitting next to me in the waiting room? 😉 ]

At any rate, I admit that in the past I too have been tempted to stop taking curcumin, just to see if my markers would remain stable. Last spring, I even asked my haematologist what she thought about my forgetting about curcumin for a couple of months. To my utter surprise, she told me that it would not be a wise move at all. Well, if she says so…!

So, back in November, just as I began my feverfew experiment, Sherlock ended her daily curcumin intake. She continued to take fish oil capsules, and I seem to recall that she also took Zyflamend (I could be wrong about that). She caught a chill in early January and came down with a terrible cough and sinus infection. She told me that she hadn’t been that ill in years and wonders if it could be because she stopped taking curcumin, which is both anti-viral and antibacterial. That could well be. Anyway, she went through three cycles of different antibiotics, poor dear.

She finally had blood tests done in early February 2009, 5-6 days after finishing her last cycle of antibiotics. She still had the remnants of a cough, though, as I recall, and that is something to keep in mind as we look at her test results (below), which, by the way, she authorized me to publish. I won’t bother mentioning any markers that more or less remained the same.

Compared to her October 31 2008 tests, her February 3 2009 tests are as follows:

· ESR went from 26 to 69.

· Calcium, from 9.1 to 10.1.

· Uric acid, from 3.7 to 4.3.

· Total protein, from 8.1 to 9.4.

· Her CRP went from <1 to <9, so there must have been an increase of some sort. I would like to note that is extremely annoying to have such an inaccurate reference range for CRP.

· M-spike, from 2.42 to 2.76. Her m-spike has never been this high.

· But her monoclonal component went from 29.9 down to 29.4. Go figure.

· A good thing: her IgM went from 0.17 to 0.23. But her IgA went from 0.11 to 0.10, and her IgG, probably because of her recent illness, was on the high side; it went from 31.30 to 35.50 g/L.

Ah, one more rather interesting number: her haemoglobin didn’t increase that much during this period (remember that curcumin is an iron chelator). It went from 12 to 12.3. Almost no variation.

So, how to interpret these results? Not easy. Sherlock believes in curcumin almost as strongly as I do (and began taking curcumin again right after having these tests, incidentally). These February results, however, don’t seem to prove much, in my opinion. In spite of the slight increase in m-spike and whatnot, she still seems to be more or less stable, which of course is excellent. Matters might have been different if she had stayed off curcumin for at least six months AND her markers had continued to worsen. But she stopped taking curcumin for only three months. Plus, the illness, the antibiotics, the lingering cough…hard to say…but any thoughts are welcome, as always!

Final comment: Sherlock is fine, now. That’s the important thing!

P.S. I haven’t been doing any research, answering e-mails or blogging lately. I apologize. It hasn’t been an easy period…I have been distracted by some not-so-good family news. One of Stefano’s relatives has just been diagnosed with inoperable pancreatic cancer. He is 40 years old and has a 4-year-old son. I am still in shock, as is the whole family. And my mother-in-law has also not been well. Quite the opposite, in fact. Nope, this has not been a good period. Still isn’t. But we are all trying to be optimistic…the glass is still half full, not half empty…and life goes on…yes indeedy.

Clock gene slows cancer growth

February 11, 2009 / / 1 Comment

Don (Myeloma Hope blog) has recently been discussing chronotherapy, or chrono-modulated therapy, in which the chemo is administered at the time of day that takes advantage of a person’s biorhythms to maximize the benefit and minimize the side effects of the drug (see http://myelomahope.blogspot.com/2009/02/plateau-continued.html).

It just so happens that I just finished reading a Science Daily article (http://tinyurl.com/dykr6y) linking the disruption of the circadian clock, the internal time-keeping mechanism that keeps the body running on a 24-hour cycle, to the slowing down of cancer growth. Coincidentally, more than a year ago I wrote a post about our complex internal ticking system (see my November 11, 2007 post; great set of comments, too). The subject is of huge interest to me, since it would be absolutely fantastic to figure out the best time of day to take supplements…

At any rate, a team of University of North Carolina researchers discovered that genetically altering one of four essential “clock” genes actually suppressed cancer growth in a mouse model commonly used to investigate cancer. A group of mice with a mutated p53 gene (p53 is a tumour suppressor under normal circumstances) lived longer, 50% longer!, when the researchers fiddled around with their internal clocks. Their experiment showed that the mutation of this clock gene reactivates the intracellular signals that can eliminate cancerous cells. Well, well…

So the idea would be to slow down the rate of cancer progression by altering the internal clock of those who possess the p53 mutation. And, since this mutation is present in about 50% of human cancers, that would be quite an impressive number of patients. Hmmm, question: how do we find out if we have a mutated p53 gene?

At any rate, The findings could enable clinicians to reset the internal clock of each cancer cell to render it more vulnerable to attack with chemotherapeutic drugs. Reset e-a-c-h cancer cell? Uhmmm…hey, Scotty, beam me up!

Seriously now, more research is needed (I know, I know, I say that a lot, then I get totally sidetracked into researching heaps of other things…oh well…). I have begun compiling a list of circadian studies…at this rate, with all the studies I have to read, let’s see, uhm, I will have to live at least another 120 years…hey, I wonder if I can reset that part of my biological ticker…!

Boswellic acid (AKBA) and myeloma

February 9, 2009 / / 2 Comments

One of the crucial myeloma survival pathways is called STAT3. The importance of this protein in myeloma is nothing new…I have already mentioned it here and there (see, e.g., my page on ursolic acid). I have also been collecting data on STAT3 for some time and will soon write a post about it. Just quickly, though, when STAT3 goes bonkers (for reasons that we will see in my future post), myeloma cells are able to survive and proliferate. The same occurs in many other types of cancer: prostate, brain, pancreatic and breast cancers, just to mention a few.

Today I want to concentrate on a January 2009 study published in “Molecular Cancer Research” (one of the co-authors is Prof. Aggarwal, quelle surprise!). It examines the anti-myeloma effects of one of the boswellic acids, “acetyl-keto-beta-boswellic acid” or AKBA, which can be found in the gummy resin of Boswellia serrata, also known as Indian frankincense. Like so many other wonderful herbs and plant extracts, this resin has been used for centuries in Ayurvedic medicine to treat a variety of ailments, in particular those linked to inflammation: arthritis, bursitis and asthma, e.g. See these 2003 and 2008 osteoarthritis studies: http://tinyurl.com/c9z88t and http://tinyurl.com/dc6gbq

A blogging friend (thanks!) sent me the full 2009 AKBA-myeloma study (abstract: http://tinyurl.com/bry5ua)

I first checked to see if boswellic acid could block IL-1 beta, but alas, I found nothing. I don’t give up easily, so I checked elsewhere. Success! A 2006 “Journal of Immunology” study (again, co-authored by Prof. Aggarwal) shows that AKBA inhibits all sorts of evil stuff, including NF-kappaB and, aha!, IL-1 beta: http://tinyurl.com/cr23qe

Oh, and guess what? This 2006 study tells us that boswellic acid also inhibits osteoclastogenesis, a huge concern for us myeloma folks. (That means that it stops the process of bone destruction.) All excellent news.

Let’s get back to the 2009 myeloma-boswellic acid study. As we can read in the abstract, the researchers found that boswellic acid blocked IL-6’s activation of the STAT3 pathway. By inhibiting STAT3, other evil thingies that cause myeloma cells to proliferate and survive were also stopped dead in their tracks, such as cyclin D1, survivin and the Bcl family members (see previous posts). As a result, with all their survival mechanisms cut off, myeloma cells had no choice but to jump off a steep cliff…without a parachute.

Speaking of jumping, let’s jump into the full study. It begins with an important statement: Numerous recent reports indicate that multitargeted, rather than monotargeted, anticancer agents have a better chance for success. Most natural products are multitargeted ‘‘naturally’’. Boswellia serrata, an Indian frankincense or Salai guggul, has been used in Ayurvedic systems of medicine against a number of inflammatory diseases, including osteoarthritis, chronic colitis, ulcerative colitis, Crohn’s disease and bronchial asthma but the mechanism is poorly understood. By the way, all the scientifically-backed anti-myeloma (and anticancer) substances listed on my blog are multi-targeted…

The following paragraph is for the more technically-inclined: AKBA inhibits constitutive STAT3 phosphorylation (a process that was found to be reversible, when the compound was removed), IL-6-induced STAT3 phosphorylation and the constitutive activation of JAK2. It also suppresses the nuclear translocation of STAT3, inhibites the binding of STAT3 to the DNA and angiogenesis (VEGF). It also blocks COX-2 and can suppress the growth of glioma, colon cancer, prostate, and leukemic cells. The inhibition list goes on and on and on. Extraordinary…

I had already read good things about boswellic acid, but I hadn’t given it much serious thought because I hadn’t (until now) read any scientific studies on its anti-myeloma effects. An excerpt from the Discussion confirms that this is the first study on AKBA’s anti-myeloma effects: Because STAT3 has been linked with survival, proliferation, chemoresistance, and angiogenesis of tumor cells, its inhibitors have potential for the treatment of cancer. In the present study, we report the identification of a novel inhibitor of STAT3. We found that AKBA inhibited both constitutive and IL-6–induced STAT3 activation in MM cells […].This is the first report to suggest that AKBA can inhibit STAT3 activation.

In conclusion, we now have another extremely valid item to add to our ever-increasing and rather impressive collection of anti-myeloma non-toxic substances. I will have to try it!

Acronym games: DMAPT/LC-1

February 6, 2009 / / 1 Comment

I have had a Google Alert for DMAPT, the parthenolide analogue (see my page on this topic), for ages, now. Whenever I receive a Google Alert on DMAPT, I get all excited, only to discover that it frequently is about a meeting of the Detroit Metropolitan Area Physics Teachers. Aaargh! I am also on a Leukemia and Lymphoma Society alert list for the DMAPT clinical trial, which was supposed to begin months ago in the UK. Until this morning, though, I hadn’t even heard a whisper about the clinical trial that was supposed to begin months ago in the UK.

Well, early this morning I discovered why. A blogging friend, Dave, to whom I owe an immense debt of gratitude!, informed me that the acronym DMAPT has been changed to LC-1. You’ve got to be kidding….double-aaargh!

Okay, but let’s not get lost in trivial matters, because, guess what?, dramatic drum roll!: the LC-1 clinical trial has begun. Yes indeedie…it began…a few weeks ago…at Cardiff University…in the UK! Hah! I am absolutely delighted, of course.

I began doing research immediately, but the more I looked the more I was puzzled. Some sources referred to DMAPT and LC-1 as the same exact thing, whereas others (http://tinyurl.com/dl7go3) called it a novel dimethylamino-parthenolide analogue. An analogue of…an analogue? That made no sense. Moreover, I was left with the doubt that, unlike DMAPT, LC-1 might not attack the leukemic stem cells. I found no mention of this anywhere, you see.

So I decided to write to one of the top DMAPT researchers (with whom I corresponded briefly last year), who responded within a few hours in spite of the time difference between the U.S. and Italy. Lovely person, incidentally. Well, it’s simple enough, and I quote from the researcher’s e-mail: LC-1 is simply the commercial designation for DMAPT, they are the same drug. Phew! Relief!

The most recent LC-1 news release that I could find is the one that Dave sent to me this morning (the DMAPT researcher sent me the same link, thank you!): http://tinyurl.com/blzqcs As you can see, apart from confirming that the trial has actually begun!, the main titbit is that so far LC-1 has been well tolerated by the patients in the study. Good!

Note: LC-1 is not a new acronym, by the way (how could I have missed that??? Dear, dear…). I came across this “Molecular Cancer Therapeutics” study that was published in 2007: http://tinyurl.com/ctuzj8. LC-1 was tested, successfully, together with Sulindac, a COX inhibitor, against pancreatic cancer in vitro and in vivo (= mice).

Well, we will just have to be sit back and be patient for a while…but you can rest assured that I will change my Google Alert…! Che roba!