I have considered doing some educational piece on brain cancer for some time, but was not sure what people wanted to know. Some patients have used this blog as a reference for a treatment plan, but solid medical advice is hidden in 1000s of words, and sometimes not actually advised (see not completely following NPO order prior to an awake craniectomy).

Over the last 6 months, I have talked to several people with newly diagnosed brain masses, under current treatment, brain cancer survivors, and relatives of those that have died. When I share my story, I’m surprised how often I hear a story, too. I am not an expert in brain cancer, but this blog will be a guide to of what to expect with a typical course of diagnosis and treatment.

I am a physician in the 21st century, so I have reliable resources immediately accessible on my phone. I can hear a diagnosis that I only vaguely remember from medical school, and after 2 minutes, become at least conversant in diagnostic and treatment strategies from UpToDate, or more and more often, Google. However, in my own case, that was overwhelming. After being saturated with prognostic factors, stats on survival, and treatment options, I frequently relied on a new friend, Chris Whalen, that had the same diagnosis 1 month prior. I wanted to know what to expect as a patient, not a clinician resource.

Cancer in General
Every cell in the body has a tightly regulated system that controls growth and reproduction. Some cells divide rapidly, others not at all. Most cancers are considered sporadic, and the theory behind their development is a multi-step process. This includes damage to DNA from either radiation or toxins, infections (HPV and hepatitis), and failure of the immune system. The cells just keep reproducing without the usual biological constraints. It can affect health by mass effect to local healthy tissues, spread to distant sites, or cause metabolic / hormonal derangements.

Patients can lower their risk in general of getting cancer by not smoking, avoiding excess alcohol intake, regular exercise, and maintaining a normal body weight. But still, it just happens.

Brain Mass
Brain masses can present in a variety of ways, depending on location and size. People can describe subacute findings with progressive focal neurological deficits, headaches, nausea / vomiting, or even personality changes for months. Others can have an acute presentation, for an example a seizure (like myself). At some point, the symptoms will lead to a very memorable head CT or MRI. The scans can be very suggestive of a particular diagnosis, but usually tissue acquired by biopsy or resection is needed to confirm. However, a biopsy is usually not the first step in brain mass work-up.

After a brain mass is discovered on imaging, an investigation will start as to the type of mass. A brain mass on imaging can be one of a several different possibilities: infection, metastatic lesion from some other cancer, or a primary brain tumor. The first test is a history from a medical provider. Fevers, chills, infectious symptoms suggest the mass is an abscess, or pocket of infection. Infection can be surprisingly difficult to figure out, and may take a biopsy for culture unless systemic infection is clear. I felt fine right up to my diagnosis, so I doubted I was infected. If a patient has a history of cancer, then a metastatic lesion would need to be strongly considered (depending on the cancer). However, my mass was solitary and relatively large whereas metastasis are frequently numerous. If the patient has no known cancer, potential cancers outside the head will still be considered first, either through physical exam or further imaging of chest, abdomen, and pelvis depending on risk factors of patient. My chest, abdomen and pelvis CT was normal like almost everyone with a primary brain tumor. The brain is a difficult spot to biopsy, so if you find a spot somewhere else, that will likely be biopsied instead. Once infection or metastatic disease are ruled out, the first consultant will be a neurosurgeon.

Due to the edema around the tumor and my seizures, I was started on Decadron and Keppra, a steroid and anti-seizure med. Decadron is the most common med given for any brain swelling or mass since it decreases edema. Since that time, I never had another seizure. Decadron is a potent steroid, driving up energy, appetite, blood pressure, blood sugar, and is overall stimulating. Sleep is difficult to come by, but not always felt to be needed. The med is not without long-term affects, so we try to use it only if needed. Keppra is a pretty common anti-seizure medication. The insert basically says fatigue and irritability as side effects. Who knows if I actually experienced that from the med. I did have a rare allergic reaction with liver test abnormalities which resolved after cessation.

If systemic infection and other metastatic cancers are ruled out, then consideration for either a brain biopsy or mass resection will occur. A neurosurgeon will be involved early in the care to determine if the mass should be biopsied or resected. The urgency of neurosurgery depends on the size, location, and acuity of symptoms. If the patient is healthy enough, tissue would be needed to know the tumor type. I had my surgical resection 1 week after the diagnosis. During that week, I had a series of outpatient tests including a repeat head MRI, CT scan as mentioned above, and further neurological testing by a speech pathologist.

Brain cancer is like real estate: location, location, location. Some cancers are close to the skull, where others are deep and near or behind very important structures making them difficult to remove. Surgical risks are dependent on mass location and overall patient health. The more challenging the location, the riskier the procedure. I was quoted based on tumor location of a 10% risk of some right sided weakness, and 1% chance of long-term right sided paralysis. These numbers cannot be very precise for individuals because every patient is so different. However, I have been fortunate to get through surgery with no neurological limitation. And many deficits from surgery can improve after the first few weeks, but the risk of long-term neurological deficit is real. The recovery in an uncomplicated resection can largely occur at home after 1 – 3 nights in the hospital.

I had an awake craniotomy. Basically, a part of the skull is removed so the surgeon has access to the brain. Depending on health status, location, urgency, the surgery will either be awake or under general anesthesia, with or without imaging while in the operating room.

The patient or family will likely get a preliminary pathology report right after surgery. The first objective is to heal. First line chemotherapy and radiation are usually delayed 3 – 6 weeks after resection to allow for healing.

Some patients are able to be discharged 1 – 3 days after surgery if all goes well. It sounds crazy. My biggest symptom was fatigue and poor sleep. I couldn’t sleep for more than 1 – 2 hours contiguously for a 1 – 2 weeks (this may have been the steroids, too). Depending on the location of the tumor, and what needed to be compromised resecting it, symptoms vary. However, I steadily improved over a few weeks. After my staples were removed, I even started swimming 1 month after surgery. I was already doing light exercise and observing a 10 lb weight limit mostly. I think this activity really helped mitigate symptoms of fatigue and depression and regulate sleep.

Glioblastoma Multiforme
There are a diverse group of brain tumors, and range from benign to malignant. I am going to focus on the most common malignant form, a glioblastoma. We try to categorize these into groups that make sense, and the most recent World Health Organization places these as a type of Astrocytic tumor, grade 4. That’s what I have. That’s the experience I can speak of. Grades 3 and 4 are considered aggressive brain cancers based on how they behave clinically and appear under the microscope (rapidly dividing). Types 3 and 4 are generally treated with maximal resection followed by radiation and chemotherapy.

There are a host of genetic markers that can affect prognosis, but the most commonly checked for is MGMT status. If you are MGMT positive, generally you have a better prognosis. This can only be determined after the biopsy or resection, and it may take a few weeks. It is not everything: age, location, size, other unknown factors play just as big of role. About 30% of patients are MGMT positive. I am MGMT negative. This is rarely an inheritable disease, however, and other genetic markers do not carry the prognostic weight of MGMT at this time. It is very unlikely that your family is at elevated risk for this brain cancer or other tumors by your diagnosis (a relief for me with 4 kids).

First Line Radiation and Chemotherapy
About 3 – 6 weeks after resection of a glioblastoma, the patient will start radiation and chemotherapy. The radiation is once daily for 6 weeks for a total of 30 sessions. It takes longer to drive to radiation than actually receive it. I had some fatigue with radiation, but otherwise tolerated it well. Patients get patchy hair loss a few weeks into radiation which may or may not return. For me, it just made sense to shave it all 3 weeks in since the ‘patchy’ was a large bald spot.

During radiation, you may consider taking memantine (Namenda). This is a Alzheimer’s / vascular dementia drug that has shown some activity in preserving cognitive function. In one randomized trial for patient’s with metastatic brain lesions receiving whole brain radiation, it did not significantly improve memory at 1 year, but other cognitive functions where better preserved in the memantine group vs. placebo. Radiation for GBM is generally not whole brain, but it is quite a bit. I took memantine since there was little to lose, no side effects were reported in the trial, it is generic now, but most of my doctors just sort of shrugged like I was taking a vitamin. You can ask your neurooncologist or radiation oncologist if memantine is right for you :). Who knows if it is helping me.

The current first line chemotherapy is temozolomide (Temodar), which is a pill taken daily during the 6 weeks of radiation (plus the weekends). The chemotherapy can cause nausea, but I found it relatively easy to tolerate at this low dose with ondansetron (Zofran). Bone marrow suppression is another possibility leading to low blood counts, and you will get weeks blood counts. After radiation is completed, temozolomide is continued as pulse therapy. This is generally a 28 day cycle where you take the pill for 5 days in a row with a 23 day break. Most use this for 6 months, although some for up to a year. This may or may not be the standard of care in a couple years as we start the immunotherapy era and more targeted therapies (ie, temozolomide only for those likely to respond).

The goal for GBM therapy is for a prolonged a maintenance phase. No therapy has been shown to convincingly eradicate GBM permanently, but the combination of surgery, radiation, chemotherapy and now immunotherapy hopefully will prolong survival in a disease that is due for a few breakthroughs.

GBM is monitored by regular clinical assessments and head MRIs every 2 – 3 months.

Somewhere between standard of care and research lies Optune. This is electrical field therapy that has been shown to prolong survival in GBM patients initially and for recurrence.  The benefit is somewhat controversial, and based on only a couple of studies.  The therapy is pretty intensive since you need electrodes on your head for 18 hours per day, and carry a backpack.

The most promising areas of research for GBM in 2016 are a class of treatments called immunotherapy. This is a strategy that employs your immune system to attack cancer like the ‘foreign’ cells they are. The trials can be challenging to get in to due to rigorous inclusion and exclusion criteria and practical limitations set by geography (Mayo Clinic is not in your town). However, there are institutional and national trials to consider.

The attempts at using the immune system have employed various strategies in GBM. Vaccines have been created using a patient’s own brain cancer cells or targeting a specific marker. This helps assist the immune system in recognizing the tumor as foreign. Besides effectiveness, the main limitation of an individualized vaccine is the time and labor intensity for individualized vaccines. At Duke, they have a phase 1 trial that made the news last year with injecting modified polio virus into areas of recurrent glioblastoma multiforme. With a small surgery, polio is actually injected into your head. The polio attacks the malignant brain cells, and creates an inflammatory response activating the immune system. This is very early in development, but made a splash after a 60 Minutes ran a feature on it.

Finally, there are a class of drugs that more directly affect check points in the immune system. For GBM, these most prominently include pembrolizumab (Keytruda) or nivolumab (Opdivo). These have been game changers for melanoma, and are currently being studied in almost every type of cancer. If you believe the hype, these were compared to the introduction of penicillin the in 1940s on the Diane Rehm show recently.

I am in a trial of pembrolizumab at Northwestern University. This is an every 3 week infusion for up to two years, depending on my own clinical course.  It is phase 1, so the point is to assess safety in a small number of subjects, not measure effectiveness against GBM. Because it is phase 1, everybody is getting therapy. Effectiveness can only be measured in phase 2 / 3 trials. There are phase 3 trials where the patient would either get placebo or drug, but not know which one (nor would the provider, hence ‘double blind trial’). This is truly altruistic of the patient, but very important to determine effectiveness. Just because I do well (or not do well) with pembro , it would not be clear if it was the pembro, or other patient factors.

The side effects from these latest immune therapies are primarily from over stimulating the immune system leading to auto-immune diseases. Basically, your immune system can start to attack normal tissue, and can lead to hepatitis, thyroiditis, or pneumonitis (-itis suffix means inflammation). These are relatively rare for the two therapies currently used for GBM, and I haven’t noticed any symptoms. The temozolimide pulses can make me feel uneasy, but I haven’t felt anything from ‘vitamin P.’

The dreaded recurrence. This is what chemotherapy and radiation are trying to delay. Options at this point include repeat resection, repeat radiation, and second line chemotherapy, depending on clinical status. This is also a time to consider a clinical trial since 80% of clinical trials for GBM are in the setting of recurrence. Sometimes, medications are given before FDA approval by compassionate use from the drug company if there is any hint it may be helpful, and this has been done on occasional with some of the newer immunotherapy medications.

Palliative Care / Hospice
At some point, further active treatment does not make sense. This is true for everybody and every condition, not just GBM or cancer in general. It is a difficult conversation for doctors to have with patients, and it is difficult for patients to think about. At some point, the effects of further treatment are actually detrimental to patients, and survival could even be longer with palliative care and Hospice (as counterintuitive as that sounds).  So much more should be said about this topic, but I am running out of time and space.

Okay, that was a lot for one blog.  And no pictures, no kids, and no Staci.  Here are a few pics from the previous week:

Figure: Left 2, Mia and I hanging out around town.  Note the hair growth.  Middle right, okay with a slow jog during my temozolomide pulse.  Right, Allison complained about a sore wrist, so we ran Friday night instead of swim practice.  Magically, her wrist was better the next day.