TMZ Hypermutation in LGG (Low Grade Glioma)

I’ve been meaning to write about this issue for several months, and apologize for the delay in sharing. I was overwhelmed by the magnitude of the report, and didn’t know how to broach it. This is by far one of the most important research studies I've ever read regarding low grade glioma. Finally, some legitimate information which should help patients decide on treatments. I have sent the papers to my tumor friends that I know are considering, or on TMZ, of the hypermutation issue, and now I know that a post has to be written for those out there on the interwebs looking for direction on whether or not to take temozolomide (TMZ) for a low grade glioma. I’m going to embed the research study, along with the supplement, and although I realize not many are interested in reading the entire report (which is actually only three pages of reading), I’m providing a few teasers so that you can either get the gist of it, or it may even entice you into reading the whole thing. Just as an aside, if I know you already took TMZ for your low grade glioma, I did not send the documents to you. I went back and forth on whether I should say something, or not, and I decided it would only be harmful, and scary. If you've already taken it, there's nothing you can do. And ultimately, most likely, if you are a hypermutator, you would have found out with a recurrence during or around treatment. 

Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma 

(TMZ Hypermutation of grade 2 glioma induced into GBM)

“Beyond maximal, safe, surgical resection, there is currently no standard of care for patients with low-grade glioma, and options include surveillance, adjuvant radiation alone, TMZ alone, or radiation and TMZ.”

"While the initial tumors and most of the recurrent tumors in our cohort had 0.2-4.5 mutations per megabase (Mb) (21, 22), six of the ten patients treated with TMZ had recurrent tumors that were hypermutated; that is, they harbored 31.9-90.9 mutations per Mb (table S6).”

"The introduction of thousands of de novo mutations may drive the evolution of TMZ-resistant glioma cells to higher states of malignant potential (1, 23). Indeed, all six recurrent tumors that showed evidence of TMZ-induced hypermutation underwent malignant progression to GBM, a high-grade tumor with a worse prognosis (8, 9).”

"We also demonstrated an alternative evolutionary path of low-grade glioma that is largely determined by adjuvant chemotherapy with TMZ.”

“Mutation rates in each tumor pair suggested that >98.7% are due to TMZ-induced mutagenesis (10).”

"There is currently no information on whether treatment of grade II astrocytomas with TMZ confers longer overall survival (8)."

"Future basic and clinical studies must weigh the initial antitumor effects of TMZ against the potential risk of inducing new driver mutations and malignant progression.”

What I see, that is lacking in our medical system, is a complete disconnect between current research and general practice. I’d like to think that doctors want us to survive, that they prescribe treatments to prolong our lives, but the fact remains that the current system is antiquated, and dangerous. It’s dangerous because there is tons of research being done, but doctors are not aware of the changes, and new developments. When a study like this comes out, every nerco-oncologist in the world should be aware, and changes in treatment recommendations should be adjusted accordingly. People are dying because of this lack of knowledge. It’s unacceptable. 

We are not receiving “best practice” we are receiving “marginal, outdated practice”. I recognize that doctors are busy, that they have massive workloads, and we can’t expect them to be up on all the latest research (or can we) but this is our lives, we need the most cutting edge information. It is my opinion that before neuro-oncologists prescribe TMZ alone (or even in combination with radiation) low grade patients should be apprised of the serious risks of taking TMZ. That using it alone (on low grade glioma specifically) has shown a 60% chance of causing a recurrence that will present as a GBM. That is a horrendous risk. It’s well known that brain tumors recur and recur and recur until it progresses to the point where it kills you, but usually with low grades (left untreated by TMZ or radiation) it most often recurs as the same low grade. At least for the first few tumor recurrences. Living a life with a glioma is a chess game. It’s always a guessing game about when to treat and what treatment to use. You don’t want to “poke the beast” with the wrong treatments, yet you often aren’t comfortable with the standard wait and watch protocol. 

It is imperative that patients know the dangers of TMZ with low grade glioma so that they can make educated decisions. That’s why I’m writing this blog post. I hope it helps spread the word that treatment with TMZ for low grade glioma has inherent danger.

Want to know what my buddy Stephen from Astrocytoma Options says? 

"As the hypermutation phenotype has been seen in some grade II astrocytomas and also in glioblastoma (14) following TMZ therapy, by extrapolation it is likely that it also occurs in grade III astrocytoma patients. The frequency of this occurrence will not be known until larger studies are completed. This new knowledge should have immediate impacts on chemotherapeutic strategies, especially for lower grade glioma." 

One of the many things I appreciate about Astrocytoma Options is that Stephen has a way of digesting information and using it to our advantage. What I'm saying in this blog post, is not that we should throw out TMZ, but that we need to better understand it's benefits and downfalls. It may still be a benefit in a cocktail approach, but needs to chosen with care. 

"If a decision is made to proceed with TMZ chemotherapy for lower grade (II and III) glioma patients in the adjuvant setting (post-radiation) or in the absence of radiation, one strategy to reduce the risk of TMZ-induced hypermutation could be to apply a combination strategy, involving a simultaneous or alternating application of other cytotoxic drugs, which reduce the evolutionary selective pressure exerted by TMZ alone."

I hope this information lives on in the interwebs, the information must get out, and it seems as if we have to change the way we are treated, literally, by informing our oncologists.

Problem Fixed

Success! I received a phone call and my neuro-oncologist will meet with us one hour after the previously scheduled, then cancelled, appointment. I feel guilty for having to be so straight forward and direct. It's frustrating to feel guilty about wanting an appointment with my oncologist. I don't enjoy being forceful. A girlfriend who is also dealing with brain cancer gave me solace though. She said that she's never been bumped by her doctor, that at each MRI review she's met with her doctor - not the doctor's nurse (different hospital). And that she would be upset if she was in my position.

I've been bumped at least three times that I can remember. The most memorable was in October. We met with my radiation oncologist's nurse, she reviewed my MRI and said that the tumor looked great, that she wasn't sure if there was any new growth or not - there was an area of concern, but it could be the positioning of my head during the scan. The nurse said that my oncologist would call the following week with the final results. Unsatisfied, my mom pressed on and said, "Is there any way to meet with the doctor?" That's when we headed over to Harborview's Gamma Knife Center, intent on sitting in my radiation oncologist's office until he would meet with us and answer our questions. It turns out that there was significant growth, and when we met with my radiation oncologist, he wanted me to immediately start radiation, the very next week. If we wouldn't have pressed on, and would have instead gone home after the appointment with the nurse, my family would have gone back to Wenatchee, Danny would have been back to work, and I would have been at home when I received the phone call with the horrible news that they wanted me to start radiation. That's not something you should have to hear over the phone. It was a massive eye opening experience, reminding me that I have to stay on top of my care. I'm lucky to have a team, my husband and family, and there's definitely strength in numbers. Follow your gut, and don't be afraid to voice concerns. It's sad that you have to stand up for yourself, but it's the medical world that world we live in. 

Either the University of Washington's neuro-oncology department is understaffed, overwhelmed, masters of double billing, are out of touch with their patients and their feelings or maybe they just don't take cancer very seriously (which I doubt). Maybe it's a little bit of all of the above. Oh well. It must be irritating for some of the nurses and doctors, I don't believe that they're heartless, but there's a bottom dollar and currently my hospital has a bad system, that's for sure. 

On another note, here's a new recipe that I made us for dinner!

Dinner

Lacino Kale Salad
10 large kale leaves, thickly shredded
1 cherry pepper finely diced (you can chop a few of the seed to add some spice)
pine nuts to taste
romano sheep cheese to taste (I zested ours, but you could grate, or it however you want)

Toss the above ingredients (except for the cheese) with a mix of olive and sesame oil, the juice of one squeezed lime, and fresh cracked pepper. Dish up, and zest some romano on top.

On a side note, has anyone else ever noticed that lacino always has a bunch of little bugs in it. They're like little aphids or something. I wash each leaf by hand, pulling the little bugs off, but it's gross. I don't think I can continue to eat it. Any suggestions before I complete give up?

Cocktail of Treatments

I am happily full. A change from the past few days. It's hard to avoid eating until 11:00 am and stop eating at 4:30 pm. But, I'm okay, I survived again, and happily, I just crammed an apple and a handful of mixed nuts into my mouth. I'm sipping on my broccoli tea, listening to Pearl Jam (it was on the radio). It is so nice to eat an apple, they're so crispy and delicious! YUM. Ambrosias are my favorite, but I also love a good pink lady or honeycrisp.

I have a few minutes before I need to jog around the lake, the long way, and swing by PCC to pick up my  whole milk and a healthy style Gatorade (the real stuff is full of synthetic sugar and food dyes). Today I take my 20 curcumin pills & 5 piperine, then twenty minutes later I blend special sprouts along with 30 pills of xymogen (broken open into the blender) and a little bit of water. I take that drink with whole milk or heavy cream, then I chase it with an electrolyte drink that helps smooth the tummy.

Last week when I was taking the drink, my parents came by and I had them try it (along with Danny). It was hilarious! It's the most horrid drink I've ever encountered. About an hour from ingesting it causes a crazy laxative effect (GROSS), and my dad and I were passing each other back and forth up the stairs to the bathroom. It's completely gross, but it's effective and that's all that matters. This is the special drink that our friends used to eradicate their brain tumor.

It is imperative that brain cancer fighters get together and share knowledge. We can save lives. People are surviving. There aren't very many because most follow their doctor's advice with standard of care even when it's proven to have little to no effect on survival. There are various treatments that have much more success than standard of care, and the information is out there on tumor blogs. Never give up. Don't be afraid to make your own path. You have to fight for yourself, fight for your life. If you come into opposition, which is very likely, stand your ground. I believe that my radiation oncologist, if he was diagnosed with the same cancer, would start researching everything he could to optimize his chance of survival. He is outspoken, extremely intelligent, and believes he is an expert in his field (which is true). Something tells me that he dives into things head on, and he would quickly become an expert on how to save his own life. But guess what, he doesn't have brain cancer and therefore does not have the energy or time or desire to devote his time. On a related note, here's another quote from my current book:

"The current medical system does not provide the best possible treatment for cancer patients, and especially not for those with brain tumors. In my own case, I would likely be dead if I had followed the advice of my neuro-oncologist. My prognosis was dismal. Rather than simply accept this small chance of success, a patient is better advised to look beyond the standard protocol for additional treatments. Different treatments have different mechanisms of action and the laws of probability imply that the more treatments a patient uses, the greater the chances that at least one of them will succeed." - Ben Williams (Surviving "Terminal" Cancer)

I am just shocked by our cancer care in the United States. Everything is dictated by our government, specifically the FDA who favor pharmaceutical companies and their multi-million dollar trials. It's important for cancer patients to remember that just because there hasn't been a trial proving efficacy, that doesn't mean a treatment is ineffective. Cancer patients are taking their lives into their own hands, choosing to save themselves. If all of us cancer fighters band together and share knowledge, which they are doing, we can save ourselves. Screw these doctors that aren't trying to save our lives. We will just do it ourselves. I will not give up, no matter how many headaches, stomach aches, pain, frustration, exhaustion, or sacrifice. I will not give up, even though sometimes I want to climb under the covers, crying, with a 10 lb bag of peanut M&M's and a pint of Karmel Sutra from Ben & Jerry's.

Life makes me want to cry when I think of everyone dying because they can't stand up to their doctors. I am not saying that the doctors are bad people, they're just ignorant. They don't have the time to research the various options out there for cancer patients, and trust me there are many, many options. I'm continuously reminded that it's important to do a cocktail of treatments that work synergistically. It's just like health. If you just cut calories, you'll lose weight but you will lose muscle mass and you won't alleviate the initial problem of why you gained the weight in the first place. It is widely known that you need to change your diet, your life style, your exercise routine, and your mental state to successfully keep the weight off. There's no easy answer in life, success comes from a whole body approach and I believe that's true with everything.

Here's a photo from yesterday. Although my suet has not attracted any birds, my sweetheart neighbor Beth Ann moved her bird feeder out so that we can both enjoy the feathery cuties. Maybe it's time for me to take Elliot's advice and put something I like underneath my feeder. If only there was a way to hang it above our car, that would be perfect :) I bet I would quickly have a Hitchcock moment.

On another note, today is the anniversary of our vow sharing beneath the Eiffel Tower. (Our actual marriage became legal in July, when our friend Clay signed our certificate as a justice of the peace.) What a miracle of a man. Dan is a main reason why I work so hard, fight with such effort, and yearn to live. He treats me with such kindness, showering me with compliments each day, telling me how much he loves me constantly, loves me when I'm bald and bloody, and is always attracted to me despite obvious ailments (like staples on my head or stitches on my breast). He is my perfect man, and I am so grateful that I get to spend my life with him! I don't know how I am so lucky, but I will not take it for granted. He is my version of perfect. I'm so glad that I didn't settle for anything less than Danny. Now, I just need to find a way to enjoy his company for years and years and years. Danny literally knocks my socks of in every way. What a gift!