Brian Bulkowski's guide to Glioblastoma Multiformea (GBM)

First draft October, 2002
Last updated November, 2003
Adding comments from Debbie Blicher, April 2004
Formatted for easy printing

Why this guide

Our story

I'm not sure how many young people are diagnosed with high grade gliomas – dangerous, malignant, brain cancer – every year in the US. A thousand or two, I believe. These people, in the thick of their lives, immediately reach out to the Internet to begin to understand what is happening, and why. They encounter information from medical professionals, medical web sites, the government, "crackpots", and well meaning individuals. It's hard to sort it all out, and in the first few days you have to make treatment decisions quickly. I know – I was there. I am not a doctor, so don't count on me while making your treatment decisions, but I might be able to help you navigate through all the people and information you will be seeing.

My partner, my love, Ann Simon, a 34 year old woman, was diagnosed with GBM in late May, 2002. She had nearly 6 months of a variety of symptoms, starting with headaches, and escalating to a weird car-induced disorientation, and then double vision. Ann's the kind of person who doesn't complain much, and didn't even mention the constant double vision to me for two weeks. We saw a variety of doctors in walk-in clinical settings without a diagnosis. It was only after seeing an eye-doctor for the double vision that the extreme cranial pressure warrented a scan, and a biopsy and diagnosis soon followed.

Ann was diagnosed at Alta-Bates Hospital in Berkeley, near where she is a graduate student. After a few days of hospital stay and a biopsy, we were released and moved our care over to UCSF, our local brain tumor center. We started seeing Dr Michael Prados, the head of their neuro-oncology department. We moved quickly to a treatment path of external beam radiation, supervised by Dr David Larson, concurrent with low-dose Temodar. Ann had a remarkable positive reaction to that treatment. All symptoms reversed, and she lived well throughout that year. The chemo course we chose was a standard course of Temodar with a phase I trial drug (OSI-774, aka Tarceva). At about 8 months she started having a strange symptom of her leg falling asleep, which - after another month - was tracked down to the cancer moving into her spine. A course of radiation to the spine didn't turn the disease around, and she died in February, 2003.

The need for guidance

I write this as a care giver to increase the amount of knowledge about the processes of dealing with the hospitals and doctors and the disease itself. As a care giver, I have a different perspective on the disease than a patient. My background is engineering - software engineering - but I am also an amature musician. As an engineer, my job is often to assimilate vast amounts of imperfect knowledge quickly, and make decisions about practical matters. As a musician, I deal with expressing and channeling the feelings of the heart. This combination has stood me well in the course of this journey.

This document has gone through a few editing passes. I wrote most while she and I were still fighting. At this point, over a year after her death, I can finally look more clearly at that time and that struggle.

Even though Ann died, her fight was strong and glorious. Her lesson - shouted from the rooftops - is not give up. Some people live, for reasons we don't yet understand.

These words, however, are my words. Ann was a writer and speaker, and during the course of her disease I let her determine our path. Now, I speak for myself.

I have found a way to grow through this loss. In some ways, my life is fuller and richer than it was with Ann, for I now understand struggle and death in a way I never had.

We all must find a reason to live, and live our lives as fully and comprehensively as possible. Often we get waylaid in the day to day tasks that make up life. During this time, all that of inconsequence will be stripped away. You can learn, and your life grow richer.

May these words help you along your path.

An aside - the nature of cancer

The one conclusion I've reached about cancer is that it's a disease of probabilities and possibilities. Cancer itself is a variety of mutations applied to a particular person's unique DNA. Today, we have only the most primitive tools to analyze particular DNA, and the mutations in someone's cancer. No one can tell you how long you or your partner is going to live. They can't tell you which treatment is going to work best. You're going to have to make terrible decisions with very little information. Diagnostics are likely one of the next frontiers of cancer technology, and rarer cancers will always be last.

An example of the lack of clear statistics is long young people live. I've read many papers that say age is a primary indicator of positive outcome, but no paper that quantified that simple fact. A small sample from Glasgow suggested that 20% of patients under 40 are long term survivors (5 years), but the data set was small.

Doctors are, as a rule, notoriously bad at statistics. If you're like many Americans, you might be, too. To someone savvy about statistics, the words "confidence interval", "multivariate analysis", "selection bias" all have real meaning. It's hard, living and making decisions in a deeply uncertain world, but you'll have to do it. You'll never know if the treatment decisions you made were right or wrong. Whatever experience you've had making and living with decisions in uncertain situations will help you now.

The first step - getting diagnosed

Our story includes 5 months of headaches, double vision, and disorientation. Each time we tried to talk to a doctor, we were told that Ann was generally healthy, and young, thus it was unlikely that there was anything seriously wrong. All of that was true, it was unlikely, yet it also turned out to be wrong. Tumors are hard to diagnose, and usually fester until an obvious symptom (falling over, losing sight) causes a scan to be ordered. In retrospect, we didn't take this as seriously as we should have, for the same reason that the doctors didn't.

General symptoms are:

A tumor will press on various brain structures. When that happens, any number of brain functions can fail, and fail in unusual ways. Other diseases, such as toxoplasmosis (a parasite), also involve growths in the brain, and are not cancer. A doctor up on their neurology can tell the area of the brain from simple neural tests, but in general the presentation is non-specific.

However, I will offer the following advice.

Use your family doctor, general practitioner, or internist. We didn't have one, and few young people I know bother to find and hold onto a family doctor. You'll need someone you trust to organize your care - there will be many specialist.

Make sure you're seen by doctors. Residents and "clinicians" and "physician assistants" in emergency rooms and urgent care clinics will present themselves as doctors, but they're not. You want an actual doctor. Whenever you talk to someone who does a diagnosis and offers an opinion, you have every right to know their training and specialty. Ask specifically if they are a doctor. It may seem rude, but it's worth it. While this doesn't get you the right diagnosis, it gets you a better shot. You're always paying for a doctor, there will be a doctor's signature on all the forms, so request to see them.

Get a specialist. I don't know how to succeed – we failed at this. We lost 2 or 3 months because of this problem. In the greater Oakland and Berkeley area we were given a list of six or seven neurologists. Most didn't return calls in less than 4 weeks. Yes, I do mean RETURN CALLS, not make appointments - I received calls a month after Ann's diagnosis that were simply the neurologist's office returning the calls on the answering services. My only advice is to be very persistent. You may have to call your insurance company directly and make a fuss.

Get a scan. There are two general kinds of scans - MRI and CT. MRIs take longer, use more expensive equipment, and are more detailed. CT scans are a form of three-dimensional Xray, are much quicker, use smaller and less expensive equipment, and are  less detailed Everything becomes clear with an MRI scan, and fairly clear with a CT scan. CT scanners are available in most hospital emergency rooms, take only a few minutes, and tell you whether you should get an MRI. On an MRI, tumors are obvious. A scan does not require a prescription. Recently (in 2002) there is a new business – "do it yourself" body scans. In these small offices, anyone can go in and get a scan. But be warned – scans can cause doctors to make diagnosis that aren't problems. This sounds like doublespeak, but the scans are marvelous tools. They show a variety of abnormalities which are not harmful. There are even theories that tumors can exist in healthy people, in balance with the body's immune system. Only the recent availability of inexpensive, high quality scans will tell us, in the future, the use of early diagnosis. See the "money" section below, but right now a brain scan, with a certified radiologist's report, costs about $1000 at these new places ($4000 is normal in a hospital). A friend of mine had a strange pattern of headaches, and got a scan and a clean bill of health. He's now much more willing to "wait and see".

A crucial point is that early detection is not clearly correlated with longer patient survival.

That having been said, the survival time without treatment is much shorter than the survival time with treatment, and starting when there are fewer bad cells must be better. There are treatments that can be followed only at earlier stages, such as topical treatments (surgery with adjuncts like Gliadel wafers). Also, external beam radiation can be focused, and will do less damage to the unaffected portions of the brain.

Finally, the only chance you have at long term survival with GBM is that you manage to kill almost every single cancerous cell. It stands to reason that if you start treating while there's 1 million cells, instead of 100 million cells, you've got a better chance of getting them all.

It's certainly true that if you get treatment while still mostly symptom free your survival time will be of higher quality.

A biopsy will be ordered if the scan shows abnormal areas. This will normally be a stereotactic needle biopsy, which involves general anstesia. A small whole will be cut in the skull, and a computer program will route the needle into an area. Some tests will be done on the sample to make sure it's a sample of the bad stuff. Recovery time for the biopsy will be a couple of days. Although a neurosurgeon will do this work, the complicated part is done by the computer.

A diagnosis will be rendered by the pathologists who examine the tissue from the biopsy. These results will be given to the surgeon, who will relay them to you. In my opinion, this was a disasterous part of the inital process. The surgeon will not be involved in your long term treatment, and has little specialized training dealing with delivering this kind of diagnosis, which wasn't even his work.

From this moment onward, there will be a mad rush of information and choices. The impending sense of dread from the previous days will turn into raw terror.

Basic terminology and concepts



A truism to remember in Glioblastoma, and cancer in general, is that each individual cancer is different. The categorization systems for brain cancer are very coarse. Just because you have been given a specific diagnosis does not mean that you will act like the "average" patient. The amount of variation in all cancers is so great that few people will respond or behave like the average. All good doctors that I have encountered understand this, and are very cautious when discussing statistics with patients. That's not because they're avoiding giving you bad news, necessarily – it's because there's a real truth.

The flip side of this fact is that most people with this diagnosis will die soon. How you plan for this reality is one of the fundamental and central truths of your struggle.

Brain cancer is categorized several different ways.

Malignant and Benign

Malignant cancers are those which can move through the body better, can infiltrate tissue better, and don't stay in a single lump. Malignant is a scary word, but although it is often the first thing that's said about any cancer, isn't necessarily the most important information. Benign brain cancers are generally treated through surgery, and shouldn't be a problem if one has access to a state of the art surgery center.

Grade

The primary tool of explaining how "bad" a cancer is is the WHO cancer grading system, which can be applied to all body cancers. That grade is from one (I) to four (IV), and the grade is primarily based on how fast the cancer grows. High-grade gliomas are grades 3 and 4, and GBM is always grade IV.

Metastatic

Metastatic is not a phrase commonly used with GBM because it's very rare. A metastatic cancer is one that has spread between parts of the body, for example a breast cancer that has spread to the skin. In general, brain cancers stay in the brain.

Multilocal

If the GBM has spread to multiple locations inside the brain, it is called multilocal. When it reaches this stage, it is usually considered that there would be no practical benefit from operating.

GBM, Astrocytic Astrocytoma, and others

GBM and AA make up the two most common brain cancer diagnoses. GBM is grade 4, AA is grade 3. The treatments for the two are similar, with the primary difference being that AA patients tend to do a little better. There are a variety of other diagnoses, but these two make up over 70% of the diagnoses.

Age matters

Most people get these forms of cancer when they are older – 60 or above. For adults, the younger one is, the better the prognosis. Exact figures are hard to find, but one study from British Journal of Cancer looking at the Glasgow population showed that all long term survivors (>6 years) were under 40. This is very important to remember when you hear survival statistics quoted. However, if the patient is a child, the situation is especially grim. Most of the current treatments go after all cells that are still growing, which does not work well for children. All of my comments here are targeted at "young" adults.

Try to discuss what you really want

Doctors will be making assumptions about what you want. Most people want the same thing - the greatest chance at an extended symptom-free life. Exactly which risks you're willing to take, and what kind of life you want, can lead to slightly different treatments. Some of these choices are horrible. Are you willing to take a 30% risk of significant irreversible mental deficit in exchange for an unknown, but slightly better, chance at beating it long term? When the first round of treatment fails, and the second treatment fails, do you want to have a few weeks being able to tie up your life, or do you want to keep fighting against now truly impossible odds?

You'll get better treatment if you can look a doctor in the eye and say, "Doc, I know I'm going to die of this disease. But I want to try to get in a few more good years of living. If you can do that for me, beat the odds by a little bit, I'll call this a success." Or whatever the truth is for you.

Get yourself to a highly rated academic cancer institution immediately

I would do it, anyway.

The calculus seems fairly simple. If you're interested in fighting this thing, you need to be at a research institution. The simple reason is that they have drugs and knowledge that no one else has. I haven't seen any figures, but the major cancer centers must treat (or at the very least consult on) a majority of the high grade gliomas in the US. They have the greatest access to clinical trials. The names that I see come up most frequently in gliomas are:

MD Anderson Cancer Center in Texas

Duke in North Carolina

UCLA in California

UCSF in California

Johns-Hopkins in Baltimore

This is not to say that there aren't great people doing interesting work in other academic institutions. There's other names that come up after these, such as Sloan-Kettering, Boston Children's Hospital, University of Oregon. Each of these places seem to have different strength and philosophy. I've based a lot of my information by going to the clinical trials web site, and looking at the clinical trials offered at different centers. I would suggest doing this for yourself. You'll quickly see names and addresses of people to call.

The only thing I'd say further is that if you are seeing an oncologist local to you, and you think they're very sharp, continuing with them as your primary doctor is a good idea. They can get a national cancer center to consult. I know our Dr Prados consults on cases in New York, for example. You might get a high standard of care, yet have the benefit of the oversight and knowledge of an expert.

To me, being in a clinical trial is just the right thing o do. There is no cure among the known paths, so the best choice is to take the unknown path. At a larger center, you'll even have a choice of clinical trials. The drug companies usually pay for treatment in clinical trials. Some people are motivated by the altruism of clinical trials, but in this case of fighting for life, I find it hard to keep that in mind.

However, you don't have to take our path. The known treatment paths can extend life about a year. If you just want another good year, you might want to take the standard treatment options.

Another factor is that I like academic institutions. They still operate as you expect a hospital to operate - for the patient, not for profit. Sometimes they might operate for the best research opportunities, or to educate their students, but at least they're not operating solely for profit. They still have a strong element of pride and ethics. This isn't to say that I didn't run into some great doctors in private hospitals - I did.

If you have a good friend who is a good doctor, call them now

The medical industry is like any other. It has jargon and terminology. A friend who understands you, and knows how to talk to you, will be able to quickly provide whatever thoughts and assistance you might need.

How sure is your diagnosis?

You probably either received a biopsy, or are about to get a biopsy. A needle biopsy is a common procedure which takes a small amount of material out of the brain for analysis. Needle biopsies are fairly straightforward these days, as they are primarily done by computer (stereotactic). A rig is used to hold the head in place, and the needle is driven by computer software based on the MRI image. This procedure may or may not require general ansthesia, but is fairly safe (one study stated 6% complication rate, 1% mortality rate, almost always from bleeding). A quick analysis is done to make sure that they've got part of the tumor, instead of normal cells.

The sample is frozen, sliced, and examined under a microscope. By looking at the number of dividing cells, the rate of replication can be determined. By looking at the morphology (shape of the cells), and by staining the sample with a variety of dies, a diagnosis will be reached. The pathology lab will issue a report, and the surgeon will deliver the diagnosis to you. Unfortunately, neuro-surgeons aren't known for their bedside manner, and they'll be your first point of contact for learning your diagnosis.

The pathology lab follows the same process as all medical diagnosis. They follow a process called "differential diagnosis", which is the language for "If I've got a choice between two things, how do you decide on which?" Doctors can't say "I don't know" – instead they'll say "This is more like X than Y, therefore the diagnosis is X", but not tell you that it's kind of like both. When looking at the shape of cells under a microscope (cell morphology), this is especially true.

Diagnosis can be uncertain. The most important parts – blood cancer vs. brain cancer – can be determined easily. Smaller issues, like AA vs GBM, may not deeply influence the treatment path. Typically, the only way to get a really clear feeling for exactly how the pathologist feels about the diagnosis is to go and ask them, face to face. Pathologists are not used to dealing with people, and our personal experience was that they often welcome being able to see people.

What else can be done in a biopsy?

So you've got a simple needle biopsy. This makes sense, because you don't know what the exact cancer type is yet. There are two further choices, however. When you go in for the biopsy, you can try to clean out as much as possible of the tumor body. This can make sense if the tumor is easy to get at, and if it's localized. The common course of action in America seems to be go for the biopsy only, at first.

This is backed up by data that shows that patients with GBM do not live longer when they have surgery. Somewhat confusingly, people who can have surgery live longer, but this denotes that the cancer is caught earlier.

There are further tests that can be done besides the common tests that lead to a diagnosis. First is a procedure called "chemosensitivity testing". The general idea is to see which chemotherapy agents the tumor is most susceptible to. While this seems to make a lot of sense, chemosensitivity testing is currently in ill favor. The reason seems to be that different labs have different, proprietary tests, and there have been no large-scale trials to determine the clinical effectiveness of following the results of the lab tests. Since these tests are proprietary, they don't have the kind of clinically tested statistics. If you are interested in this course, you have to choose a lab and have your samples overnight-shipped to the lab immediately after biopsy. Even 24 hours is too late. We didn't take this route.

Finally, there are tests for certain proteins. Many of the new therapies are suspected to work better if certain proteins are overexpressed in the tumor. For example, an EGRF blocker would make sense if EGRF is in abundance in the tumor, which is true of 40% of GBMs. However, it is currently not common to test for these.

The power of the pathologist

In cancer, the initial diagnosis sets the treatment direction. You'll get only one or two cracks at treatment. The pathologist is the only team member you'll never meet. You'll see names on reports, but they don't come in and take you through the diagnosis. You don't get to ask questions of them, to look in their eyes and try to determine for yourself how much they know. You'll meet every doctor but them.
Why not meet them? I don't know. Maybe in other parts of the country you do meet them. Ann's father tracked down the pathologist that did our case, and learned first hand what diagnoses he was considering. Carl put a personal face on the diagnosis, and I believe we got better treatment based on that.

However, there is a big difference between world class pathologists and the pathologist you might find in your local hospital. If you get referred to a regional cancer center, that center may or may not have a crack pathology group. For this cancer, I would certainly work as hard as possible to get access to the best pathologist you can.

Late in Ann's case I realized that we probably should have done more in getting a world class pathologist to review the work. Ann's case took such an unusual turn that perhaps a more complicated pathological diagnosis could have been a factor in getting a more unusual treatment. My understanding is that the best may be Dr Miller of NYU (http://www.med.nyu.edu/clinicians/milled01.html). Apparently treatment doctors generally dislike Dr Miller because he never gives a straightforward diagnosis, but the reality of cancer is that you can't be sure.

When does it make sense to ask for a second opinion?

Second opinions – consults – make sense in several circumstances. If you are choosing a surgeon, you want to get a good surgeon, one with the skill to succeed. If you don't trust the surgeon you have been assigned at a hospital, you can ask for a consult. But how do you know the skill of one over another? A general practitioner or family doctor can help guide you in this selection. In a hospital environment, an attending physician is responsible for you. However, you can't just ask if a particular surgeon is incompetent. The phrase doctors use is "Should I ask you for a consult on this particular surgery?" at which point the attending physician can say "Due to the particular nature of your case, I think you should ask me for a consult." or they can say "I have complete confidence in Dr X in this matter." The attending doctor hasn't "ratted out" a particular surgeon, and can say with a straight face that you asked for a consult, and they had no choice but to provide one.

Second opinions make perfect sense when it comes to lab results. If you transfer from one care group to another, the pathology lab within the new care group will usually go back to the original biopsy slides and reexamine them. If you're unsure of the diagnosis, you can take the slides elsewhere and ask for a new pathology report. My personal experience is that re-questioning the pathology report is not often done. A regional cancer center often focuses on research of a disease, not on pathology.

Treatment decisions are a bit of a different case. In any field, there is a hierarchy of doctors, from regional medical centers, to large city medical centers, to research centers, to research centers that specialize in the disease in question. At each center, there will be again a hierarchy, from residents up through the doctors that have been working there a long time.

Doctor and patient communication

I found this to be the most bizarre and difficult part of our travel. I can only hope you have access to someone you trust deeply who is a doctor and can guide you through the thicket of problems in communicating with doctors.

The law

By law, someone with a medical degree can only discuss treatments that are known to work. While there is some slop in the terms of 'known', this generally means publishing in a peer reviewed medical journal. Talking outside of the strictly known can get a doctor's license removed, or at the very least a malpractice suit. Dealing with cancer patients can be especially difficult, because they're under stress and may blame the doctor later. If you want more information, liberally sprinkle your talk with doctors to include statements like, "I know very little is known about the positive effects of a given treatment, but in your opinion…"

The doctrine of patient autonomy

In order to avoid the legal responsibility of difficult decisions, the common current doctrine is that doctors must present the patient with all relevant information, and a decision is made by the patient. This sounds great, and certainly is better than a doctor deciding everything. But in practice, this doctrine is problematic at best. We have highly trained doctors so that each of us won't have to learn medicine. To place the burden of life and death decisions on the shoulders of lay people doesn't work on a practical basis. Sometimes it seems that the doctor presents you with a choice that's not really a choice – they present what they believe in, and don't mention any opposing points of view. Later, you might find that there a greater difference of opinion on different points than the doctor represented at the time. The greatest benefit of this doctrine is that as a patient, you can continue to say "I am not satisfied with the amount of information I've received", and they're give you more. You can also come pretty close to demanding your treatment option (within the limits of FDA rules, and within the limits of what a particular doctor is comfortable with).

I've encountered situations where I didn't feel that I'd gotten quite enough information, and was unable to get more. Sometimes, the real question I wanted to ask was "What do you recommend?" This is a great question, and they have to answer it for you (on the doctrine of full information exchange.) Sometimes the situation will involve a bit of pushing, and sometimes you won't succeed.

The reality – risk and benefit

A good doctor is weighing a huge quantity of information, certainties and uncertainties. Cancer has many unknowns, and high grade gliomas are especially uncertain. Treatment options have risks – big risks. Some chemotherapy regimes have fairly terrible risks, like a substantial amount of "treatment induced mortality". You need to tackle the hard question of how much risk you're willing to take, without really knowing what the risk looks like. When someone tells you there's a "substantial risk of abstract reasoning deficit", how can you know if you're willing to live that way or not? You do need to make some kind of stab at it, as hard as it's going to be.

The basic risks you're going to be facing are the risks of surgery, the risks of radiation therapy, the risk of chemotherapy, the risk of taking unproven drugs, and the risk of not doing enough. It's going to be a fairly snap decision, and will be deeply influenced by the doctor.

Notes for caregivers

Right about the time that Ann and I started staring into the reality of risks and benefits was when I discovered some of the subtleties of communication as a caregiver. At first, it seemed simple. Ann wanted to know everything, and of course I should tell her everything. There are never secrets between us. As we started living with the diagnosis, we started to agree on a division of labor. As someone who can master technical facts quickly and has a grasp of chemistry, anatomy, and statistics, I would do all the medical research, and present summations for her, and answer questions. She didn't couldn't spend weeks pawing through a mountain of research papers, so I would, and be available when she needs to ask for clarification and advice.

The subtle point was that she felt that she needed to be isolated from some of the knowledge for the simple reason that she needs to keep up hope. She can't be always butting into those statements that start off any research paper about high grade gliomas – "With the treatment options that are currently available, prognosis is poor for a vast majority of the patients." Yet, she still needs to know everything, in order to be faced with how serious the situation is, and be able to make the decisions at the right time. Often, I've wanted to take the doctor out of the examining room, and say, "Look, Ann doesn't want to hear this from you, but you'll have to tell me, and I'll tell her in the way that's best." That opportunity doesn't come up, though. I get depressed reading the medical literature. There are few bright spots in the research, so far.

I sympathize quite a bit with the doctors now. Ann and I have had a number of very serious discussions about exactly how she wants to slice this problem, where she wants various lines to be drawn, what level of detail she wants to know. You need to have that discussion, and figure out where to draw that line in your own relationship. In our case, there was no obvious

Notes for friends

I've heard a lot of cancer stories now. I don't know if the rate of cancer is increasing, but it seems that so many people have family and loved ones who have confronted cancer. Most cancer happens to older people, and isn't quite as tragic. I can't imagine cancer with children. A friend of mine had cancer happen to his two year old son, and I can only barely imagine.

As a friend, some of what you can do is just be there. There will be times of abject fear and pain, and that load should be shared. You'll feel helpless, and we're all helpless before cancer like this. Just stay in there. Call as often as you can. Listen, more than you speak. Just saying, "That's horrible, I'm so sorry." has a positive impact. One good friend said that while dealing with his young son's cancer, he eventually came to hate the good natured people who would relentlessly talk about "Did you read about this?" and "Did you think about this?" when all he wanted was to be sad.

Modern hospitals

Hospitals in America are divided into two general models. One model is how we commonly consider a hospital: a monolithic institution where doctors work. You get admitted to the hospital, and you're seen by doctors who work for the hospital. The second, newer, model is of the hospital as a place of business of independent contractors. In that case, only the nurses and cleaning staff work for the hospital, and everyone with a license to give an opinion is part of an independent company. This will be covered more completely in the section on money, but it has an impact on communication. When a hospital is simply a place of business, doctors are independently liable for any mistake, as opposed to the hospital itself. Doctors become even more cautious. In the old hospital system, my experience is that doctors aren't motivated as much by fear of individual retribution, and work together for your health. Old style hospitals are found in teaching hospitals, and in our area, the Kaiser HMO system (which owns its own hospitals).

How do I know if my doctor is good?

This is a hard question. Doctors, like any professionals, are reluctant to say that a particular colleague is inept or dangerous, yet a few of them are. A clear statement of that sort can lead to direct legal action, as well as sanctions within their business. The reality, however, is that there is no impartial central registry for doctors. Statistics are not kept on the outcome of a particular doctor's patients. A recent New York Times article on mammography detailed that some regional experts who analyzed thousands of mammograms per year were missing 30% of the positive mammograms, where a good doctor would miss less than 5%. In general, doctors are highly trained and motivated people who are doing a great job at healing. Similarly, in any large medical institution there's one or two doctors that probably shouldn't be treating anyone, and you certainly don't want them treating you.

I need to be clear and differentiate between differences of opinion, and differences of competence. When we were talking with our surgeon about the biopsy, he said it was clearly the thing to do. After the biopsy, he broke down and said there was a controversy in the industry, and he generally chose to go in for the minimal amount of tissue, while the other choice was while you're going in, get as much of the cancer out as possible. This is a tough choice, and different competent doctors can have different opinions. I'm talking about something else -- rank incompetence.

You want to make sure that your pathologist, or surgeon, or oncologist, is at the very least excellent, and certainly competent. As consumers in the modern world, all of us are commonly in situations where we have to make decisions about technical matters we know very little about – buying computers, cell phones, even cars. In this case, the stakes are immeasurably higher.

The short answer is you have to find someone you trust, and get them to guide you. It could be anyone in the system, even a nurse that's been around a long time. You may have a family doctor, or a true friend that's willing to tell you the "inside scoop" of the doctors you are dealing with.

If you have an exceptional long-term relationship with a doctor, you can ask them straight, but with doctors who you perhaps have just met but have a good feeling about, you might have to be more subtle. You have to give the doctor "plausible deniability". One strategy that a doctor taught me is words like the following:

"Just like you, we're only concerned with getting the best possible outcome. Dr X has been assigned to handle this portion of our treatment. Should I ask for a consult on this matter?"

At this point, the doctor you're asking can say two things. They can say "In this situation, given the complexity of the case, I think you should request a consult". This generally states that he doesn't think that the doctor can handle the situation, but can fall back on the argument that the case was just not to the strength of the doctor in question, without specifically stating that the doctor isn't competent. They can also say something like "I have every confidence in Dr X in this situation". This exchange allows them to give you the information they want to give you, but without the complexity of possible legal hassles. It also shows that you know the code, and can be trusted to use the information wisely. As is common with coded communication, if too many people know the code they change it - by the time you read this, they might use a different interaction.

The role of the attending physician

In a hospital, one doctor is designated the attending physician. The role of the 'attending' is the doctor who looks out for you during your hospital stay. In broad strokes, they are legally responsible for your entire experience. Unfortunately, you don't get to choose your attending physician in an emergency situation, but if you schedule your stay ahead of time you are likely to have greater choice. In any case, you should use your attending to check the opinions of other doctors, and to get an overall sense of who is doing what. There are times when you'll be just waiting in the hospital, not really knowing what you're waiting for, or what will happen next. It may seem that everything's out of control. You should always be able to get in touch, nearly immediately, with your attending, and ask them what is happening. In our hospital stay, the attending was a "group" consisting of two neurologists, and one of the two was on call at any given time.

Surgeons – a special case

When deciding on the drugs to take, a doctor looks at a set of information and sifts through the desires of the patient, the information about particular medicines, applies their own intelligence, and comes up with a recommendation. You can ask another doctor, and get another opinion. Surgery is different. A plan can be made, but the outcome becomes dependent on the skill and training in a person's fingers. At that point, you have to do "due diligence" in researching the background of your surgeon, then stand back and trust them.

The stereotypes of doctors

Doctors of different specialties get stereotyped. In my experience, there's quite a lot of truth to those stereotypes. After the long haul of medical school, people have strong insights into what they want to do for the rest of their career. Knowing these stereotypes gives you a leg up when confronting a new doctor.

Surgeons are stereotyped as arrogant, poor communicators.

Oncologists are cheerful and put the best face on situations - but commonly have the worst news to give you.

Emergency room doctors have a broad range of experience and a moderate bedside manner, but will often put things bluntly. GPs or internistsare similar, just not as quick.

Radiation oncologists are sharp, can-do people with a particular technology they believe in and little understanding of the complexities of anything else.

Pathologists are bookish technicians who you rarely see.

rock stars are the researchers at some institutions who have built up a huge reputation. They are hard to get ahold of, and it's not clear that they have any corner on the truth.

The long silence

There's one oddity in dealing with good doctors that no one ever mentioned to me. The best doctors have a huge amount of options and opinions and thoughts for any given situation. They don't want to confuse you or upset you with information overload. As a first cut, they tend to stick to simple facts. The diagnosis, and what they recommend. Then they stop, look at you, and there's this big silence while you process the information and round up some questions. Over and over again, you'll find yourself in situations that you didn't prepare for, so short on knowledge that you'll not even know the questions to ask. Doctors sometimes use this long silence as a crutch, or as a way to avoid talking about information they consider confusing or difficult. For example, I've asked doctors what the side effects of a drug are, and had them come back with a list, then stop, and give me the long silence. I've learned that I have to ask, "Is that all the known side effects?", and sometimes they will continue listing more side effects. A common strategy is to go into any doctor's meeting with a list of questions, and to make sure each is answered to your satisfaction. However, my experience is that you'll sometimes be hit with information that you just haven't considered. My advice is to start building up a set of stock questions that work in a variety of situations. Examples that I use now are, "Are there any questions I should be asking you?" "What side effects do you usually see?" "Are the side effects reversible?" "How often have you performed this procedure?"

Convincing, or likable, doesn't mean right

While we'll never know whether the treatment option we choice was the best, we had a very different opinion from the two radiation oncologists we saw. The first was likable and direct, persuasive, put presented a black and white choice: you need to take 60 Grays of radiation, whole brain. There would be a good chance of permanent damage, but it was a risk to be taken. Our second doctor, who had trained the first, was more thoughtful, and suggested going to 30 grays, and taking an interim scan. If the treatment went well, we could reduce the size of the radiation exposure so that there would be no risk of damage. If the radiation had no effect, maybe we should just do less. This is not a common treatment option, but given Ann's young age and the terrible effect of radiation damage to a person who has lived all their life depending on their brain, it seemed like a good option. Our second doctor was actually something close to shocked that the first doctor had suggested a straight treatment of 60 grays.

On a gut level, I felt a strong tug toward the first doctor, until we met the second doctor. By pulling the stops out, at very least we feel we've done more.

So, do you have a family doctor?

Most of the young people I know are not used to the idea of having a family doctor. They've been told over and over again that they "should" have one, but the practical situation with American health insurance is that trying to see the same doctor every year is quite difficult. You change jobs, or your job changes insurance companies, and your old doctor isn't covered. You only saw them once or twice, so you don't mind seeing a new one next time.

Now is a good time to get a constant doctor in your life.

Dealing with "Why Did It Take So Long To Diagnose"

This can be a hard. Our story was one of visiting 3 different doctors in clinics, and each time being told the headaches and stumbling and double vision were probably nothing. It was finally an optometrist who found the problem - an appointment we got when a clinician wouldn't venture a guess about Ann's double vision. Time from first symptoms to diagnosis was about 5 months. It has occurred to me that in some cases the diagnosis was bungled.

It would be very easy to be bitter about these problems. In reality, this is just a hard disease to diagnose. It's one of my reasons for writing this and posting it to the web. It might really reach only the hypochondriacs, but for the rest of you, the message is get a scan.

Money

The first point about money is that you'll be spending a lot of it, but there are a variety of tricks you can use to bring the cost down.

Why insurance matters so much – the benefit of PPO

It's not just the fact that you probably don't have $50,000 or $60,000 to cover the first 6 months of service, it's the fact that insurance companies get a different deal from folks who walk in off the street. The doctors bill at a certain rate, but in order to be in the PPO they agree to accept whatever the insurance company gives them. The insurance company is negotiating on your behalf, and they get a much better deal. Typically I see a bill come in, and the insurance pays no more than half – often much less, as low as 10%. And that's it. You don't pay any more.

How state insurance (Medicare) works

I have no idea about this.

How much things cost

First, remember that the cost is to the insurance company, not you.

One night in a hospital - $10,000 / day billed, $1,500 paid

5 days (one month's worth of Temodar oral chemo) - $3,500

One fairly limited blood test - $250 to $1000 billed, $50 to $100 paid

One MRI scan - $4000 billed, $2000 paid

Biopsy - Surgery, anesthesia, follow up care - $15,000 billed, about $3000 paid

One ambulance ride of 7 miles - $350 billed, $350 paid

So you can see that without insurance coverage, just about every time you talk to anyone will cost you a few thousand dollars, and you're not likely to bargain with them up front. I just don't know what would have happened, without insurance. The bills just for the first 5 days after diagnosis would have been roughly $100,000.

Getting a partner onto your insurance

If the caregiver's work provides insurance, and you're eligible to sign up for it, you might have to wait until a certain time of year (open enrollment period). It's likely you won't be able to change anything about your plan until then. My company was very open about the insurance, with no preexisting condition clauses and domestic partner support carried by a single affidavit. Still, I had to wait 7 months for that period to roll around.

In retrospect, signing Ann up on my policy didn't work out well. Ann was then double-covered, and the insurance companies disagreed about who would be primary and who would be secondary. The new company, Aetna, was a complete jerk, and only when UC Berkeley threatened legal action did they move quickly. The confusion was large, though, and would have been avoided by just keeping a single insurer. However, the risk we were covering was that Ann's disease would last a long time, and she'd want to get out of the UC insurance. We would want to avoid the gap.

Trials are cheaper

Getting involved in clinical trials can vastly reduce your expenses. Our experimental drugs are free, our scans are paid for by another study.

Current treatment options (current 2002)

The one truism that I've heard over and over is that a good theory rarely translates into a good treatment. High grade gliomas have had many therapies tried, many that work in test tubes and mice, and don't pan out in large scale human trials.

The road to a cure is littered with great theories. You can go down to the medical library and read paper after paper from even a few years ago where the theory sounds good. Animal studies sound good. Then they try it in people, and no dice. A good theory doesn't make a good treatment. This is especially important to remember when dealing with the "science" of "non-traditional" treatments.

A digression on diagnosis

The way medicine works is that researches have to come up with a "cookbook" therapy. Receive this diagnosis, take this course of action, get cured. They want to make a bullet-proof system so that any country doctor can successfully treat the disease. Any difficult diagnostic issues should be resolved with a clear-cut lab test. The current pattern is that a recommended treatment should work for a good slice of the people with a particular diagnosis (50% or more), otherwise research will be ongoing.

In cancer research, you'll see that a particular treatment may have a positive effect for 10% or 20% of people. This is considered a failed treatment, and will be abandoned. A promising treatment may be combined with other treatments to get the odds up, as long as it could be theoretically seen that the chemistry of the drugs won't clash with each other.

Yet, if you're in the 10% for whom that treatment will benefit, you may want that therapy. If you have 5 drugs that each cure 20% of the cancers, and it turns out that they each cure a different 20%, the only remaining research would be to figure out which people to treat with which drug. Tighter diagnosis of different forms of cancer is an area for research. One issue is that fine grained diagnosis is harder to trial, because usually you enter a trial after receiving a diagnosis. Another is that diagnostic procedures have different patenting issues than drugs, and a diagnosis is only done once, limiting the amount of money someone makes. Drug companies are starting to wake up and fund the diagnostic side.

General theories of treatment

The difficulty in any cancer treatment is to target the cancer cells. The first and most obvious way to target the cancer cells is with surgery. Surgery is, in some ways, the most obvious treatment path, as the risks can be clearly stated. The risks are not getting all the cancer, and hurting parts of the brain.

Cancer cells are your own body's cells that stay in a neoplastic state instead of differentiating into a particular cell type (such as a blood cell or a skin cell). In the neoplastic state, the cell does no good for the body. To kill all neoplastic cells interrupts all cellular division in the body, which hurts all sorts of processes, such as the regeneration of the liver, the creation of blood cells, and immune system cell replication. In adults, many cells in the body are at statis, and don't need to replicate, they just need to function.

There are two general methods for going after all neoplastic cells. One is chemotherapy, and the other is radiation. Chemotherapy involves drugs that interrupt the replication of all cells by going after general replication systems, such as DNA duplication. Radiation involves inducing DNA errors through "hard" radiation. The theory is to induce enough errors that normal cells can't replicate, but can continue to function. The goal of radiation is to hit that "sweet spot" and cause fast-replicating cells to die, but once you do, that area of the body can't have any more radiation in your entire life.

There are two newer theories of treatment. One is cellular communication mechanisms. Cells build certain proteins in order to communicate with neighbors. For example, if a cell needs more blood flow, it can express a certain protein which will tell nearby cells to extend the blood vessels. These proteins are typically involved with growth and/or action of cells. It is considered likely that many cancers express certain proteins in order to expand and grow. Blocking those proteins may slow a cancer to the point where the body's natural mechanisms can overcome it. The general benefit is that these therapies can be very light on the body, as they don't effect all cellular replication, and the immune system can continue to function at full strength. The problem is that it seems various people's cancers use different mechanisms.

Gene therapy is a completely different attempt at curing cancer. In this theory, a retrovirus (similar to chickenpox or AIDS or Mono) is introduced to the body. Retroviruses are special in that they can insert new DNA into all the cells in your body. This added strand of DNA can be designed to remove or alter or repair certain sequences. At this point in history, this is "James Bond" medicine, messing with the DNA in your cells. The effectiveness of a given therapy depends on which gene is targeted, and what the replacement gene is.

Surgery

We were not candidates for surgery, so my experience in this area is second-hand. If you ask enough doctors, it's possible to find a surgeon to operate on just about anything. However, there are studies that show that after the tumor has spread, surgery might not be beneficial. There's even evidence that shows that surgery is not beneficial at all (on average) for GBM patients. Being eligible for surgery means your case isn't so bad, and the common wisdom is to do it, and do it quickly. Any subsequent therapy will work better. However, glioblastoma in specific is highly invasive, so it is always sending "tentacles" down into the healthy brain. It's also mobile, spreading to other parts of the brain. From post-mortem studies, we know that those cells are there even if MRI can't detect them, and are where a surgeon can't reach them.

Surgeons have an incredible array of tools now. They have real-time "MRI Wands", which can show on a monitor exactly how close the target areas are, and allow the guidance of the knife more accurately. Pure stereotactic systems exist, where everything is driven by computer. In one paper, Dr Prados stated that with modern tools, any surgery could be done. The primary issue is the benefit, if the disease is multilocal.

Gamma Knife, a blend between surgery and radiation therapy

Gamma Knife is technically a radiation therapy, but the radiation is so focused that it can be considered an alternative to surgery. There are over 200 point sources of radiation, and they focus on a single point. The radiation fries whatever is at that point. Gamma Knife is typically reserved for the brain, where deep surgeries are difficult, but can be used anywhere in the body. The negative is that the surgeon can't have a look around, can't take biopsy samples, and can't use topical therapies (brachytherapy (radiation chips), gene therapy, Gliadel wafers (chemo chips)).

There are currently a fair number of Gamma Knife machines in America, although they're not exactly common.

Surgical adjuncts

The reality is that glioblastoma almost always (over 95%) recurs in the tumor bed, or original site of tumor. This has lead to treatment strategies where the surgeon can leave something curative at the site of the tumor. The first effort was made with radioactive iodine and cesium chips, to basically be a form of long term, focused radiation therapy. While this therapy is commonly used, the long term data on it has not been especially promising. A very promising area of treatment is called Gliadel wafers. Giadel is a form of long-term release CCNU, a very effective form of chemotherapy. By staying at the site, the CCNU poisons the tumor bed, but doesn't have a harmful effect on the bone marrow. It's even somewhat unknown why this treatment works as well as it does, because it's likely that the Gliadel effects only 10% of the cells. The experimental numbers of this therapy are currently very exciting, but work is ongoing. The third major form of therapy is gene therapy. Retroviruses attack cells at the point of replication (mitotis), thus target only growing cells. The retrovirus inserts DNA into the cells it infects, but has had genes omitted so the infected cell doesn't create more of the virus, thus limiting its effect to the area where the therapy is inserted. This general technique has huge promise, but depends on exactly what the inserted genes try to do. One recent trial involved adding genes that express a certain surface protein that AIDS infected cells express, then using anti-AIDS drugs. In general, these forms of gene therapy haven't yet panned out, but are likely to when we understand more about the human genetic system.

Gliadel recently was turned down by the FDA as an approved treatment. After reading so much positive research out of Duke, it was hard to see why. The data published by the FDA was much more negative, showing positive responses in only a small number of patients - hardly significant. The cost of the drug is high - about $10,000 for the surgical treatment. I guess I would ask for it if I was having surgery, but knowing what I know, I wouldn't have surgery for this kind of cancer.

Radiation

Radiation therapy hasn't changed much over the last 20 years. The head can take a fair amount of radiation, because the neurons in the brain don't replicate much in adults. The standard limit of radiation is 6000 units (centi-greys, or 60 Greys) over the entire lifetime. Current data suggests that effectiveness against the cancer goes down dramatically after 50 Greys, and damage goes up badly after 60 Greys. That's the sweet spot I mentioned before.

The rule of thumb for radiation therapy is that one-third of people have clear shrinkage, one-third stabilize, and one-third are not helped. It is not known what is different about these sets of people, but there is work ongoing to examine certain naturally occurring DNA mutations to see if they effect the outcomes. There are several DNA repair mechanisms. If you have a natural mutation where one or more of these are knocked out, your radiation might be more effective, but similarly, the healthy tissue might be more effected, leading to permanent deficits. The chances of permanent deficit are very real, and must be discussed with your doctor.

A few years ago a technique called "hyper fractionalized radiation" was tried. In this technique, the patient is treated multiple times per day, instead of once a day, but with the same dose per day. Although this sounded good on paper, it didn't turn out to have any clear clinical benefit. It was easier on the healthy tissue, but also easier on the cancer.

Radiation can be focused to smaller regions. By also hitting a smaller region from multiple angles, the healthy areas will receive a smaller dose. For example, by hitting a spot in the middle from the front and from the right, the healthy tissue will receive half the radiation. This technique is called "conformal mapping" or "coning down".

Radiation is annoying, but fairly easy. The process is that a mask will be made to hold the head exactly in place. A CT scan will be taken with that mask and that table to determine the exact target areas. The angles will then be computed. This set-up process is called a "simulation" After the simulation is done, the patient arrives every day, gets strapped into their mask, and spends a minute or so receiving the radiation dose. There's always a certain amount of waiting for your machine to be free, but you don't see a lot of other patients. Since radiation is the second treatment tried (after surgery), patients tend to be healthy and in good spirits.

The general course of treatment is to decide what part of the brain you're hitting at what time, and then go through the entire course of treatment, and get a scan in 8 weeks after it's all over. Taking scans during the treatment is not common, but our doctor recommended it given our young age.

Radiation often includes some form of concurrent treatment. Chemo treatments can be given, on the theory that this is one of the best chances to get as many cells as possible. Protective treatments can also be given, to reduce the chances of damage by the radiation. Chemo during radiation is fairly standard, and we went with a half-dose Temodar regime. The literature on this exact course is based on a single paper that has been contested on a number of grounds, and it could be that other chemo regimes (BCNU, CCNU, Procarbazine) are as effective. We were not offered and did not investigate any of the other options, but even now there are a variety of studies available for drugs of this sort.

There is a single paper out of Japan about hyperbaric treatment, where the patient is put in a high pressure oxygen tank so that all the cells absorb more oxygen. That seems to have an effect of intensifying the radiation, based on some kind of theory that rapidly dividing cells will consume more oxygen, and then be more damaged when the oxygen has an electron ripped loose and becomes a free radical. To my knowledge, this treatment is not in common use, and I don't even know of an American trial of the technique.

Hyperthermic treatment

This is a treatment pioneered and used widely in Germany. The general theory is that intact tumors have much cruder methods of dissipating heat than healthy tissue, and can't take elevated heat levels. There are a number of general tools used in hyperthermic treatment, but the most common resembles a body-sized microwave oven. For the head, I understand that holes can be drilled and probes implanted in the brain. I know one person in Germany who had very positive results with this treatment for a body-based cancer, but I also talked to our radiation oncologist, who had run studies and published papers using hyperthermic treatment, and did not speak highly of its effectiveness for brain tumors. We decided not to take this direction.

Chemo

Wow, chemo. This is really the mainstay of cancer treatment, and is quite complicated. I'll go through an overview, and specific drugs.

Overview

The general theory of chemotherapy is to introduce a drug into the system that kills cells at their earliest stages of growth. This is a point when they have not yet differentiated. This stage is "neoplastic". In an adult, few cells are rapidly dividing, so a broad-spectrum anti-neoplatic treatment should considerably slow a fast-growing cancer. This does work, and works better for some cancers than others. Different drugs work better for some cancers than others, for reasons that are not understood. Most researchers are frustrated by the fact that the old mainstays work about the same as all the new stuff they've developed.

When you hear "chemo", you might think of vomiting and feeling terrible. Ann's experience wasn't like that. She would be tired for a few days after taking a dose, but that was it. The new anti-nausia drugs they have are wonderful. Expensive, but wonderful. Unless you're in a rare percentage of people, you won't have any problems with nausea.

Blood counts

The cycle of chemo is that you take drugs for a few days, then have the rest of the month where the dose is effective. The drug stays in your system, and has more and more profound effects on all the rapidly replicating cells. For an adult, the one area that regenerates rapidly is the cells of the immune system, which are grown in the marrow. The cells of greatest importance, which only have a lifetime of a few days, are the white blood cells. Although there are several types of white blood cell, the entire group fights off bacterial infection. The level also goes up and down if you are fighting an infection - bacterial or viral.

The general cycle of treatment is that you take the dose, then monitor your white blood count every week. If your white count doesn't recover, then you can't take another dose of the drug. Normal white counts range from 4.5 to 10.0 (thousand cells per mL). A low white count is called leukopenia (leukocytes are white blood cells, 'penia' means 'lack of'). The Neutrophil could was also closely monitored. These are a particular type of white blood cell.

There seem to be a number of philosophies about the interaction between white counts and drug doses. At UCSF, they flat out refused to give doses when Ann's white count was low, even if she promised to stay in isolation. Similarly, they didn't give drugs that boost white cell production (G-Gsf), having done a study before that giving these drugs in combination with CCNU gives a longer period that chemo can be given, but not a longer survival time for the patient. There are two "good theories" about this kind of treatment. You can say that the chemo is effective, and giving more is better. You can also say that the risk that you run by giving the growth factor is that the marrow will get permanently damaged, because it has to replicate new cells while in a toxic environment. Without doing the experiment, you don't know which theory is true - and the UCSF research indicates that it's not even an important issue, so why bother.

There's another general theory that says that the chemo isn't really working unless the white count is going down. Dr Prados' group believes that the best treatment is one that gives your body as much chance to throw off the cancer by itself as is possible. The drugs are there to help, not to beat down the body's system. At the moment, this theory is as good as any other.

Temodar (temozolomide)

Temodar is the standard first line treatment for GBM currently. The great benefit of the treatment is that it's a pill that can be taken at home. All the other good chemos are injections that have to be done at the doctor's office. Differences in how insurance companies work can cause significant differential in what this costs you. Temodar is generally far lighter on the body than the older drugs, so these days is always given as the first line drug. It was developed solely as a chemo for brain cancers.

I read a "metaanalysis" out of a british group that showed that Temodar was, in the end, no better than BCNU. In America, Temodar is commonly considered better, based on several papers. Temodar is more expensive. Certainly the fact that you can take it at home is a very, very nice thing.

BCNU, CCNU (Carmustine), Procarb, Cisplatin

These are the old-line nitrosureas that are still in use for other cancers. There's a great review on virtualtrials.com . I belive that BCNU and Procarbizine are typically seen as the leaders in this group.

Retinoic Acid therapy

Standard cancer textbooks from the 90's state that retinoic acid is a well known anti-cancer agent. A particular form, Accutane (13-cis retinoic acid), is also a treatment for acne. This is a very specific form of vitamin A. It's a general anti-neoplatic drug, and high dosed of Vitamin A during pregnancy cause birth defects. The amount of Accutane given for GBM is very high. Accutane is not FDA approved for GBM, but under the rules, a doctor can prescribe any approved medication for any disease.

Dr Prados said that of the non-trial alternatives, he recommended Temodard with Accutane as a first-line treatment. As he was trying to steer us toward a trial, he was somewhat unforthcoming about Accutane, to the point of withholding research that his group had done (his office finally faxed me the abstract, which was unpublished, after a week of pestering). Although I don't have the paper, and it was unpublished although the research was completed, I did like the numbers. I think Dr Prados general effort to get people on trials is good, and he didn't lie to us. I do feel that he stretched the truth, but he did it in pursuit of a greater good.

Coctails - PCV

This is the general name for combining Procarb, lomustine, and vincristine. The theory was that you had the best chance of knocking out all the cancer cells if you hit them all at once, from all different sides. The reality has been that this treatment is not successful. These drugs are never going to get all the cells, so by using them all up front means you expend all your possible ammunition at the same time, and the cancer gets you quicker. Similarly, it's a very toxic combination, so you can't give it as long before the body has problems with white blood counts. At least, Dr Prados was very down on PCV therapy.

Irinotecan (CPT-11)

Dr Prados was running a CPT-11 trial while we were under treatment, and I asked him how it was going. "Very toxic", he said. He was suggesting that the effects were so toxic that, for him, it was not an acceptable drug.

VP-16 and high dose tamoxiphen

Dr Prados considers this a reasonable second or third line therapy. I believe it has not been fully experimented with - at least, I've never seen numbers. VP-16 is oral, and doesn't have cross-over resistance with Temodar. VP-16 is considered a low side effect drug, suitable for old people and children. Everything I've read about it says it might be the sleeper of common chemo drugs.

EGFR blockers - ZD1839, OSI-779

Ann was on an OSI-779 trial. The benefits of both of these drugs is that they cause very few side effects (skin rash being the worst), and completely complimentary to standard chemo.

In a recently published interview with guys at Duke, they said that they were now commonly giving ZD-1839 with Temodar as their first-round treatment. At the time that Ann was enrolling in trials, the ZD-1839 trial was closed because of kidney complications. However, they soon reopened the trial after determining that the side effect rate was low. Trials on ZD-1839 are continuing.

In general, it seems likely that these pills are not a cure. Upcoming papers will show how much they help. The Duke guys think they help, and that's something.

IL-13 Pe38QQR (Interlukin-13)

This is yet another cytotoxin, similar to Temodar and the rest. Dr Prados is running a trial on it. It wasn't available when we were trialing. It seems that this is a drug injected into the tumor site. The number of places trialing this drug seem to make it an attractive choice in 2003. If you look at the other breakthroughs in cancer, at some point they find the one toxin that just really works against this kind of cancer. Or they finally figure out a better categorization, recategorize, and apply the right drugs to the right patients.

Monoclonal Antibodies

This might be one of the most exciting areas of current research, even if it hasn't fully born fruit yet. The general idea is to help the immune system recognize the cancer cells as bad, and go after them. It has the benefit of working with the immune system, where standard anti-neoplastic elements end up hurting the immune system. It's still hard to find trials of monoclonal antibody treatments in America.

One trial, sponsored by Peregrine Pharmaceuticals, was for an antibody called TNT-1/B. Right now this trial is listed as no longer recruiting patients, which is generally a bad sign. I can find a few other trials, but not a huge amount of work being done in this area.

Gene Therapy

Gene therapy was, and continues to be, one of the great hopes of the genetic age. The idea that one could engineer a "genetic fix" to some part of the system, in essence a "patch" as we do to software today, and thereby cure a disease, is a holy grail. With GBM, a number of "patches" have been engineered. These are applied through retro-viruses which attack a cell exactly as it is dividing, thus targeting the cancer cells above the other cells.

One design was to insert a gene that would make the cancer cells more susceptible to other drugs. In general these therapies had to be injected, as the retrovirus used for delivery doesn't cross the blood brain barrier efficiently.

In trials, these therapies have done poorly.

Viral Therapy

There's an interesting result out of the University of Calgary that a certain kind of fairly common retrovirus (same category as herpes, mono, and AIDs) may have very strong anti-cancer activity. It's called "reovirus", and the doctors I talked to at UCSF were aware of the work, but not completely up on it. Most of the news reports I see are from 1998 and 1999. At that point you'd expect that news of a truly excellent, working therapy would have spread. On the other hand, one news report from 2001 says that they'll be starting clinical trials. Communication with a UCSF doctor in early 2003 said that they were in the middle of the trial, but had halted it. The doctor didn't know why they had halted it, but that everyone was curious what their results would be.

Angiosupressive therapy

Dr Brem at Moffit in Florida is continuing a trial on the use of ketalating copper. You can read a number of statements about this treatment on the internet. The general theory is that copper tends to accumulate in GBM tumors, thus denying copper might be an effective strategy. As copper is one of the critical elements in how cells generate energy, one can't get rid of it entirely. A drug used to treat a condition of too much copper in the body is penicillamine. Ann also had a general low-copper diet. One of the big surprises with copper is the amount in Shitaki mushrooms - several grams per half-cup. Liver and crab, of course, have high levels as well.

One of the original doctors working on this therapy was at Michigan, and Ann's father Carl is a professor at Michigan. There were a number of strange things we heard about that fellow's work. He wasn't a clinical doctor, but instead a geneticist, although one with a MD. His use of the drug was under a "grandfather clause". It's a treatment that takes months to work, thus not making it highly suitable for this disease (which can often kill months after the diagnosis).

However, the research is being continued.

Similar is work on Thalidomide. This work was originally pioneered by Dr Judah Folkman in Boston, who is a friend of a friend - Ann's friend Holly's aunt is his admin. Dr Folkman was quite high profile, with a 60 minutes interview and a recent ghost-written book called "Cancer Warrior". Still, the work from Dr Folkman's animal studies just hasn't proven well in humans. People are still trying with that class of drugs, trying to see why the animal models don't yet work in people. Of course, Thalidomide caused birth defects - but the reason was that it prevents the growth of blood vessels necessary for fast-growing parts of the body (fetuses, or cancers). In general, drugs that cause birth defects are candidates as anti-cancer drugs. One of the big drawbacks of thalidomide treatment is that Thalidomide was developed as a sleeping aid, and at the dose where they might be effective as anti-cancer drugs, the patient is asleep most of the time. Given that you might have only a year to live, you don't want to spend that year asleep.

Doctors and hospitals - naming names

Getting recommendations for treatment in the medical community is like pulling teeth. No doctor wants to "rat out" another doctor. However, how will you know which doctors are good, and which are bad, without some kind of information?

Alta Bates Hospital, Berkeley

Alta-Bates is a very good hospital for a non-research institution. I prefer them greatly to Summit or Highland in the East Bay. With few exceptions, every person I ever dealt with there was a highly professional and competent person.

One exception with Alta-Bates was our first attempt at getting diagnosed. Ann had terrible headache pains, and was rolling on the floor screaming. In the morning, she and I went down there. We were waiting in the ER for an hour, and I finally decided to go out and get some juice at the Whole Foods. When I came back, Ann was gone. She had tried to call me on the cell phone, so I knew she was in there, but I couldn't call her because of the hospital's prohibition on cell phone use. The nameless security guard refused to tell me where she was, and threatened to have me thrown out of the hospital - in direct violation of hospital policy of one visitor per patient. The clinician that Ann saw diagnoses Ann with benign positional vertigo, a complete crock. Ann never saw a doctor. I suspect that Ann may have played down her symptoms, as I often saw her doing later.

One minor mess-up we had at Alta-Bates was the mislabling of Ann's biopsy report under the name "Singh" instead of "Simon". This is apparently common, and easy enough to straighten out - there was only one brain biopsy performed that day.

UCSF, Parnassus street

Once I really understood these people, they were great to work with. You have to be able to deal with the fact that you've got residents, teacher/doctors, and "lifers". Generally, you need to get past the residents and get to the doctors, and make friends with the lifers. (By "lifers" I mean staff like administrators, phlebotomists, nurses, ER staff). One of UCSF's benefits is that they're a real, old fashioned research hospital. Most of the workers aren't motivated by making money. Every bit of equipment is there, and there's an expert for any field you might need help with.

UC Berkeley Tang Center

The doctors we saw at Tang Center were excellent and exceptional. However, Tang Center is tuned to work for college students who are fundamentally healthy. They don't have a scanner (CT or MRI) on premises, and they don't have a provider they work with to get such things. They don't stock drugs like chemo drugs in their pharmacy, and even ended up making a policy that allowed them to avoid even ordering them for us (causing no end of insurance hassle for us). They perpetuated the fact that Ann didn't get a scan until it was far too late. If I could make two changes at Tang Center, I would say that every student should be seen by a doctor, and that they should have a CT scanner on site. Given the amount of medicine they do, a CT scanner (or a simple way for doctors to refer to a CT scanner) is a necessity.

Dr Jeff Nelson, Berkeley Tang Center

The only real doctor we saw during the diagnosis period was Dr Nelson, a neuro-muscular specialist at UC Berkeley Tang center. Although he was wrong (talking about how unlikely it was to have a serious problem), he was very nice. He called right after we finally had the first scan, and knew things were really wrong. I relied on him over and over during the following few months. When we had problems diagnosing Ann's leg problems, he stepped in and did a thorough neurological exam, and broke the bad news to us.

Dr Nelson was one of the few doctors who treated me like a real, bona fide human. Maybe we were closer in age. Maybe he couldn't say that he knew everything - after all, he missed the first diagnosis. He was willing to do the one thing that really mattered - tell me, in plain language, if another doctor had a bad reputation. He was also a little naive, thinking that we could talk to a neurologist just because there were phone numbers in the referral book. In any case, I think he's a damned good doctor. He mostly does sports medicine, but if I ever had a problem and could be seen by him, I'd choose him.

Dr Brad Wrubel, neurologist

Although we dealt with Dr Wrubel only on the weekend when Ann was hospitalized at Alta Bates, I found him easy to get along with, and that he was a straight shooter. I was in the middle of learning how to communicate with doctors, and he was one of my first. If all doctors had been that easy, the whole process would have been better.

Dr Schienberg, neurosurgeon

I'm not sure if Dr Schienberg is still practicing. I got a letter from their medical group talking about where the records would be kept, as their practice was dissolving. I remember getting a very negative review about the head doctor of the medical group, but Dr Schienberg was listed as a good surgeon, but a bad communicator. He was the one who broke the news about the diagnosis of Glioblastoma, and he did it very poorly. On the other hand, it was a good biopsy, cleanly done.

Dr Hildebrandt, pathology

Rarely do you ever talk to pathologists, and it was only the freak circumstance of mislabled samples which brought us into contact with him. He was very good to talk to, and opened up to Carl (Ann's father) about his internal conflicts about the diagnosis. He forwarded the samples over to a colleague within Alta Bates (at Summit) about the diagnosis, so we knew there were two brains on the case. However, what he finally submitted to paper was cut and dried (Glioblastoma), in a case where he felt conflict. Given the further very unusual progression of Ann's disease, it might have been better for him to issue a more comprehensive report. Much later I was introduced to Dr Henry Miller at NYU (?), who was a pathologist we should have met earlier.

Dr Champion, radiation oncology, Alta-bates cancer center

Dr Champion was the woman I mentioned earlier who gave us a very different treatment path than Dr Nelson. Ann had a very negative reaction to her, and I felt like she really didn't take the time to understand the kind of treatment Ann wanted. She wanted to keep Ann alive, and Ann wanted a combination of life and a life worth living. Ann freaked out in Dr Champion's office when she recommended a standard treatment of 60 Grays across the entire brain, and really would have done only that treatment, regardless of the fact that this treatment would give a good chance (30% or so) of permanent damage to speaking and abstract reasoning areas.

In retrospect, the area where the cancer regrew was in the area that Dr Champion would have treated with full radiation, and where Dr Larson coned down. But we also don't know if Ann would have been damaged, and whether it would have left her in a life that she didn't want to live. Ann was a little conflicted about these choices. She often stated that she was willing to take any risk, but this risk was somehow too much. Ann often reacted on her gut instinct, which in this case was partially based on a certain pushyness of the staff. We were in transition between Alta-Bates and UCSF, and the staff went ahead and booked a series of appointments at Alta-Bates without asking us. This offended Ann deeply.

Dr Cassedy, Alta-bates oncology

Dr Cassady and I only spoke on the phone once. In that conversation he impressed me greatly. Just about every other doctor wants to take the case, wants to direct your care, wants to push you around. Dr Cassady called me after getting the biopsy report (before it was officially read to us) and said we needed to get over to UCSF as soon as possible, and that he would arrange an appointment with Dr Prados as soon as possible. That simple personal phone call and attention was a great salve in a rather terrible couple of days. I don't know what Dr Cassedy would have been like to deal with on a regular basis, but with only that single conversation to go on, I'd give him a call if I was ever diagnosed.

Dr Prados, UCSF neuro-oncology

I have very conflicting thoughts about Dr Prados. All my research about him says that he is the go-to guy in the Bay Area. His office runs more clinical trials than any other office outside of MD Anderson and Duke. In person he's a warm and personable guy, and I can appreciate what he's trying to do. He has a huge amount of experience, and I wouldn't be surprised if he plays a large role in finding whatever cure is eventually found. That being said, he's hard to get time with, hard to get a real attachment from. Our office visits often were a quick exam then him stepping out of the room for 20 minutes. At the point of our first major treatment choice, I could not get him to tell me about the benefits of Accutain as adjunctive therapy - primarily, I believe, because he didn't want to talk up a non-trial drug.

Dr Prados is trying to find a cure. In a perfect world, he would like everyone to be treated as they would be treated in a standard clinical environment. They get a diagnosis, they get the drug they need. A system that demands insight and personal brilliance by the doctors doesn't scale. Thus he tries to go by the book, doesn't go overboard with unusual theories, or extra treatments. He can't, or won't, really go out of his way to cure you - although he desperately wants to cure you.

I felt that every conversation with Dr Prados was a game of chess. I would have to find just the right questions, just the right tone to take, to get the best motion from him. Sometimes I won, and sometimes I didn't.

His office was incredible. The nursing staff - Jane, Margeretta - were a constant help. There's no way I could have gotten through the whole ordeal without them.

Dr Chang, UCSF neuro-oncology

Dr Chang is Dr Prados' number 2 at UCSF. She and I hit it off well when she had to break the news to us that they had mis-dosed Ann with the experimental medicine (OSI-774), and we were very pragmatic and not angry. Dr Chang also didn't consider other options when trying to figure out Ann's leg. Ann felt very negatively toward Dr Chang, feeling almost jealous that Dr Chang and I had good rapport. Ann ended up screaming at Dr Chang, saying that she was trying to kill Ann when she strongly suggested Ann be put in the hospital. I thought Dr Chang was more open than Dr Prados.

However, I hear that patients have a similar reaction to Dr Chang as Ann had. I have some theories about this, but don't really understand it. I think I would prefer Dr Chang, who was easier to get ahold of, and easier to talk to. She was less smooth - after dealing with Dr Prados, where I felt like I had to be chess master, Dr Chang was a breath of fresh air. But maybe she wasn't as tough - maybe Ann felt like she needed a tough fighter. Our bad moment with her was when she wanted to put Ann in the hospital, and Ann said Dr Chang was trying to kill her. Dr Chang was looking to me, trying to find a way to decrease my burden. I was clearly struggling, but the nature of our fight was to struggle, and we wanted to struggle the best way we could. Dr Chang didn't seem to quite grasp that.

Dr Eric Burton, the other guy at UCSF neuro-oncology

Dr Burton joined the UCSF staff while Ann was under treatment. He seemed to be getting his bearings, and not fully wired like Dr Prados. Although he seemed to cover a routine exam OK, I can't really imagine having to go over a hard scan with him. Perhaps he's learning, and much better now.

Dr David Larson, UCSF radiation oncology

This single doctor was the most thoughtful, kind, attentive, and competent doctor we came into contact with. He gave us hope. He broke the rules. He got us more scans. He was more open to other therapies (like hyperbaric treatments). His manner is completely winning. Ann said that he would save her life, and dealing with Dr Prados was worth it if we could keep Dr Nelson. He's on some list as one of the top 100 doctors in America, and I would completely agree.

Dr Renneker, "no stone unturned"

There's an unusual doctor, Dr Renneker, who is on the family practice staff at UCSF. He calls himself "the medical equalizer", and has a non-typical look on the medical community. For a hefty fee he takes on "interesting cases", and if you can get him, he'll turn your case around. He acts simply as a consultant, consulting by phone about your diagnosis, the doctors you're talking to, and explaining what is happening. He is like a shadowy figure out of some super-hero story. He practices, unappologetically, "positive medicine", trying many different things.

He and I also hit it off very well, and after a faxed letter we talked on the phone. I only wished I had talked to him months earlier, but as it was, his intervention in the case came just a little too late. If you are truly desperate, find him. It's like some kind of TV drama, but he is that good.

UCSF - residents

In general, the resident staff at UCSF was very good. Our first oncology resident seemed OK, but we didn't really click that well. The second one, who came there from Stanford, was great. He'll make an excellent doctor. It was just clear how hard he worked to get the details right. There was a guy, I think a resident although may have been some kind of visiting scholar, Dr Parney, who was very good to us. He went over a difficult scan with us, and had an exceptional bedside manner. One sunday morning he met me with a prescription. I remember clearly one thing he said that had a great effect on Ann. She asked if, because of this scan, they were going to give up on her. He looked her dead in the eye and said, "I'm from the bronx. We know how to fight there. No one is giving up on you." It was the one thing she needed to hear.

Sutter VNA and Hospice (Visiting Nurses Association) -

We needed these people's services later, and they came through in spades. They bent the rules for us regarding not entering into a hospice agreement, although we got excellent hospice level care. They kept Ann out of the hospital and at home. I recommend them highly.

Mr Broffman - Pine Street Clinic

I hesitate to put Mr Broffman in a list of doctors. He bills himself as a chinese herbalist, which is technically true, but he didn't fit any of my expectations of a chinese herbalist. He's a young jewish guy, not a doctor, and he was able to introduce me to a variety of medical papers and concepts. He gave capsule summaries of all the oncologists we ever ran into that were accurate - the truth that doctors rarely tell about other doctors.

He divided up treatments into "high tech" and "low tech", and pointed out that all the "western" procedures that were under investigation in America were under investigation in Beijing, thus making them "chinese". In this way he attempted to be a bridge between the crackpots and the doctor community in a way that was fascinating. We only met him once, and didn't work very closely with him. I would recommend him, though, but consider him a "medical consultant", not a herbalist.

Dr Dianne Kaplan, biofeedback and relaxation

Ann was really pleased with Dr Kaplan. I only met her a few times. It was certainly true that Ann's ability to control her breathing and pain got better through working with Dr Kaplan.

Resources

Bernie Segal's book, and tapes, on being an exceptional patient. Although I don't agree with all of it, I think he says good things about being exceptional.

http://brain.mgh.harvard.edu/PatientGuide.htm

http://clinicaltrials.gov/

http://home.earthlink.net/~sdepesa/

That book by Michael Lerner

http://www.bjcancer.com/

Addendum - the rest of the story

Ann's journey has ended. Ann died on February 24th, 2003. In early January the disease started progressing, but was growing on the spine, below the area of the brain scans. This is a very rare path in disease progression. Although we were seen by our oncologist on January 5th complaining of numbness in one foot, we didn't get the spinal metastasis discovered until about 3 weeks later. At that point we embarked on a high powered and aggressive radiation path, which we hoped would do well since radiation had done very well before. However, this time the cancer did not budge, and quickly took over. The progression through her spine was quick, and she rapidly lost the ability to walk, then control her bowels. We had some excellent home care, which made much of the difference.

I was not very happy with the care we got from our oncology team at this point. Ann said she wanted to fight this completely, but Dr Prados would not prescribe further chemo. We should have been on a different chemo starting the day the cancer was discovered, but instead he removed all chemo drugs. He raised issues with blood clots to get Ann to not demand further chemo, whcn blood clots were the least of her problems. Although I agreed with Dr Prados' (and every other doctor I talked to) theory that far into disease progression, no treatment was the best option, but that's not what Ann wanted.

Dr Prados and I had a long talk regarding this entire phase, so I believe I know where he was coming from. He believed that when the end was in sight, the patient should be made aware of that, and be allowed time to make their peace with the living - for the sake of the living. He was hoping that she would have a few weeks to spend with us without and horrible symptoms, and to allow us those weeks to bask in each other's love. He said that patients who don't do that last bit of communication leave a horrible burden to their survivors. Although I can completely see where he came from, I also feel bad that I don't think we (he and I) did what Ann wanted.

The last stages of this disease are horrible. I've been unable to finish writing this document because it brings up memories of the last month. The time I'm drafting this section is just past 6 months after Ann's death. I'm sitting in a cafe in Berkeley, CA. It's an astonishingly beautiful day, with sun streaming in the windows, and I have an entire life ahead of me - yet I can just barely write this without the aching pain in my chest taking over.

First, Ann lost the use of her body, which took a few weeks. The pain was sometimes terrible, and it took me a bit of work to master the use of the morphine needed to keep the pain under control. Ann was fairly adamant about staying at home - she felt that if she went to a hospital, it would be to die. We had home care from a visiting nurses' association, Sutter VNA, which was excellent. They taught me how to dress wounds, how to change her diapers with the least stress, how to feed her and keep her hydrated. Dr Prados removed the chemo drugs, and clearly the cancer started progressing in Ann's brain as well as along her spine. She lost some powers of cognition, and wasn't able to read. She did recognize us, and me, until the end of her consciousness. She had some kind of unusual time disassociation in her last few weeks of consciousness, so that she would jump back in time a few minutes. She started singing, something she couldn't do while healthy - sang songs I barely remembered, sang songs I've never heard.

After she had lost the ability to walk, but before she lost much of her mental abilities, she gave a poetry reading in Oakland at 21 Grand. She read all of her favorite poems. I could tell she was having problems. She never stumbled over a single word during a reading, and this time she lost her place several times. The overwhelming emotion, though, was one of an exquisite moment, a moment of bright red and yellow heat before a body is utterly destroyed, and is no more. It was like a funeral with the body still living, as we had to bring a bed and have Ann read from it. At the end, since she couldn't sit up, people gathered around and talked to her, one by one. In many cases, it would be the last time they saw her alive.

In those last few days I had contact with Dr Renneker, who I think is an amazing guy. He and I hit it off well, but the reality was that we were too far down the curve to really help Ann, although we tried. He and I both knew that he was really supporting me, and supporting me in the promise I made to Ann. This was during a time that I had only barely allowed my own desires to surface, so allowing there to be a shift to what was right for me was very helpful. Dr Renneker is really a double edged sword. He does practice optimistic medicine, and the "doublethink" required to be optimistic about someone who is clearly in their last few days of life is tough.

Ann never admitted that she was going to die, and fought with every breath. I tried to fight along side her, and make all the decisions as she would have wished them to be made. She was never admitted to a hospital, and died at home with me, her brother Dave, her step-mother Susan, and our friends. One of the last things she did was say my name, and smile. I understand that some people who die of GBM lose their memories, and lose control of their emotions. Although Ann was taken apart, piece by piece, she never lost whatever was her until she took her last breath.

I threw a terrible, manic energy into planning a funeral for Ann, and a celebration of her life. Throwing a party of that magnitude on a few days notice is not simple, but both were excellent - the funeral especially. Ann died on Monday, we had a service on Friday at Chapel of the Chimes in Oakland (which I highly recommend), a celebration of her life on Saturday, and most people flew home on Sunday.

The months since her death have been hard. In the following weeks I was blessed and cursed by a hyper-accurate view of the world. My therapist called it "high contrast living", where everything seems so clear and either true or false. I was mostly alone for a few weeks, and going crazy. I met a friend of my band, Gitty Duncan, and moved in with her. The reality of being in the house where Ann died was just too much.

For myself, I had to move on quickly. The pain of being submerged in things Ann was just too much. One of my closest friends was worried that I wasn't grieving enough, but others said that perhaps I had already grieved enough. I've let my hair grow back, based on the symbol that I wanted to remember and attach to Ann as she was alive, not view her only through her illness. Now, just past 6 months after her death, can I finally look back to her and feel simply sad and happy. Happy to have known her, and sad that she's gone.

An idea that I'd add for caregivers and friends of caregivers is that the death of a primary partner in the middle of life has one special difficulty. Quickly, it seems, friends melt away. They don't know what to say, they don't want to be reminded of the deceased. But the surviving partner is now terribly alone. Not only does he not have his usual set of friends, he's also missing his best friend, his partner who he thought would always be there to share the hard times and the joys. I felt all these terrible surges in emotion, anger and happiness, zooming to dizzying heights and terrifying lows, but without my best friend to share them with. If I could say one thing to caregivers of caregivers - just stay in contact. If you care, extending a hand, keep reaching toward them, even if they complain. They're now deeply in touch with what being alone is about, and what being cared for is about. If you approach them with an open, caring heart, nothing you can say will be wrong.