GRACE :: Treatments & Symptom Management

Can You Get “Chemo-Brain” Without Getting Chemo?

Cognitive dysfunction among cancer survivors, particularly breast cancer survivors has received increased attention in recent years and is frequently referred to as “chemobrain” as patients view it as a side effect of their chemotherapy. This term became popular after women with breast cancer began noticing mental “fogginess”, concentration issues and memory difficulties beginning around the time they were being treated with chemotherapy. Breast cancer however is rarely treated with chemotherapy alone. As a result, chemobrain is a poor name for this issue as it is undoubtedly caused by a wide variety of factors in addition to chemotherapy including the impacts of surgery and anesthesia, menopause, hormonal therapy, fatigue, depression, and supportive care medications, to name just a few. It is likely more accurately labeled “cancer or cancer-therapy-associated cognitive dysfunction” but unfortunately that isn’t nearly as catchy of a name as chemobrain.

Typical complaints reported by patients with cancer and cognitive dysfunction include memory difficulties, difficulty concentrating on a task, difficulty remembering details such as names, dates, phone numbers, and difficulty multitasking. These complaints are associated with a measurable decline on cognitive testing. In the past, however studies have been small and they differed in their definition and measurement of cognitive dysfunction making it difficult, if not impossible to compare studies.

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The Biology of Aspirin

There is newfound excitement in the world of cancer over the role of aspirin, thanks to a recent study in the journal Lancet on the chemopreventive effects of aspirin.  This article was published on the heels of a media frenzy surrounding the invention of a new “super aspirin” called NOSH-aspirin.   Because of all the renewed interest in a century old drug, we thought it would be a good time to revisit the biology of aspirin for those of you who may be interested.  Aspirin is one member of a drug class called non-steroidal anti-inflammatory drugs, or NSAIDs.  Aspirin is primarily used as an analgesic (pain-reliever) and an anti-inflammatory drug.  The effects of aspirin in combatting pain and inflammation arise through the ability of aspirin to inhibit the formation of a molecule called prostaglandin 2, PGE2. 

PGE2 is an important signaling molecule in your body that can cause all sorts of physiological effects from muscle contraction to pain and blood clotting.  Aspirin blocks PGE2 to relieve pain and prevent inflammation by thinning your blood, among other things.  Aspirin blocks PGE2 by directly inhibiting cells from making PGE2, a function which is normally carried out by the enzyme cyclooxygenase (COX).  There are two main forms of cycooxygenase in the body, COX-1 and COX-2.  Aspirin is capable of inhibiting both COX-1 and COX-2, depending on the dose, and it can exert a great effect in cells like blood cells because platelets can’t regenerate COX once it is rendered dysfunctional by aspirin.  This is helpful for the blood thinning functions of aspirin such as preventing stroke, but this is also where the serious bleeding side effects of aspirin are derived.  Further, PGE2 has known protective effects in the gastrointestinal tract which is why many people suffer gastrointestinal irritations with frequent aspirin use.

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Hematopoiesis (Creating New Blood Cells) and Growth Factors

There are numerous types of cells that make up the bone marrow, each with their own specific function.  I’m going to focus on the three most commonly affected by chemotherapy: neutrophils (white blood cells), erythrocytes (red blood cells, measured by hemoglobin or hematocrit) and platelets (blood clotting cells).  These cells are born primarily in the bone marrow and then eventually leave the bone marrow to circulate in the peripheral blood.  When your blood is drawn in the clinic, the number that comes back reflects the number of each particular cell in the peripheral blood.  Each of these cells starts out as an immature stem cell that has the potential to be any type of blood cell.  However, what type of cell the immature cell becomes depends on the type of growth factor that acts upon it.  For example, if the body senses it needs more red blood cells, it will release more erythropoietin which will tell more of the stem cells to become erythrocytes which will mature in red blood cells.  

Growth Factor

Immature cell

Adult cell

What they do

Granuloctype colony stimulating factor(G-CSF)

Myelocyte

Leukocyte/Neutrophil (White blood cell)

Fight infection

Erythropoietin

Reticulocyte

Red blood cell

Carry oxygen

Thrombopoietin

Megakaryocyte

Platelet

Help blood clot

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Next Webinar: Let’s Talk About Pain, Nausea, and Vomiting with Dr. Harman on a Friday Afternoon!

OK, it’s not as glamorous as a new molecular marker or treatment, but topics like pain control, nausea and vomiting, depression, and fatigue are absolutely important in the lives of cancer patients and caregivers.  Dr. Stephanie Harman, faculty member at Stanford University (and GRACE), is an expert in helping people live better and more comfortably, managing the symptoms of cancer and treatment, and in our upcoming webinar with LUNGevity, she’s going to cover these important issues and ASCO’s new clinical opinion/recommendation on integrating palliative care efforts into ongoing cancer treatment.

She’ll be joining us on Friday, April 20th, at 4 PM Eastern/1 PM Pacific to cover management recommendations that people need for these very common problems, then will be open for questions from our audience that day.

As always, registration is free, and you can do that here.  In addition, we’ll have the content available in podcasts after the program, but it would be great to have you at the live program for this practical discussion of these all too frequent symptoms for cancer patients.     


Drug Development Update: MEK Inhibitors

Growth factor receptors are well-known targets for cancer drugs like Tarceva (erlotinib), Tykerb (lapatinib), and Avastin (bevacizumab), among others.  These receptors activate cell growth by initiating a chain of events that results in progression of the cell cycle which leads to cell division.  You have probably heard about the growth factor receptors EGFR, HER2, and perhaps VEGFR.  One of the limitations of targeting these receptors is that many of them share the same intracellular pathway to activate cell growth.  When just one growth factor receptor is inhibited with a targeted therapy, other receptors can still activate the same downstream growth pathway.

To combat this, scientists are currently developing drugs that target these growth pathways further downstream than the growth factor receptors.  The most common signaling cascade for cancer cell growth involves growth factor receptors activating a protein called Ras, which then activates Raf, which then activates MAPK/ERK kinase (MEK), which then activates ERK.  ERK then directly activates proteins called transcription factors (namely Myc, Elk1, Fos, and Ets) that bind to DNA and tell the cell to make proteins from certain genes that drive cell division forward, such as Cyclin D.  ERK also indirectly activates proteins called RSK that speed up the protein-making machinery inside a cell, allowing the cell division to move ever faster. 

from Pratilas C A , Solit D B Clin Cancer Res 2010;16:3329-3334

  (click to enlarge)

Because this Ras/Raf/MEK/ERK pathway can be activated by multiple growth factor receptors, promising emerging targets in the treatment of cancer are the MEK proteins.    Since many growth signals converge ultimately with the activation of ERK, deactivating MEK should stop ERK from functioning in the cell.  Unfortunately, two of the first MEK inhibitors were discontinued after disappointing phase II clinical trials.  This was most likely due to problems with the specific drug design, however, and newer second-generation MEK inhibitors such as selumetinib demonstrate much better pharmacokinetics.

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Cancer Drug Shortages: Why, and What Can Be Done?

It seems as if every day brings a new shortage of an essential drug. In recent years, drug shortages have become increasingly common and put patients at risk as there are often no good alternatives to the affected drug. Oncology patients have been particularly impacted by these shortages as most chemotherapy agents as well as many supportive oncology drugs are injectable drugs which have been hardest hit. In 2010, for example, of the 178 drug shortages reported to the FDA, three quarters were injectable drugs.

So who or what is to blame?  Well, unfortunately there is no single cause that can be easily addressed and the issue is not likely to go away in the near future. Multiple issues have been raised by health-care experts as contributing to the problem. One issue is recent consolidation within the pharmaceutical industry resulting in a situation in which most injectable drugs have a single manufacturer producing the overwhelming majority of the drug.  With fewer “back-up” manufacturers, there is little ability to compensate for a production problem at any individual site. And most of the recent oncology drug shortages have been the result of quality-assurance and manufacturing issues.

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Catching Your Breath

Shortness of breath, air hunger, breathlessness, or the medical term dyspnea—all terms trying to capture one of the most unsettling feelings that a person can have.  That feeling that you are under water and need a snorkel.  The sensation of tightness in the chest and anxiety all wrapped up together.  That feeling of being “too aware” of your own breathing.  Dyspnea is the medical term for this symptom, and for simplicity’s sake, I will use that word to encompass all the different terms.  For patients with cancer, this symptom occurs commonly but is difficult to treat and has gotten far too little attention than cancer-related pain.  It has been estimated to occur in 80% of patients who have an advanced cancer and in up to 20% of all cancer patients regardless of the stage of their disease. 

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Why Not Palliative Care? Some thoughts on resistance…

I consider GRACErs a very enlightened bunch regarding of palliative care, but outside of GRACE, there remains a lot of resistance to palliative care amongst patients, families, and oncologists (medical, surgical, radiation). Why? Why do people resist even the discussion of palliative care, even in the absence of end-of-life issues?

Before I launch into further comments, a brief disclaimer: not all of this is evidence-based, but based on experience and what patients tell me when I ask them. I will also say that there are two major areas to discuss here-palliative care as a new specialty, and the difficult conversations we face when things don’t go as we wish.

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The Black Box: Early Palliative Care in Metastatic NSCLC

In 2010, the world of lung cancer, and cancer in general, was abuzz with an intervention that improved quality of life and mood, and extended survival in patients with metastatic NSCLC. It was not a new chemotherapy or molecular biological agent. It was “early palliative care.” The original New England Journal of Medicine article several months ago were covered by both Dr. West (here) and Dr. Ramchandran (here). A group from Massachusetts General Hospital (Harvard system), led by Jennifer Temel, conducted the study.

What exactly is “early palliative care”? What exactly was happening in those visits? Could it be replicated? I’m a palliative care doctor, and I’ve been trying to figure this out myself.

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Q&A Session with Dr. Mario Lacouture on Dermatologic Problems with Cancer Therapies

Following Dr. Lacouture’s presentation on management of skin, hair, and nail side effects of cancer treatments, we had a Q&A session from the audience. This covered a lot of ground on a range of practical questions. Here’s the audio podcast from that program, along with the transcript:

qa-dr-lacouture-on-skin-hair-nail-side-effects-of-treatment-transcript

This was really all audio without associated slides, so no figures or video version for this one.

Thanks again to LUNGevity Foundation for their partnership with GRACE in this program and the podcast. I hope it’s helpful.

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