Paclitaxel and other taxanes

Whereas most chemotherapeutic agents attack the DNA of cancer cells, by disrupting their replication or perhaps inducing breaks in the helix, paclitaxel (or taxol as it is commonly known) instead attacks the "microtubules" of cells. What is a microtubule? In general, when cells are dividing into two pieces, the DNA must be synthesized (for the new cell) and then distributed into the two dividing sides. How does the cell put a copy into the new cell, while leaving one in the old cell?

The science is more complicated than that. When DNA is made prior to division, an entire new copy is made by breaking apart the helix, and using each half as a template to generate two helices. Each DNA helix is now a composite of an old half and a new half! These two helices are usually stuck to each other. Now that there are two DNA helices, these must be distributed properly. The way the cell does it is by throwing out protein filaments onto the DNA, latching it onto the cell membrane, and then pulling it apart as the cells split asunder. So the two DNAs are literally pulled apart. The protein filaments are the "microtubules". The name is actually amusing and reminiscent.

So what does paclitaxel (or taxol) do? It basically sticks to the building blocks of the "microtubules". These building blocks (like lego blocks) are called tubulin. Taxol uniquely sticks to tubulin, preventing it from assembling into a protein filament for the division process. Like other cytostatic drugs, taxol has a negative effect on cell division, and therefore affects the fast-dividing cancer cells, in contrast to the slow-dividing normal cells which don't feel such a strong destructive effect from taxol because they are not always in the state of division.

Chemotherapy and DNA

A large number of adjuvant chemotherapy drugs are also DNA damaging agents. When the drug is transported across the cell barrier, it interacts either directly with DNA (cisplatin, 5-FU), or it interferes with cellular machinery for maintenance of DNA quality (camptothecin, topotecan). A few others such as taxol are even more indirect, instead hitting the "structural" parts of the cell which hold it up or together. But in general, the chemotherapy drugs damage DNA in some way.
If you read what is adjuvant chemotherapy in this blog, you will find that these drugs hurt all cells. Understanding that the way they work is by damaging DNA, also makes it obvious why these drugs are hurting all cells. But importantly, because cancer cells are dividing rapidly, they must continually make DNA so are susceptible to the DNA damaging agents.

Most interesting are the class of drugs for adjuvant chemotherapy known as the topoisomerase inhibitors. Topoisomerase is a cellular machinery that winds and unwinds DNA as it's about to be replicated. DNA exists as a double helix, but must be "opened up" so that it can replicate and divide into two for each daughter cell. The topoisomerase inhibitors are drugs which interfere with the topoisomerase preventing it from winding or unwinding the DNA effectively. As a result, the DNA of the cells become damaged due to incorrect unwinding and winding.

There is also an very interesting compound known as "cisplatin", which contains the metal platinum. It is a very "simple" drug in the sense that it contains an atom of platinum, surrounded by just a two nitrogens and two chlorines. The other compounds mentioned have much more complicated chemical formulas and structures. Their complex structures give them the ability to break DNA by mimicking it, or by specifically shutting down proteins and enzymes that maintain DNA integrity. But the cisplatin is slightly different. The platinum atom has a structure which allows it to draw in atoms from other molecules. In particular, when placed near a DNA molecule, the platinum atom draws in DNA atoms and bends it. Breaks in the DNA is thought to occur when it is bent by platinum. The cisplatin family has spawned a series of other platinum compounds such as oxaliplatin with various additives that enhance its cancer killing ability. However, for some reason certain patients become resistant to platinum therapy. While nothing can prevent cisplatin from binding to DNA, the cancer cells likely evolve DNA repair strategies or short-circuit the cell-death processes which generally lead to destruction of cancer cells.

The resistance of cisplatin adjuvant chemotherapy can be potentially overcome with other types of drugs such as taxol.

Neoadjuvant chemotherapy for breast cancer

This site is called adjuvant chemotherapy, meaning chemo in addition to whatever surgical procedure is used to remove the breast or colon or what not cancer in patients. What is neoadjuvant chemotherapy? In certain cases, a patient will have an outsized growth, while not metastatic (i.e. it hasn't yet "spread"), is just so big that it's too hard to remove by surgery alone. It may have bulged into tissue that's surrounding it, and removal would incur great damage because of the need to excise lots of tissue around any one particular tumor. This is where neoadjuvant chemotherapy comes in. The latin word "neo" means new, and in this case, for a new tumor one is targeting it with chemo before hitting it with surgery. The purpose of this is to attempt to shrink the tumor. Of course, any patient who undergoes neoadjuvant chemotherapy is still going to suffer from chemotherapy side effects such as sickness and hairloss and fatigue. Success with this kind of therapy is if the tumor shrinks, and then becomes easier for the surgeon to remove. For a patient, this is probably a harrowing time, since any patient who has cancer probably wants to get the thing excised as soon as possible. Now with the physician telling him or her to wait out a few months taking chemotherapy must be nerve wracking. Basically, the idea is to get the tumor to shrink.

There are certain kinds of breast cancer for which neoadjuvant chemotherapy is indicated. For example, inflammatory breast cancer (IBC) is characterized by inflammation of breast tissue, and growth in sheets rather than solid masses. This makes the cancer difficult to localize for surgical removal, and as such, drugs would be most suitable for treating this type of disease manifestation. Some symptoms of IBC are given by:

* Changes in skin surface of breast, such as localized thickening
* Extra warmth, due to blood vessels dilating in response to inflammation
* Pain, sharp or dull
* Color changes of the areola
* Itchiness
* Sudden swelling, sometimes a cup size in a few days
* Erythema, with texture like skin of an orange
* Nipple retraction
* Nipple discharge

Worse still, IBC may not be detectable via traditional imaging methods such as ultrasound or mammography because of its diffuse, nonsolid nature. Physicians are usually advised to be cautious in interpreting imaging of breasts that have the above associated symptoms. A needle biopsy may show more definitive results than using ultrasound or mammograms. Finally, IBCs have been known to progress to more aggressive cancers at a higher rate than solid mass tumors. This is not well understood, but is thought to be due to the complex nature of the inflammation. Inflammation of tissues is usually associated with deranged signaling processes of the cells, which can trigger changes that lead to cancer metastasis. Metastasis is the dreaded "spread" of the cancer from its primary site to far, secondary sites. For example, a tumor in the breast may break off in pieces and lodge itself in the lungs, giving rise to lung cancer. Such metastatic cancers are difficult to treat with surgery, and one must rely completely on the efficacy of neoadjuvant chemotherapy in wiping them out.

Beyond chemotherapy

It's important to know that there are options beyond chemotherapy: scientific, medically powerful options. For example, these are the non-chemotherapeutic agents are known as "targeted" agents, and include drugs such as Gleevec for leukemia, or Iressa for lung cancer, and Herceptin for breast cancer. Because these medications strike particular kinds of cancer cells with high precision, they leave fewer side effects and can be enormously effective at eradicating cancer cells. They are no substitute for adjuvant chemotherapy, but they do play a great role nowadays in second line defense or, in some cases, first line therapy if the clinical trial data is very good. Whether or not your regimen will include these targeted therapies prior to chemotherapy depends on your particular condition, and what the gold standard line of care indicates. For example, Erbitux for colon cancer patients is only indicated for those who have stopped responding to the first line chemotherapies, such as 5-FU (5-fluorouracil).
The story is actually even more complicated: not all patients will respond to a targeted therapy, because the genetic background of cancers can be very different and as a result, may or may not respond to the targeted therapy. Sometimes a genetic test on the primary or secondary tumor can reveal this information. You should consult a well-informed oncologist to make these technically challenging decisions.

Troubling news: chemo-loving cancer cells

It's disturbing to find that drugs taken for treatment may actually make the cancer more aggressive. At Memorial Sloan-Kettering, a big research hospital in New York, a group found that Temozolomide administered as chemotherapy to brain cancer patients could strengthen the disease and make it more lethal. This mechanism isn't well understood, but seems to be linked to a transporter gene responsible for uptake or expulsion of the drug from cells.

Justice Ginsburg and "precautionary chemotherapy"

One of the recent things we've been reading is that Justice Ginsburg had been diagnosed with pancreatic cancer, which incidentally is a tough-to-diagnose and consequently deadly form of cancer as it presents few symptoms until very late in disease progression. After her surgery, she is reported to be undergoing "precautionary chemotherapy". From the sound of it, this is simply another way to say adjuvant chemotherapy confusing everyone. As is the case with many surgical resection of cancerous masses, even though the disease is not detectable by examination alone, cancer cells can still circulate the body or remain undiscovered in small pockets of tissue. The purpose of adjuvant chemotherapy is to eradicate these last remaining cancer cells.
Apparently ex-justice O'Connor also battled cancer, as did Ginsburg herself many years ago.

Side effects of adjuvant chemotherapy

Because there are many kinds of chemotherapeutic agents, the side effects due to treatment will vary from patient to patient. And even when two patients are taking the same chemotherapeutic regimen, they may suffer slightly different side effects due to genetic or other sources of variability. But there are some general patterns to the side effects, because many types of chemotherapy agents act on the cancers in similar ways.

Chemotherapeutic agents are called "cytotoxic" chemicals. This means they attack cells that are rapidly growing and dividing. While this means the cancer cells, which are rapidly growing, are attacked, other natural, rapidly dividing cells of the body are attacked. Among these are blood, hair and digestive tract cells.

Blood cells are continuously growing, to replenish old ones and keep the immune system healthy. So when they are hit by chemotherapy, patients may generally see blood-related problems, such as bruising or bleeding, lack of energy, and perhaps even trouble fighting off small infections due to compromised immune systems. Hair cells are also continuously dividing. When they are hit by chemotherapy, the result may be hair loss. And finally, the lining of the digestive tract is always renewing itself. When being treated by chemotherapy, the lining is unable to renew efficiently, and the patient may suffer from nausea, diarrhea or vomiting. How should one expect the nausea comes about? For some treatments, nausea hits immediately but for others it may arrive several hours after. Consult with the physician to get an understanding of how and when side effects arise.

Aside from waiting it out, patients or their physicians may opt for supplementing treatment with even more medication to combat the side effects. Anti-nausea medication, also known as anti-emetics, can be taken orally or via IV or injection. One will need to know not only which anti-emetics to take, but also how often and how long it needs to be taken to control these unpleasant feelings. Common anti-emetics are the following: Emend, Zofran, Kytril, or Aloxi.

There are other courses of action to take to combat the side effects other than medication. Patients can opt to control how and what they eat or drink. For example, adequate intake of water is encouraged, but not during meal times. Eating of heavy, greasy foods is not! Instead, patients should take in small amounts of dry foods, throughout the day to minimize the stomach sickness from chemo. Finally, one should be aware that surgery and chemo treatments may have averse effects on taste. Flavors may change or become dulled, and pleasant foods from before may no longer be so. Worse still, because of association, foods eaten during bouts of nausea may become disgusting for the patient and should be deferred until much later after treatment. After eating, it's recommended that one does not do exercises, which can accentuate feelings of fatigue-induced nausea. Instead, control the environment by getting into comfortable clothes and recline oneself. The setting should be made as soothing as possibly, perhaps with light music, comfortable temperature and reduced noise levels.

Finally, though it's expected that one suffers from some side effects in adjuvant chemotherapy, there are some warning signs that should be heeded to return to the physician for more advice. Excessive vomiting, pain, or hurting one's ability to take food and keep it down are signs that one should go back to a physician.

This column is really about what some expect during adjuvant chemotherapy and should not be construed as medical advice. Anyone under the care of a doctor needs to go back to that doctor and ask directly! Never self-diagnose from what you read on this website.

Adverse effects of chemotherapy

Chemotherapy leads to uncomfortable side effects for the patients. It is a "non-targeted" medicine, thought to be poisonous to all cells, in particular cells that divide frequently. Because cancer cells are abnormally fast dividing, they seem to be damaged by chemotherapy agents more so than other cells. However, as one might guess, chemotherapy will also damage regular cells that are growing, like those in the blood, in hair follicular cells, and epidermal cells in the gastrointestinal tract.

As a result, patients will suffer blood-related disorders like infections or bruising, loss of hair, and shedding of abdominal tract that leads to nausea, diarrhea and loss of appetite. One course of action recommended by physicians is to periodically fast, perhaps every two or three days. Such an action seems to slow down the metabolism, thereby reducing some of the adverse effects of chemotherapy.

Adjuvant therapy

How is adjuvant therapy given? It can be either via oral pathway or by injection. Both routes allow the drugs to enter the body systemically, hitting cancer cells that may be spread throughout tissues and organs. Typically, chemotherapy must be administered on a schedule of treatment and then rest, during which the patient can recover from the effects. The schedule cycle occurs on the order of days, so for a few days the patient may rest, and take drug on one day, then continue to rest for a few more days.

The adjuvant therapy can be quite grueling due to the tremendous toll on the body from side-effects of chemotherapy damaging all the cells of the body not just the cancer cells. During this time, cancer patients may suffer from hair loss, anemia, weight loss, nausea and vomiting in addition to other side effects. Adjuvant treatment may last for several months until a positive outcome is observed. To deal with the effects of adjuvant therapy, some patients also fast every two days, a procedure that seems to counteract the debilitating side effects.

In addition to physical side effects, chemotherapy also seems to cause mental ones. Patients often experience a "cloud" effect on memory, with declining ability to remember episodes during treatment. Although there is no hard science to prove this effect, it is widespread enough that it has come to be known by a unique and somewhat macabre name: "chemobrain". Under chemobrain, patients have decreased ability to recall, focus, and do complex multitasking tasks. The unfortunate patient variable is that some patients have only short term memory problems while others never seem to fully recover from the mental damage done by adjuvant therapy drugs. This area is undergoing research, and some think it's related to the cancer itself. Further confounding the symptoms is the fact that some of the anti-nausea drugs may also interfere with thinking, or the fact that many patients tend to be older so are more likely to suffer some memory impairment. But basically if you're undergoing adjuvant therapy and you're noticing strange, small mental or psychological changes, it may very well be a real effect and not to be dismissed lightly. Plan your daily activities accordingly to reflect this state of mental alteration. Don't do important or complex tasks, but defer them to another day. Not only might you be too weak after treatment, but you may not be in the right frame of mind to deal with it. Take a proactive stance by using a data planner (electronic or book form) to meticulously schedule events and follow it. Use your spare time to exercise your mind, keeping it focused with active reading, and puzzle solving like crosswords or Sudoku.

According to American Cancer Society (ACS), the symptom of chemobrain seems to occur in 20-30% of patients, a rather high number, and irrespective of whether the patient is a man or woman.

Similarly, tamoxifen hormonal therapy targeting ER-positive breast cancers must be a systemic treatment. Clinical studies dictate that a five year period of tamoxifen provides protective effects against recuring cancers.

Another type of therapy for patients suffering from cancer is radiation therapy which involves using high power ionizing radiation focused on localized tumors to kill them. Radiation can penetrate skin, and if several beams are focused on one spot, there is minimal damage to the respective paths to tissue, but at the focused spot there is a lot of energy to kill cancer cells. It is not only the fact that cells succumb to radiation, but that radiation selectively targets cancer cells in the same way as chemotherapy selects out fast dividing cells. Radiation has the effect of damaging DNA, which for replicating cells like those in the tumor is vital. In other normal cells, damage to DNA is quickly repaired. But in cells that are dividing, the repair mechanism on top of the cell splitting into two makes it much easier for radiation to be damaging. There is also total body irradiation, which is used for destruction of bone marrow in preparation for a patient to receive bone marrow. The source of leukemic cells in patients with leukemia is bone marrow which produce malignant blood cancer cells, and therefore warrants its destruction via radiation. Ironically, radiation is also known to cause cancer to some low probability extent. In cases of cancer, the benefits completely outweigh the risks.

Hormonal adjuvant chemotherapy for breast cancer patients

Hormonal adjuvant chemotherapy refers to treatment of breast cancer patients before or after surgery. The estrogen receptor, a component of human cells, is often found to be aberrant in breast cancers. The way the receptor acts is by uptaking chemical signals called 'estrogen'. To combat this, researchers have developed a drug called 'tamoxifen'. It was found that treatment of patients with tamoxifen (which mimics estrogen but competes with it) turns down the activity of the aberrant estrogen receptor. Both early breast cancers in men and women can be treated with tamoxifen. Clinical studies show that when used as adjuvant chemotherapy, hormone treatment suppresses recurrence of the original cancer, as well as diminishing cancers that occasionally arise in the other breast.

In addition to tamoxifen for hormone therapy, there are newer drugs (which nevertheless behave like tamoxifen) that are more potent or have beneficial effects such as suppressing development of other cancers. Raloxifen is one such newer drug. Remarkably, one more beneficial side effect of tamoxifen is that it reduces bone loss caused by osteoporosis. However, tamoxifen hormonal therapy also suffers from adverse side effects, such as increasing the risk of endometrial and uterine cancers. This is understood to be due to tamoxifen's uneven effects on these other tissues.

What is adjuvant chemotherapy?

After surgery to remove a maligant tumor, often in the breast or colon or bladder, traces of cancer cells can still remain. In part this is because the surgical removal procedure (resection) is imperfect, possibly leaving traces of cancer cells behind, but also because cancer cells often break away from the original site of the tumor and settle in other parts of the body (a phenomenon known as metastasis). Without the technology to identify whether there are remnants of cancer cells left in the patient, which can quickly proliferate again and develop into multiple tumors, the usual recourse is to take "radiotherapy" or "chemotherapy". In the case of chemotherapy, because it's in addition to surgery, it is called "adjuvant", meaning that it's taken in conjunction with or in addition. If there is also radiation treatment, this is called "chemoradiotherapy," which is quite a mouthful to say. What is chemotherapy exactly? It's simply a course of treatment which involves patient uptake of one or more chemical compounds that have been formulated to kill cancer cells. Because the cancer cells may be systemic, that is, distributed in different parts of the body, the therapy needs to be system-wide also. Therefore, chemotherapy is often dosed via an "infusion" injection or intravenous drip. Unfortunately, because the chemicals are toxic enough to also harm normal cells, the treatment can also cause side effects. Patients frequently experience nausea, hairloss, weakness. To some extent, fasting (by not eating food) for extended periods relieve some side effects.

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