The Mind-Body Connection

Google "mind-body connection" and you'll get more than 4.7 million hits covering everything from affective response to yoga. Too funky a reference, try "integrative medicine," or"psychoneuroimmunology."

Belief that the mind contributes to illness and wellness has existed least as long as there has been recorded history. "Writing near the time of the birth of Christ, the Stoic Lucius Seneca allowed that "it is part of the cure to wish to be cured." (Felten)

In 1981, neurobiologist David Felten and researchers at the Indiana University School of Medicine "...discovered a hard-wire connection between the human body's immune system and the central nervous system under control of the brain." (Felten). This finding gave substance to earlier research at the Rochester University Medical Center by pychologist Prof. Robert Ader (1974) who in rat studies, demonstrated the capacity of the rat-brain to shut down the immune system.

More than twenty years later there is still resistance from the traditional medical community to so-called "alternative medicine" based on the mind-body connection. The general response seems to be, "I doubt that it will help, but it probably won't hurt you either, so go ahead if you think it will help."

There is an interesting twist, probably unintended, within that comment. According to proponents of alternative medicine involving the mind-body connection, "...if you think it will help" is precisely when it will help. The opposite is true too, if you think it won't help, it won't. This is essentially the same premise on which Viktor Frankl's theory described in his Man's Search for Meaning (1956), is based, as well as the many books about the importance of "hope" for surviving cancer (see "books" sidebar).

In 2007, during my 50th University of Pennsylvania undergraduate reunion, I attended one of many seminars offered to alums. This one was at the Medical School, home of the Abramson Family Cancer Research Institute. During the presentation on new trends in cancer treatment, the following "story" was told;

The patient, an older man, was in the final stages of cancer, within days, weeks at most, of dying. The doctors didn't want to admit him to a clinical trail that had received very favorable initial reports, but the patient and his family insisted until finally he was admitted. Within days, his tumors began to shrink, and within months there was no evident disease. Shortly, thereafter, a more detailed research study of the drug effects was published showing the initial optimism was not justified and the new drug was no better than the standard treatment. After being made aware of the new data, the patient's tumors returned within days and the patient died with a few weeks.

Apocryphal? Possibly, even probably, but not uncommon of the kind of anecdotal evidence widely available and used to justify further research and to support a variety of mind-body practices.

Next post: Self-healing through Guided Imagery

Beer and Pizza?

I workout three times a week. Here I am this morning grinding away on the elliptical and watching CNN on the TV to help pass the time. A medical segment comes on - "The Beer and Pizza Diet - a Cancer Cure" turns out it really isn't, but the segment is about the effect of diet generally on cancer prevention. View it at CNN.com (sorry about the commercial lead-in).

Coincidentally, I was planning my next posts on so-called "alternative therapies," so I'll begin with food. First off, there are no magic silver bullets, but there are some very interesting avenues for exploration. One is the effects of food as a form of chemotherapy; another is food and the mind-body connection - food today, mind-body tomorrow.

All foods consist of chemical components which are absorbed into the body with beneficial or detrimental effects. Green leaf vegetables like spinach, kale, and broccoli, root vegetables such as carrots, and fruits, notably blue berries, are associated with positive effects. High fat foods, red meat, and fried foods are associated with negative effects.

Generally, the positive effects work through supporting one or more essential bodily functions, notably, the immune system. As I learned from posting about immunotherapy, the immune system and its ability to generate T-cells is critical to the bodies defenses against cancer. It may play a less significant role than was once thought, but with costimulation or inhibition the performance of the immune system can be significantly improved. The bottom line, give your immune system all the support you can by eating healthily.

Conversely, combinations of foods consumed in quantities which lead to obesity are bad. When I was (much) younger and competing at an international level, I consumed 6,000 to 8,000 calories a day and had trouble keeping my weight up to 175 lbs. Within three months of retiring from competition, I was eating less than 2,500 calories a day and still ballooned to 220 pounds.

At the time I retired from work the first time in 2000, I weighed 195 and was leading an active life skiing in the winter and working outdoors in the summer. I decided to go to my high school 50th reunion in 2003; coincidentally, the year I first learned that I had melanoma. I decided that I would make the effort to get down to my high school graduation weight, 185 lbs - ah, vanity. It took about six months, but I did it.

When I learned I had melanoma, one of the first treatments I considered was chemotherapy that involved a toxic cocktail the side effects of which were so devastating and the reward so small, that I did not choose it. The experience did, however, convince me this was going to be a physical fight, so I'd better get into the best shape possible. Six years later, my weight is stable at 185, I've lost 4" around my waist, and I'm hitting my drives 15-20 yards farther - good stuff. The melanoma has spread, but I still feel healthy and mentally prepared for whatever the next treatment brings.

Next post: the mind-body connection.

My Treatments

I've posted about the chemicals and vaccines. Now it's time to put the information to use to clarify my treatment options that I posted on August 13, 2009.

Option 1: Gleevec (Imatinib Mesylate). This drug is a protein-kinase inhibitor, specifically tyrosine kinase. It has been FDA-approved previously for the treatment of chronic myeloid leukemia (CML). It specifically targets an enzyme that allows the growth of cancer cells. This drug has been shown to significantly reduce the number of CML cells in treated patients within one to three months. The purpose of this trial is to determine how effective Gleevec is for melanoma that has spread from the skin to other parts of the body. The spread of melanoma cells is facilitated by the protein C-KIT, which is expressed as the result of a genetic defect in the tumor cells.

Gleevec is thought to bind to these defective cells and stop the spread of cancer. Side effects include fluid retention and edema, rashes, nausea and vomiting, diarrhea, heartburn, and headache. More serious side effects, which occur less frequently, include liver toxicity and internal bleeding.
This trial is available in Boston or Chapel Hill, NC. About one person in five whose melanoma began on the skin (as mine did)is expected to manifest the C-KIT mutation. My tumor tissues have been sent to a lab to determine if I have the C-KIT mutation present. If not, I'll proceed to Option 2.

Option 2: Temodar + ABT-888. Temodar (temozolomide) is classed as a lipid-soluble alkylating agent which crosses the blood-brain barrier, and has been used previously for treating certain brain tumors. ABT-888 is a PARP (Poly ADT-ribose polymerase) inhibitor. The PARP enzyme is active in cell growth and repair. Blocking PARP, may prevent the cancer cell from growing or repairing itself. Using the two in combination may make Temodar more effective.

This is a randomized, double-blind study with three arms, two of which use both agents in different dosages; the third (control) arm uses Temodar alone. Possible side effects include low platelet count increasing the possibility of bleeding, fatigue, constipation, nausea, diarrhea, vomiting, anorexia, and headaches.

This option is available in Charlotte, NC.

Option 3: Biovex. The lead product of Biovex Inc., now a part of Triathlon Medical Ventures, is OncoVEX, a manufactured, virus-containing vaccine to “carefully pollute cancer cells” while leaving other cells unaffected. The virus appears to be able to affect melanoma cells even after metastasis has begun. The assumption is that the cell pollution will lead to apoptosis or senescence.

The chief drawback of this trial is the there most be one or more tumors on or sufficiently near the skin surface for periodic biopsies to track the vaccine effect, a condition which I do not have at the moment. Side effects are unknown at this point. This treatment would be available in Chapel Hill.

Option 4: Avastin + Ipilimumab. Avastin (bevacizumab) is a monoclonal antibody produced in a laboratory and used in the treatment of colorectal cancers. It is classed as an Angiogenesis inhibitor. Avastin functions by blocking the action of the VEGF protein (vascular endothelial growth factor) which stimulates the growth of new blood vessels (angiogenesis); therby, denying new blood needed for tumor growth.

Avastin side effects include increased blood pressure, fatigue, muscle weakness, blood clots in veins, diarrhea, nausea, loss of appetite, low white cell count, headache, nosebleeds, and pain at the tumor site. More serious, less frequent effects include perforations, inability of wounds to heal, internal bleeding especially in patients with lung cancer, bleeding in the brain resulting in strokes, blood clots in arteries, uncontrolled high blood pressure, and kidney damage.

Ipilimumab is a human monoclonal antibody that binds to to a molecule on T cells (CTLA-4)that plays an important role in activating and regulation the immune system. Ipilimumab blocks CTLA-4 function, which otherwise suppresses the immune system. Maintaining an active immune system should make the Avastin treatment more effective and less debilitating.

In prior trial uses Of Ipilimumab, there has been about a 2% fatality rate and 20% auto-immune response. This trial is currently not recruiting, but might be available again in Boston in November.

Option 5: Temodar (temozolomide). This is currently the standard treatment for metastatic melanoma. Its function and effect would be the same as Arm 3 of Option 2 above.

This creates a quandary for me. If I chose Option 2, there is one chance in three of getting the same treatment as Option 5. The only differences are that I will have to go the Charlotte rather than Chapel Hill and participate in a significant number of procedures (exams, scans, blood tests) the only purpose of which would be to maintain the integrity of the double blind research design.

This point is irrelevant if my tumor profile shows the C-KIT mutation needed for participation in Option 1, so I’m holding my breath for another few days to get the answer.

Immunotherapy

Is Vaccination against Cancer the Answer?

Initially considered a part of chemotherapy, cancer immunotherapy is evolving into its own class of treatments. The basic purpose is to stimulate a person’s immune system to build up its defenses against cancer to prevent its spread and eventually eliminate cancerous cells. The process, which most of us have experienced in childhood, is vaccination with a laboratory-manufactured antigen (vaccine) which stimulates the creation of disease fighting antibodies. Cancer vaccines can be made from the patient’s own tumor antigens or cells (autologous vaccine) or from someone else’s (allogeneic vaccine).

The elements of the immune system are your body’s soldiers. Dendritic cells act as scouts seeking out infections or diseases. When found the scouts capture data about the foreign cells and instruct the killer T-cells to attack and destroy it. The problem is that our “armies” are under-staffed, so the number of killer T-cells programmed to attack the tumor are insufficient to overwhelm it, unless the immune system can be stimulated to attack more aggressively (co-stimulation). The objective of immunotherapy is to get the immune system to direct a greater percentage of its killer T-cell army against the patient’s tumor to increase the probability of victory. Hoooah!

All T cells derive from haematopoietic stem cells in the bone marrow.

There are several types of T cells, each with its own function:

(1) Cytotoxic T cells (Tc), also know as C8+ T cells, destroy viral infections and tumor cells and are instrumental in transplant rejections.

(2) Helper T cells (Th) when activated divide rapidly and secrete small proteins (cytokines) that help the immune response. These cells are also the target of HIV infection.

(3) Regulatory T cells (Treg) act to shut down T cell mediated immunity toward the end of an immune reaction to prevent a body-damaging autoimmune response. Treg cells can be distinguished from other T cells by the presence of a FOCP3 intercellular molecule. Mutations of FOXP3 can prevent Treg development leading to a fatal autoimmune response.

(4)Natural Killer T cells (NKT) are lymphocytes that link the adaptive immune system with the innate immune system. Once activated these cells can perform the functions of Cytotoxic and Helper T cells, the release of cell killing molecules and cytokine production.

T cell Development and Activation

All T cells derive from haematopoietic stem cells in the bone marrow. The activation process begins with the release of hematopoietic (blood forming)progenitor stem cells populate the thymus and expand by cell division to create immature thymocytes - a lymphocyte that develops in the thymus and is the precursor of a T cell.

The thymocytes pass through a multi-stage process and emerge from the thymus into the surround tissue as immunocompetant T cells. Only 2% of thymocytes complete the process. The surviving cells are then activated through interaction with certain pre-existing antigen complexes or by molecular co-stimulation with antigen-presenting cells (APCs).

Certain cancer vaccines have added ingredients (adjuvents) that increases the antigenic response. Adjuvents include things like cytokines, proteins, bacteria, viruses, and chemicals. There have been promising results from studies in which vaccine has been used before or after treatment by other Cytotoxic treatments, as well as, vaccine alone.

Some vaccines, such as Ipilimumab, using monoclonal antibodies, identifiable by drug names ending in –mab, have shown promising results for some cancers, including melanoma.

The first vaccine approved in 1981 for cancer prevention protects against HBV infection (hepatitis B). Most children are vaccinated against HBV infection shortly after birth. In 2006 and 2008, Gardasil was approved for prevention of cervical cancer caused by human papillomavirus (HPV) types 6, 11, 16, and 18. Types 6 and 11 cause about 90% of genital warts; 16 and 18 cause about 70% of cervical cancers.

At this point, there are no other vaccines approved as mainline cancer treatments. There are many vaccines being tested in clinical trials, forty-five listed for melanoma. Here’s a typical example:

Vaccine Therapy in Treating Patients With Recurrent Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

Alternate Title: Pilot Study of a Peptide Vaccine Comprising MART-1:27-35 Peptide, gp100:209-217 (210M) Peptide, and Tyrosinase Peptide With Sargramostim (GM-CSF) and CpG 7909 Emulsified in Incomplete Freund's Adjuvant in Patients With Unresectable Recurrent Stage III or IV Melanoma.

Purpose: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy together with GM-CSF, CpG 7909, and incomplete Freund's adjuvant may make a stronger immune response and kill more tumor cells. This clinical trial is studying the side effects and how well vaccine therapy works in treating patients with recurrent stage III or stage IV melanoma that cannot be removed by surgery.

More information about vaccines and clinical trials can be found at cancer.gov.

So, forget all the mumbo jumbo, forget about looking for a quick fix, and support stem cell research. When the breakthrough in cancer treatment comes it will be huge and vaccines will be an important element.

Chemotherapy - Drug Classification II

Mechanisms of Action

A second method of classification involves grouping by the mechanism of action – how the drug of choice works. The two main ways in which anti-cancer drugs work is through inhibition or disruption of normal DNA functions.

Angiogenesis Inhibitors

Cancer tumor cells require additional blood supply. Angiogenesis is the process by which cancer cells form new blood vessels to support tumor growth. These blood vessels also facilitate the spread of cancer cells (metastases). Inhibiting angiogenesis “starves” the tumor cells leading apoptosis or senescence and may limits the spread of cancer cells to surrounding areas. Thalidomide, associated with severe birth defects, is now being considered for anti-cancer use because of its angiogenesis inhibiting properties. Other drugs used include Endostatin, Fumagillin, Genestein, and Monocycline, etc.

DNA Intercalators/Cross-linkers

Intercalation refers to the act of inserting a DNA altering substance. Cross-linking involves building a connection (link) between gene strands. Either process is intended to alter the DNA structure of a tumor cell to disrupt its function. Carboplatin and Oxyplatin form cytotoxic adducts with DNA and induces apoptosis. Bleomycin inhibits DNA synthesis, induces breaks in base DNA sequences, and inhibits tumor angiogenesis. Other drugs in this group include Carmustine, Chlorambucil, and Cyclophosphamide.

DNA Synthesis Inhibitors

Synthesis is the process by which cancer cells split and proliferate. Synthesis inhibitors, as the name suggests, are more active in the S phase of the cell cycle. These drugs bind to specific DNA types to block production of enzymes needed for cell synthesis. For example, Menthtrexate and Aminopterin are folic acid antagonists which block thymidine biosynthesis by which cells in S phase are synchronized. Other drugs in this class work similarly to inhibit production different enzymes also affecting synthesis.

DNA-RNA Transcription Regulators

During cell synthesis, the cell’s DNA template synthesizes messenger RNA to carry genetic information from the DNA molecule to new cells. This process is called transcription, a necessary function for cell replacement. Unfortunately, it works as well for tumor cells as it does for normal cells. DNA-RNA Transcription regulators attempt to block synthesis and or induce apoptosis in cancer cells by inhibiting or reversing production of RNA components. For example, Actinomycin D works by inhibiting cell proliferation and blocking production of mRNA by RNA polymerase to induce apoptosis.

Enzyme Inhibitors

Molecules that bind to enzymes and decrease their activity are called enzyme inhibitors. The following picture shows a representation of HIV protesase enzyme as red, blue and yellow ribbons with the bound protease inhibitor ritonavir as a stick-and-ball model in the center.


Different drugs bind to different enzymes to increase the specificity of drug choice. Enzyme inhibitor binding is either reversible or irreversible. Irreversible inhibitors change the chemical composition of the enzyme. Reversible inhibitors produce different types of inhibition depending upon whether it binds with the enzyme, the enzyme sub-strate complex, or both. In either case, the purpose is interrupt the enzyme activity resulting in apoptosis and/or interruption of synthesis and transcription.

Gene Regulation (therapeutic gene modulation)

This class of drugs alters the expression transcription, translation, and phenotypic manifestation) of a gene at one of the various stages. Most clinical research seems to be in the area of translation through RNA interference. Examples include Melatonin which inhibits proliferation of breast cancer cells by inhibiting estrogen receptor action and Tamoxifen, a selective estrogen response modifier used with estrogen-sensitive tumors.

Microtubule Inhibitors

Microtubules are cylindrical, hollow structures that support cell structure and facilitate cellular movement and transport. Tubulin, a globular protein, is the basic structural constituent of microtubules. Most drugs in this class function by binding to tubulin or β-tubulin to induce apoptosis or prevent cell division. Paclitaxel and Navelbine are two examples.

New drugs are appearing almost weekly, many with unique functions that do not easily fall into on of these classes.

For more information about specific drugs, visit Chemocare.com

Chemotherapy - Drug Classification I

Drugs used for chemotherapy can be classified in several ways. From my perspective, the two most useful ways are: (1) Chemical basis; and (2) Mechanism of Action. In the post, I’ll discuss the former in this post; subsequently, the latter.

There are seven major classes of chemotherapy drugs, two of which are most active during the M phase of the cell cycle. For each, I will summarize the chemical source and main side effects. For additional information on this topic, select the link for each class. A more detailed version from which this post is abstracted can be found here.

1. Alkylating Agents

The oldest class of anticancer drugs is nitrogen mustards originally developed for military uses (poison gas). They bind to the negatively charged oxygen, nitrogen, phosphorus and sulfur atoms in DNA. By doing so, cellular activity is stopped and the cell will die. Alkylating agents are effective at all stages of the cell cycle and are used for most types of cancer. All alkylating agents can cause secondary cancers, the most common of which is Acute Myeloid Leukemia, even long after treatment is completed.

2. Antimetabolites

Based on work with folic acid by Dr. Sydney Farber in 1948, antimetabolites are synthesized to target naturally occurring compounds or key enzyme reactions during metabolism. Nearly all antimetabolites interrupt metabolic pathways, including those necessary for DNA formation. Antimetabolites are most effective during the S phase when DNA formation is most active. Patients with certain natural enzyme deficiencies may suffer severe toxicities when treated with antimetabolites which target enzyme reactions.

3. Anthracyclines

Anthracyclines are derived from naturally occurring sources (fungi). They work through the formation of free oxygen radicals, which cause DNA strand breaks and enzyme (topoisomerase) action, both of which inhibit DNA formation, replication, and transcription. They are not cell cycle specific agents. Since the free radicals created also attack the heart muscle, cardiac toxicity is a major concern.

4. Antibiotics

Everybody has probably used an antibiotic, such as streptomycin or neomycin. Guess what, bleomycin is a small peptide synthesized from Streptomyces verticullus fungus and is used in chemotherapy. It action is similar to that of the Anthracyclines – free oxygen radical formation. It is an active agent used in testicular cancer and Hodgkin’s lymphoma. Lung toxicity due to free radicals is of greatest concern.

5. Camptothecins

The enzyme Topoisomerase is required for ongoing DNA formation (cf Anthracyclines). Camptothecins act by forming a complex with topoisomerase and DNA which disrupts mitosis in the M phase of the cell cycle. They are synthesized from a naturally occurring alkoloid found in plants such as the Chinese Happy Tree, Camptotheca acuminata. Other chemotherapeutics, although not classed as Camptothecins, are derived from the mandrake plant and Vinca rosea (periwinkle) and function similarly. The main toxic side effect is neurotoxicity (nerve damage, loss of feeling).

6. Taxanes

Taxanes such as paclitaxel and docetaxel were first derived from the bark if the Pacific yew tree, Taxus brevifolia . Paclitaxel was identified as the active component in 1971. Taxanes are M phase specific agents. They bind to the microtubules, which support DNA movement during cell division (mitosis), where disrupt the microtubule function. The most common side effect is anemia.

7. Platinums

Metal derivatives used in the treatment of cancer create cross-links between two DNA strands or within one strand which inhibit DNA synthesis, transcription, and function in any cell cycle phase. Cisplatin, used in lung and testicular cancer, is a first generation platinum derivative significant kidney toxicity. Carboplatin, a second generation derivative, has less effect on the kidneys. Oxaliplatic, a third generation derivative, has not kidney toxicity, but may result in nerve damage (neuropathies).

The long a short of it is that all these chemotherapeutics function by inhibiting normal DNA function leading to suspension of cellular activity (senescence) or cell death - apoptosis or necrosis. The former is “normal” cell death by which cells commit “suicide” when they are no longer useful and are absorbed into surrounding tissue or shed, Cancer cells do not do this and will continue to multiply unless apoptosis can be induced by use of chemotherapeutics or other treatments. The latter, necrosis, is cell death from injury, disease or other pathologic state, including some chemotherapies. Necrotic cells do not send the same signals to the immune system as do apoptotic cells, so they are not removed from the body by a natural process, which leads to a build up of dead tissue and cell debris – not a happy prospect.

Chemotherapy – Targeting

In my most recent (I don’t use “last” anymore) post, I mentioned the 4-phase cell cycle and suggested that tumor cells are most sensitive to chemotherapy in the G1 and M phases. Sounds like a logical approach to targeted treatment would include identifying the cell state and treating it when it is most sensitive. Logical, but unfortunately not practical, as cells don’t cycle through their phases in lockstep and the time span of each cycle will vary and be too short to be useful.

So what can be done to improve targeting? Virtually all of the newest research is focusing on DNA/RNA for the answer. Preliminary results suggest that the genetic structure of a person’s cells, especially tumor cells, can provide valuable information about how to attack cancer for a specific individual, as well, more general approaches.

Targeted therapies, which include cell growth inhibitors and immunotherapy, are emerging as a fourth approach, different from chemotherapy. A distinction being made is that traditional chemo- is a “chemical approach to a biological program,” where as targeted therapies can be characterized as a “biological approach to a chemical problem,”

Although there is a growing belief that traditional chemo is more limited in what can be achieved than targeted therapies, there are still benefits to be gained from genetic research, especially in choosing the most appropriate chemical approach and avoiding more harmful ones. It is likely, therefore, that genetic profiling will become one of the baseline tests for cancer treatment. Lobby you insurer and Congress folk to make sure it is covered by private insurance, Medicare, and Medicaid – it’s not cheap yet.

Truth in advertising – genetic profiling is a powerful tool in the fight against cancer. Unfortunately, in order to be most useful, tumor cells must be present and accessible. For example, when I had my first episode of a very small tumor in my lung, it was removed surgically. At that point, I was “NED” – no evident disease. Shortly thereafter a promising clinical trial opened up, but I was ineligible because you must have detectable, observable tumors so the clinician-researchers can determine the effect of the treatment being tested. For a melanoma patient, this is particularly frustrating, because you know the mutated cells are there, they’re just too small to be detected.

Again, within the last month, a new trial for an immunotherapy agent was announced. This time, with tumor aplenty, I am still ineligible because the lesion must be on the skin or sufficiently close under the skin so it can be accessed physically and fairly frequently. Mine are out of reach without significant surgical damage – ineligible.

In my next post, I will have more to say about traditional chemical approaches and how it is being modified by new knowledge.

Pip pip – stiff upper lip.

Chemotherapy – Introduction

The object of chemotherapy, as is true of all cancer therapies, is to kill cancerous cells without doing significant damage to normal cells in the surrounding tissue. As discussed in earlier posts, radiation therapy attempts to do this with targeted beams of energy radiation (cf my May 22, 2009 post). Surgery physically removes cancerous cells, whenever possible using minimally invasive procedures, such as video assisted thoracic surgery (VATS).

At its most basic level, all cancer is dysfunctional cellular mutation; that is, cell mutation which produces negative consequences. Until relatively recently, chemotherapy has been limited to the use of drugs which do not discriminate well between cancerous and non-cancerous cells. The results from the Human Genome Project are now contributing to the development of more targeted approaches for chemotherapy, allowing potential intervention at the sub-cellular level (DNA/RNA) to inhibit further mutation or induce cell death in cancerous cells by interrupting its growth cycle.

All cells go through four phases, referred to as the “cell cycle,” G1, S, G2, and M. G1 is most active in protein synthesis, during which few chemotherapy agents are effective. DNA replication is most active during the S phase, during which the cell is highly sensitive to some chemotherapy drugs. During G2, RNA is most active and some protein is formed. The M phase is when cell division (mitosis) occurs.

Consequently, many of the new approaches involve DNA modification of destruction. However, the human body has its own defenses against DNA damage, which work to repair damage, whether its from the cancer itself or a well-meant attempt to kill cancerous cells. The result is that, while the chemical intervention may kill the cancerous cell, it may also overwhelm the immune system, with its attendant risk of infections, or so stimulate the immune system that it produces an auto-immune response with risks, such as lupus or rheumatoid arthritis. The challenge of chemotherapy, as always, is to get the right drug, to the right cell, in the right amount, at the right time.

More about how that is happening later.

Update on My Treatment Plan

After a visit to Dana-Farber Cancer Institute in Boston earlier this month and some additional reserch, my UNC oncologist and I now have a treatment plan, with contingencies. It looks like a Imatinib Mesylate (Gleevec) clinical trial at Boston or Chapel Hill, if my tumor shows a KIT mutation; if not, a Temodar + ABT-888 trial in Charlotte, NC, or Temodar (temozolomide) alone at UNC. If that doesn't work and there is a lesion on or just below the skin, a Biovex trial. No skin lesion, an Avastin + Ipilimumab trial.

I stuck this post in here between blogging about new treatment options, so you can see that at least one person may be benefitting from the availability of research and clinical trials for melanoma and gets to feel good about contributing to the knowledge base.

Keep smilin'

Advances in Cancer Treatment

I am in awe of the changes in cancer treatment that have occurred since I was first diagnosed with prostate cancer in 1998.. At that time, I had three options: (1) Surgery (the "gold standard'); (2) radioactive seeds; and (3) watchful waiting. Now, surgery, in most cases, is the last choice.

In 2003 when I was first diagnosed with melanoma, I had four choices: (1) Surgery; (2) radiation; (3) chemotherapy; and (4) watchful waiting. Surgery meant whacking out cancerous body parts, when necessary replacing critical parts, if available.

Chemotherapy consisted of injections of various and sundry combinations of highly toxic chemicals which killed cells, both mutated and normal, with the hope that with the correct dosage, you wouldn't die from the treatment before the normal cells had time to regenerate.

Radiation was, similarly, a shotgun approach - fire a beam through the tumor to kill it and every other cell in the beam path before and after the targeted tumor.

Now, in August 2009, I still have the same four choices at the macro level: (1) Surgery; (2) radiation; (3) chemotherapy; and (4) watchful waiting, but a world of difference at the micro-level.

Surgical options now include minimally invasive procedures, for example, in 2007, when a lesion was found in my lung, I had it removed by Video Assisted Thoracic Surgery (VATS), procedure which require three 1" incisions for the insertion of a fiber optic connected video camera and two resection tools, used a bit like chopsticks, to remove the tumor. I was out of the hospital in three days and playing golf in less than 4 weeks. The surgeon had suggested a shortened back swing would probably help my golf game. In my case, the surgeon was physically present, but similar procedures, and even much more complicated ones, are now done routinely using robotic surgery during which the surgeon may be hundreds, even thousands of miles distant.

Radiation need no longer only be a through-and-through blast as from a shotgun. In my May 23 entry, I described my experience with Cyberknife, a way to deliver multiple low doses of radiation with very narrow beams intersecting at the tumor site. The dose level for each beam is so low that it is lethal to cells only at the point of intersection where all the beams, 270 in my case, converge to kill cancer cells with their cumulative effect.

If this is not enough, you can bring out the really big gun - proton beam therapy - which uses a particle accelerator, once called an "atom smasher," to fire an atomic particle (proton) at a tumor where it "explodes" releasing its energy to kill the tumor cells without affecting the surrounding tissue. Like Cyberknife, the entire process is computer-controlled and the proton delivery can be controlled in 3-D to the exact size and configuration of the targeted tumor.

Although not a treatment option, cancer care has been dramatically improved by the use of radiation for scanning for both diagnosis and during treatment to track progress. While X-rays are still used for two-dimensional imaging, computed axial tomography (CAT or CT scans), Positron emission tomography (PET scans), and magnetic resonance imaging (MRI scans) offer 3-D images in great detail. Although similar in concept, each has its strengths , and in some instances are used sequentially for greater resolution or in different areas of the body. For example, a brain scan is usually done with MRI. Scans may be done with or without "contrasts," which are injected or swallowed fluids which include a dye, radio-opaque substance, or radioactive tracer used to improve the tumor image.

I've had them all multiple times and can attest to the fact that they are not invasive or painful. Yes, there may be discomfort from lying still for 30 or 40 minutes or from an MRI's loud thumping (ask for earplugs if they are not offered), or the threat of mild claustrophobia from the tight quarters of the short tunnel through which you slide during the process. My strategy is to ask how long will the process take, figure out how many seconds it will be, close my eyes, and start counting breaths. If I don't fall asleep, which usually happens, my count never reaches the estimated number of seconds before the process ends, so the end comes as a pleasant surprise.

The advances in Chemotherapy are so numerous that they warrant a post of their own. That's next.

Access to Clinical Trials

I went up to Boston this past Monday in anticipation of a visit to the Dana-Farber Cancer Institute to see Dr. F. Stephen Hodi on Tuesday. Coincidentally, that day the New York Times, published an article by Gina Kolata, "Lack of Study Volunteers Hobbles Cancer Fight, (NYT, August 3, 2009) the gist of which was that "There are more than 6500 cancer clinical trials seeking adult patients" .... (but) ... "More than one trial in five sponsored by the National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result, ..." The entire article is worth reading.

I shared the article with a friend and cancer co-warrior. I'm repeating her response for anyone thinking about finding or struggling to get into a trial:

"Maybe they ought to make it easier to get into trials."

"It should be patient choice if you want a study drug over the "gold standard", which only has a 7% response rate and horrendous side effects. But you have to be debilitated first by the gold standard and watch your disease progress before they let you into the majority of trials."

"They need to make trials more attractive."

"A lot of new drug trials won't let you increase your dosage as new safety and efficacy info comes through. So, as in my case, women all over the world are getting twice the dosage for parp inhibitors that I get and I'm stuck at this dose because I'm in a trial)."

"They also need to make information from the trials more accessible to the patient."

(In a trial involving PARP inhibitors)..."Why shouldn't I be told if there is any PARP inhibition going on in my body. They've got my blood. They could tell me. If the drug isn't doing anything I should know early on and not wait weeks for scans to tell me my cancer is progressing."

"Right now, trials are largely for the benefit of the researchers and pharmaceuticals and patients 15-20 years down the road. They need to make trials for the people who are in them. We're already taking risks and undergoing far more exams and scans than normal."
As a statistician/researcher myself, as well as a cancer patient, I understand the basis for the tension between the need for clean research and the needs of the patient. The sicker I get the less sympathetic I am toward the research needs - no surprise there. Because of this, the European "laxity" in the limitations to drug access becomes more appealing - assuming it's not sloppiness or greed-driven - of course, I believe babies are found in a cabbage patch and there's a pot of gold at the end of the rainbow, too - Not.

What's Happening

Obviously, from the dearth of posts, not much has happened since July 5th; however, thanks to a visit to the Dana-Farber Cancer Institute, that is about to change. Rather than one big post, I'm going to do several shorter post organized by topic, most of which relate to news about clinical trials.

Keep on, keepin' on , friends!