EGCG Clinical Trial Results
My interest in EGCG ( chemical name “epigallocatechin-3-gallate”), main component of green tea extracts, started in the Fall of 2001 soon after my husband PC was diagnosed with CLL. Like most of you, I came across anecdotal stories of cancer patients who tried green tea extract as well as glowing testimonials extolling its virtues on websites that were hawking capsules of their brand of green tea extracts for a hefty price.
I dug a little deeper. I read most of the earlier laboratory research papers that discussed the possible cellular mechanisms that might explain the biologic impact of green tea extracts. While there were no credible reports that translated the lab work into actual clinical results of green tea extracts used in CLL patients, the science was intriguing and I was hooked.
From the lab bench to the patient bedside
This is where most new concepts and “miracles-of-the-month” fall by the wayside, making the transition from the lab bench to the patient bedside. The million dollar questions were these: does green tea extract help in controlling or rolling back CLL in real life patients? If the answer to this is yes, how high does the dose have to be to do some good? How much of a price tag is there in terms of adverse effects at an effective dose level?
These are important questions and they cannot be answered by anecdotal information. Anecdotal information is simply too unreliable. I am not talking about obvious commercial bias built into internet shops hyping stuff they sell, I am also talking about wishful thinking we all indulge in at some point or the other when facing an incurable cancer. Won’t it be wonderful if all you have to do is drink lots of green tea and your CLL goes away? Problem with wishful thinking is that it rarely pans out and when the unjustified optimism wears thin payback is a real bitch.
Patients in the drivers’ seat
I am a scientist, I have been one pretty much my whole professional life. I am very familiar with the process of the well constructed hypothesis and carefully conducted clinical trial to test the hypothesis. I hoped green tea extracts would be helpful in treating CLL, the early work suggested it might, but there was no solid proof. We needed a formal clinical trial conducted by credible researchers before we could answer questions of efficacy, dosage and safety.
I knew there was not going to be a deep pocket drug company backing this trial (hard to patent green tea or its extracts and therefore hard to make a lot of money off of it). If this project was going to go anywhere, it would have to be driven by CLL patients’ interest and funded by their hard earned cash.
I made a list of every CLL expert center in the USA and wrote letters suggesting this clinical trial concept. We registered CLL Topics as a non-profit and started collecting donations from our members, to pay for the trial we hoped to kick start. We waited breathlessly to hear back from the CLL Consortium experts. One expert, just one, called us back and expressed interest in our proposal. I will always be grateful to Dr. Neil Kay of the Mayo Clinic for his vision and his willingness to work with a newly formed patient group. Our partnership with his team was a first of its kind in many ways. With sincere desire on both sides, it was surprisingly easy to sort out the details and Project Alpha was launched December 2003.
Goals of the EGCG clinical trial
First step in designing the clinical trial protocol was determining exactly what will be used as a well defined green tea extract. Mitsui Norin of Japan had already developed a relationship with the NCI and formulated a well characterized green tea extract that they named “Polyphenon E“. It contained a mix of ‘catechins’, biologically active compounds including the most famous one, EGCG. Having access to a well characterized green tea extract was a huge advantage and it got our trial off to a fast start.
I hoped the Mayo clinical trial would answer the following questions:
- Is Polyphenon E safe for human consumption? This is the first hurdle to cross. Yes, we know Japanese and Chinese cultures have elevated drinking green tea to an art form for centuries with no obvious toxicity. But in this clinical trial we are talking of using much more concentrated form of green tea and much higher doses. That can be a whole new ball game.
- What is the right dose? Every early phase trial hopes to establish a “therapeutic window”, a dose range where the dosage is high enough to be effective but not so high as to cause toxicity or other adverse effects. Researchers need to establish a “maximum tolerated dose” (MTD), beyond which the adverse effects are simply unacceptable.
- Is there risk associated with taking a therapeutically effective dose for many months? Neither Mayo nor I had illusions that taking green tea extract for a couple of days would do the job. Most likely it was going to take months of dosing volunteers with Polyphenon E. Is that safe?
- Once toxicity issues have been addressed to everyone’s satisfaction, we come to the real $70,000 question: does Polyphenon E actually help control or treat CLL?
- Did particular groups of CLL patients benefit more than others? We all know that CLL comes in many flavors and it is important to know if Polyphenon E worked in one set of patients but not others.
We had $70,000 of your hard earned donations on the line, as well as many months of hard work on the part of everyone associated with this project. We had hopes, but we did not know the answers ahead of time. And that is the whole point of doing well designed clinical trials, to get answers that are credible and dependable.
The results are finally here, published in a well regarded professional and peer-reviewed journal, blue ribbon author list of Mayo Clinic researchers (lead researcher Tait Shanafelt). You can be proud that CLL Topics is listed among the sponsors. Below is the abstract of the article. If you are interested, I can help you locate a full text copy of it. My cheat-sheet review of the paper follows the abstract.
J Clin Oncol. 2009 May 26.
Phase I Trial of Daily Oral Polyphenon E in Patients With Asymptomatic Rai Stage 0 to II Chronic Lymphocytic Leukemia.
Shanafelt TD, Call TG, Zent CS, Laplant B, Bowen DA, Roos M, Secreto CR, Ghosh AK, Kabat BF, Lee MJ, Yang CS, Jelinek DF, Erlichman C, Kay NE.
Department of Internal Medicine, Division of Hematology; Division of Biostatistics, and Departments of Immunology and Oncology, Mayo Clinical, Rochester, MN; and the Department of Chemical Biology, and the Ernest Mario School of Pharmacy Rutgers, the State University of New Jersey, Piscataway, NJ.
PURPOSE: To define the optimal dose of Polyphenon E for chronic daily administration and tolerability in patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Previously untreated patients with asymptomatic Rai stage 0 to II CLL were eligible for participation. Polyphenon E with a standardized dose of epigallocatechin-3-gallate (EGCG) was administered using the standard phase I design with three to six patients per dose level (range, 400 to 2,000 mg by mouth twice a day). Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the National Cancer Institute (NCI) Working Group (WG) Criteria. RESULTS: Thirty-three eligible patients were accrued to dose levels 1 to 8. The maximum-tolerated dose was not reached. The most common adverse effects included transaminitis (33%, all grade 1), abdominal pain (30% grade 1, 0% grade 2, and 3% grade 3), and nausea (39% grade 1 and 9% grade 2). One patient experienced an NCI WG partial remission. Other signs of clinical activity were also observed, with 11 patients (33%) having a sustained >/= 20% reduction in absolute lymphocyte count (ALC) and 11 (92%) of 12 patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.9 to 3,974 ng/mL (median, 40.4 ng/mL). CONCLUSION: Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. A phase II trial to evaluate efficacy using 2,000 mg twice a day began in November 2007.
Clinical trial design
- Previously untreated patients in Rai stage 0 – II CLL who did not yet have any symptoms or need treatment were recruited. Basically, the trial was looking to see if otherwise healthy CLL patients can be helped by EGCG
- The original plan was to let the patients take the capsules on an empty stomach. This was later changed to taking the capsules with food, to address some concerns raised by the FDA. Dose range in the study was 400 to 2,000 mg by mouth twice daily for up to 6 months.
- With the approval of the treating hematologist, patients who had not experienced disease progression and who desired to remain on EGCG were provided capsules at their assigned dose level for up to 12 additional months.
- All patients underwent comprehensive prognostic testing including assessment of CD38 and ZAP-70 expression, FISH detectable cytogenetic defects, and IgVH gene mutation status. This was a big deal. Back then, some of these tests were not readily available and not too many insurance companies covered the cost of getting the testing done. Giving innumerable tubes of blood for all the monitoring and testing was part of the deal. But many of our members thought getting prognostic testing done at Mayo was one of the valuable fringe benefits of participating in this clinical trial.
It is important to get a clear picture of the kind of patients who volunteered for this trial, how they stack up in terms of their disease staging and prognostic profile. As you can see in the table below, most of the patients were early stage with a sprinkling of folks with the undesirable prognostic indicators (ZAP70 and CD38 positive, unmutated IgVH, 12 Trisomy). All in all, not a tough crowd and this was the intent of the trial, to see if green tea extract can help stabilize or even reverse their disease status.
Patients were enrolled in all 8 dose levels, ranging from 400 mg to 2,000 mg twice daily. There were only two patients who experienced any kind of dose limiting toxicity (DLT). One patient at a dose of 1,200 mg twice daily had trouble swallowing (grade 2 level) and another patient at the highest 2,000 mg twice daily had problems with sweating, gas, nausea and tummy bloating (grade 2). Not much to write home about. Remember, toxicity is graded on a scale of 1-4, grades 1-2 are considered mild and researchers sit up and take notice only when the problem escalates to a higher grade of 3-4. In addition to these two cases of dose limiting toxicity, one patient experienced grade 3 abdominal pain and another patient had grade 3 diarrhea.
Now we come to the real interesting part. Was the green tea extract biologically active or was it like taking capsules filled with lawn clippings? Based on the results of this study, the answer is clear: EGCG is biologically active in this CLL patient cohort. Table below gives the decrease in ALC (absolute lymphocyte count) observed.
Frankly, I am more impressed by the reduction in size of lymph nodes. Out of the 12 patients who entered the trial with any kind of lymphadenopathy, an impressive 11 of them got at least 50% reduction in size. Not bad! Overall, 55% of the patients fulfilled the criteria for biologic response (sustained decline in ALC of more than 20% and/or more than 50% reduction in lymphadenopathy). Just about right for the proverbial half full glass, in my opinion.
As one would expect, achieving a biologic response appeared to be related to dose level; two (17%) of 12 patients treated on dose levels 1 to 3 achieved a biologic response where as 16 (76%) of 21 patients treated on dose levels 4 to 8.
There was no statistically significant difference based on prognostic indicators (IgVH, ZAP70, CD38), but patients with 12 Trisomy seemed less likely to respond.
Editorial: Putting it into perspective
Did this clinical trial achieve its objectives? Yes, it did. In a well characterized and monitored group of CLL patients green tea extract was shown to be well tolerated with few adverse effects and biologically active when orally administered. It did what I hoped it would do, provide credible information on safety, efficacy and dosage. Our $70,000 contribution to fund this trial is money well spent.
Now let us look at the details. Did green tea extract cure anyone’s CLL? The clear and unambiguous answer is that it did not. It is important to know what we can expect from any given drug treatment. Wishful thinking does not do a whole heck of a lot for cancer patients.
So, what is the big deal here? Well, it is always a question of weighing costs and benefits. EGCG clearly does not have the oomph of more conventional therapies such as fludarabine, Rituxan or combinations thereof. But on the other hand, it does not have the toxicity associated with just about any of the conventional therapy options available to CLL patients. Even the modest benefit from green tea extracts becomes significant when seen in the context of very low toxicity.
Watch & Wait is a frustrating concept to most Type A personalities. We want to do something, anything, that can possibly help us, while we wait for the disease to continue its upward march. After the completion of this trial and publication of the results, I feel comfortable telling patients it is perhaps a good idea to cultivate the Asian habit of drinking several cups of green tea each day. If you can make a relaxing ritual of it and thereby reduce some of your stress as well, what is not to like?
But taking green tea extracts as supplements is a whole different thing. For starters, we are still stuck with the problem of what brand to use. Polyphenon E used in this trial is not commercially available to consumers. I do not know how easy it is to get hold of it even if you get your doctor to write a prescription for it. I am not in the business of shilling for any particular company selling green tea extracts and the best advice I can give you is to do your home work, buyer beware is a good mantra. I also want to warn you that taking large amounts of green tea extracts without medical monitoring may not be so good to your liver. Please read the FDA concerns we reported in our earlier article.
The clinical trial pointed out another issue with oral dosing of green tea extracts. The highest dose used in this trial was 2,000 mg twice daily. They reason why they stopped at that level was not because of toxicity or reaching maximum tolerated dose but because it becomes a logistics headache telling patients to take more than 10 capsules of the stuff twice daily.
There is reasonable indication that the response was determined by dose level, more patients got a better response at the higher dose levels. The problem is one that we identified even before the start of the trial: green tea extracts have very poor bioavailability when taken orally. For starters, taking large amounts upsets your stomach, secondly even the small amount that is absorbed in the gut is mostly broken down in the liver before it can get into blood circulation and do any good. This is called “first pass metabolic loss”. A fancy term that means your liver sees the green tea extracts as toxic and promptly breaks them down and gets rid of them. A very large percentage of the green tea that volunteers were swallowing was being excreted by their bodies, literally getting pissed away. This is what we mean by poor bioavailability when taken orally.
This issue was discussed in an article on our website that drew a lot of attention, an article with the whimsical title of “Harvey’s chocolates“. If you have not read it I suggest you do so now.
Oral ingestion of drugs is notorious for poor dose control. How much you absorb depends on many details, such as what you just ate, the level of acidity in your stomach, the health and vigor of your liver (damaged livers cannot get rid of perceived toxins as effectively), how long the capsules stay in your gut before getting excreted etc.
Many drugs share the problem of poor oral bioavailability and we have already invented ways around this problem. How many of you are familiar with the concept of skin delivery of medicine, as in nicotine patches to help quit smoking? Transdermal drug delivery gets rid of the upset tummy and first pass metabolic loss issues, not to mention the extra load on the liver. We know how to do this. It is “just” a case of getting a reputable and interested drug manufacturer to develop, test and market green tea extract skin patches. Easier said than done. It took us roughly 6 years to get the Mayo clinical trial done to this stage.
How about buccal delivery? By that I mean drug transport through the inside of your mouth, the inside of your cheeks and under your tongue. Any of you take sublingual (under the tongue) vitamin B products? People at risk of heart attacks are also familiar with sublingual nitrate pills. Again, we already have a well known and well understood mechanism of doing a better job of drug absorption than swallowing pills or capsules. Harvey’s Chocolates is a layperson approach to the same concept. I understand there are several firms out there now that do sell EGCG candies that you can keep in your mouth and suck on for long periods of time.
As you can see, much remains to be done. Whether things gets done and how long it will take to get a move on some of these concepts is anyone’s guess.
I would like to close this long editorial with one last comment. My sincere and heartfelt thanks to each and every one of you that participated in this clinical trial, as well as the generous donors that made it possible for us to fund this trial to the tune we did. I regret that this intense level of patient involvement that made pateint recruitment a breeze and kick started the trial in the first place did not merit a special “thank you” from the Mayo authors when they published their paper. This is a pet peeve of mine, that researchers do not seem to understand clinical trials will not happen unless patients risk their bodies and their lives by volunteering. This is not hubris, I am not talking about me or CLL Topics. I am talking about thanking the actual volunteers that made the trial possible. Talk of partnership is wonderful, but I would like to see it acknowledged and acted upon more openly.