Part three 3 treatments: Tumor cell growth and radiation

Tumor cell growth is very important to understand. First, it is highly variable with the time required to double the number of cancer cells ranging from less than 24 hours to more than 300 days. Furthermore, cells in the center of a tumor mass may not even be alive if they have outstripped their blood supply and delivery of nutrients and oxygen. Thus, tumor growth depends on the number of cells dividing over time. Usually, the larger the tumor the smaller the percentage of dividing cells and the longer it takes cells to divide. There are elegant models; one of the most common is the Gompertzian model that I am discussing. Some general rules apply. Growth rate is most rapid and often exponential during the early days of a tumor. Thus instead of two cells going to four, then eight, then sixteen; two cells may go to four, then sixteen then two hundred fifty six. Therefore, the growth fraction or the number of cells dividing is high. The portion of tumor cells that are growing decreases as the tumor gets larger and often plateaus because of nutrient supply. This may help one to get a handle on these numbers. It takes one billion cells for just one gram (about 28 grams to an ounce) of tumor tissue. One gram is about the lowest level at which we can detect cancer. That is equal to about a 1 cm mass in a breast or 1 cm nodules on a chest x ray. One thousand and one million times that amount is about 2-20 pounds of cancer and usually results in severe organ damage and major medical problems and death.

Sadly, tumor cells have multiple mechanisms of innate or acquired resistance to chemotherapy. Tumor cells within a given cancer may have some diversity in this regard. Some tumor cells are naturally (innate) drug resistant and eventually become the predominant cell. This is particularly true if chemotherapy eliminates all the sensitive cells. A theory called the Goldie–Coldman hypothesis asserts that the probability of a tumor having resistant cells is proportional to tumor size. Thus, tumors can become more resistant to chemotherapy as they grow. However, chemotherapy makes some tumor cells quickly make enzymes or use other techniques to neutralize the drug. This is acquired resistance. Some tumor cells make substances in high concentration that not only lead to destruction of the chemotherapy drug but also quickly repair any DNA or other damage the chemotherapy drug may have caused.

DNA on chromosomes is tightly coiled. There are specific enzymes that let it uncoil so it can duplicate DNA for its children. Some chemotherapy drugs either try to inhibit the enzyme that allows the uncoiling or try to keep the DNA for the children cells stuck on the spindle on which this occurs. Once again, tumor cells can acquire resistance to this. Sometimes the mere exposure of a drug to a tumor cell prompts the tumor cell to make a transport protein to carry the drug actively out of the cell before it can do damage. Sometimes this tumor cell reaction leads to not just resistance to one chemotherapy drug but induces the tumor cell to make a multidrug resistance gene. A gene is a portion of a chromosome that carries the code for one specific message; typically, for a protein that has a very specific job. Human cells have tens of thousands of genes. The multidrug resistance gene helps the tumor cells create a very effective pump that pumps chemotherapy drugs out of the tumor cell before they can cause harm. There is more than one multidrug resistance gene and unfortunately, there has been only minimal success in blocking these genes actions. Many of the above reasons are why we use non-cross resistant chemotherapy to try to hit the tumor from multiple angles. The concept is similar to using a cocktail of drugs against the cancer cells that are sufficiently different so that we hit the tumor cells multiple ways.

Regarding how much chemotherapy is enough; more often than not, more is not better. Very high does, which only work for a few tumors, require the support of bone marrow transplants to rescue the patient from the damage the high dosages of drugs inflict on normal cells.

Thus, if caught early enough, a dozen or so of human tumors are clearly curable with chemotherapy alone. There are about seven or so that are very responsive but cure is not typical with drugs alone. There are many, depending on their stage, which are highly treatable for long durations. Then there are the groups of only occasional responders such as advanced melanoma, the common type of kidney cancer, many forms of brain cancer and advanced cancer of the bladder and pancreas.

We previously discussed adjuvant chemotherapy. This is treatment given after the primary removal of the tumor when there is no evidence of remaining tumor but there is a well-known risk of recurrence. The intent is to prevent recurrence. Adjuvant therapy of breast cancer is the model for this concept and changes the odds of survival for countless patients. Neoadjuvant chemotherapy refers to treatment  given before primary surgical removal of a tumor to ease the removal, make surgery less invasive and offer the benefit in some cancers of determining whether the drugs chosen are effective or not. Salvage chemotherapy refers to treatment given after failure of initial therapies. It is not synonymous with unsuccessful treatment as many patients see prolonged survival free of progression or recurrence while enjoying a good quality of life.

Most chemotherapy drugs can also be categorized based on how they work rather than just when. Thus, there are alkylating agents that target tumor DNA and try to bind to it thus disrupting a tumor cells ability to have offspring. Some are anti-metabolites. These drugs mimic small molecules the cancer cell needs to keep living. These function like a computer virus by not allowing the cell to proceed in cycles, as they are dysfunctional copies. There are anti tumor antibiotics, which generally are drugs derived from microorganisms and are usually not cell cycle specific. These are often useful in slow growing tumors. There are plant alkaloids that function by not letting the spindle we talked about earlier form and thus halt the tumor cells from dividing. These drugs may also make the spindles’ structure unstable.

Finally, as will be touched on somewhat in the section “The Future”, other agents exist that do not neatly fit any of these classes. These novel drugs may destroy essential enzymes or function as a hormone or hormone receptor manipulator necessary for tumor growth. If a receptor or keyhole needs to work for a tumor cell to grow, blocking the keyhole could be very effective. Some chemotherapy agents can be very disabling by affecting the ability of the tumor cell to eliminate harmful by-products it produces as it grows.

Some drugs interfere with molecules necessary for the tumor to grow. Some drugs are estrogens, anti-estrogens and anti-male androgens. An exciting relatively new and promising type of treatment is immunologic therapy and biologics. We will discuss this in more detail in “The Future. The earliest effective treatment of this type is interferon. There have also been attempts to “beef up” immune cells of the patient outside the body of the patient and re-inject them in hopes they will find the target tumor cell and help the immune system. Finally, there are agents that try to force tumor cells that are “stuck” in a primitive always “on and dividing” phase go through orderly controlled cell growth and life. These drugs are trying to make the rogue cancer cells grow up, mature, straighten out and become normal. These are known as differentiation agents and have met with some success in some forms of leukemia.

A very exciting breakthrough of only the last decade is not true chemotherapy to fight cancer but rather employing genetically engineered drugs to fight the effects of the cancer on you and your bone marrow. We make all of our blood cells in the marrow. There is a complex army of specialized white blood cells to fight infection and red cells to carry oxygen. There are now genetically engineered drugs routinely available that largely are identical to your body’s normal molecules that stimulate red and white blood cell production. Anemia and dangerously low white blood cell levels can occur either from the therapy, the presence of the tumor or both. Enormous fatigue and poor quality of life is associated with anemia and infections which can be life threatening are more common with low infection fighting white blood cells. Both are now very effectively treated. There is also a genetically engineered product to help your body make platelets (which help blood clot). It is not as effective as the other two.

Thus, these hematopoietic (blood) growth factors have had an enormous impact on the ability to both fight, defray and hasten recovery from chemotherapy induced low blood counts and the secondary risks of infection and fatigue. These little miracle molecules are precise genetic replicates of your body’s’ own growth factors that can now be mass-produced by recombinant genetic engineering. Furthermore, longer acting versions are now available through manipulating the molecules and thus decreasing the frequency of injections. Thus, we are more effectively fighting fatigue, avoiding transfusions and decreasing the risk and expense of infection. Furthermore, oncologists are more frequently able to deliver full doses of chemotherapy on time in cases where cure and benefit depends on that.

The first widely used genetically engineered product was the red blood cell growth factor called Erythropoietin. This can improve the anemia and fatigue of many cancer patients if needed. This is an injection, similar to an insulin injection, self administered by the patient as infrequently as every 1-3 weeks in some cases. The other wonder drug, billion dollar sellers are G–CSF and GM-CSF, which like the red cell drug are administered sub-cutaneously. They support white blood cell counts ( infection fighting)  There are both daily and with every 2-3 week forms available. These have changed the practice of Oncology. These two drugs alone have markedly improved the quality of life for millions of cancer patients.

In summary, not all tumors are the same in terms of chemotherapy sensitivity. We design drugs to exploit unique cancer cell weaknesses and take advantage of their usual higher rate of growth. There are numerous ways to attack the malignant cells. These cancer cells are clever, adaptive, enemies that may be quick to find a way around our armamentarium. Wonderful new therapies exist to support patients undergoing some of the toxicities of therapy. As will be discussed in “The Future”, exciting and novel treatment approaches have arrived. Thus, the sooner we get to the cancer the better, the more we can do to prevent it the better and the more patients we can get on well designed clinical trials, the faster we will conquer this frequently devastating disease.

 

Radiation Therapy

 

Radiation therapy uses high-energy radiation to kill cancer cells by damaging their DNA. Radiation therapy can damage normal cells as well as cancer cells. Therefore, treatment must be carefully planned to minimize side effects. The radiation used for cancer treatment may come from a machine outside the body, or it may come from radioactive material placed in the body near tumor cells or injected into the bloodstream A patient may receive radiation therapy before, during, or after surgery, depending on the type of cancer being treated. Some patients receive radiation therapy alone, and some receive radiation therapy in combination with chemotherapy.

The care of the oncology patient must be multidisciplinary. Pathologists, radiologists, clinical laboratory physicians and immunobiologists are crucial members that render the correct diagnosis. In many cases, a team comprising the medical oncologist, surgeon or surgical oncologist and radiation therapist assess what treatment techniques are needed. Finally, there are chemotherapy nurses, technicians, and social workers rounding out an integrated team.

Radiation oncology is a clinical discipline devoted to the use of ionizing radiation for patients with cancer as well as some other diseases. We give radiation alone or in combination. The goal is to deliver the maximum lethal dose to the tumor and minimize any toxicity to surrounding normal tissues in hopes of eradicating the tumor while maintaining a high quality of life. Radiation therapy may also have a role in treating or preventing symptoms. This includes pain, restoring the opening of blocked airways, helping prevent bone fractures owing to tumor having spread to them and other organ function while again trying to minimize suffering. Just as the medical oncologist, the radiation oncologist must assess all the factors relevant to the patient’s situation and determine whether more radiation is safe and beneficial.

Many types of radiation are used. The most common kind is external beam irradiation using photons or electrons. Photons are x rays or gamma rays and may be considered as bundles of energy that deposit a damaging dose to the tissue as they pass through it. These beams are carefully shaped with shielding of the normal surrounding tissue. Depending on the voltage used, which can vary a million fold, these x rays may travel barely a millimeter to a depth of 3-4 cm with techniques used to spare the overlying skin. Radioactive isotopes create Gamma rays, the most common of which is Cobalt 60. Most facilities no longer use gamma rays because of the need to replace and frequently recalculate dosages due to the natural radioactive decay of the isotope. The gamma knife is an exception that radiates brain tumors with precise accuracy and employs up to 201 Cobalt 60 sources.

Other sources of external beam radiation are protons and neutrons. Protons are positively charged particles that have the advantage of depositing dose at a constant rate over the majority of the beam with most of it at the end of the beam. Protons, unlike photons, fall off quickly in their ability to do damage beyond the target. Although this vastly limits damage to normal tissue, the enormous expense in generating these rays has limited their use to only a handful of centers in the Unites States. Neutrons are uncharged heavy particles that are produced a number of ways. Neutrons collide with protons in the tumor cell nucleus and can be very effective. Experience with these units is limited again because of enormous cost and clinical trials are under way comparing all these types of radiation.

Brachytherapy is a physically different way of delivering ionizing radiation. In this technique, the physician places or implants sealed or unsealed radioactive sources very close to the target. Since the dose of radiation falls off very rapidly as distance increases, this is one technique to deliver higher doses of radiation to the target than external beam in most cases. The dose is generally delivered over days and is seen in use in some cervical, prostate and breast cancers. Various radioactive substances are used as the radiation-emitting source.

Radiation therapy may be intended to be curative or rather simply for symptom control. Cooperation of all members of the team is essential to achieve these goals. Furthermore, tumors have highly variable sensitivity to radiation doses. Importantly, normal tissues have maximum doses that can be tolerated after which severe damage can occur. Thus, as is true for chemotherapy, the probable benefit of radiation must be weighed on a careful case-by-case benefit against the probability of damage to normal tissue in the way of or near the beam. This is not a simple business and extremely close coordination with the physicist, dosimetrist (physicist who calculates the right dose), and treatment planning staff is standard.

So why does radiation work? First, one can kill just about anything with enough radiation; the issue is that you cannot safely give enough. High doses may be irritating or lethal depending on the tissue radiated. Thus, so called dose response curves exist for all tumors. These tell us the correct dose to get the desired effects of killing tumor cells. These curves also exist for each type of normal tissue, e.g. bone, brain, nerves, bone marrow, intestines, mouth, etc. Furthermore, the sheer bulk or lack thereof of the tumor will also play a pivotal role in the maximal tolerated dose or the necessary dose.

You may hear the term “Boost Volume” which is used to describe the residual tumor volume receiving the highest doses of irradiation. This is often necessary in larger tumors where a higher dose is delivered to where viable tumor cells may well be and would then, unchecked, multiply and grow. In addition, since radiation works better with plenty of oxygen and many of these cells are at the oxygen poor core of the tumor, the boost is helpful.

Molecular oxygen must be present at the time of irradiation for maximal tumor cell killing. The probable mechanism is that the radiation creates free radicals that are very damaging to tumor DNA. Nearly all cell death from radiation results from disruption of cancer cell division and the new tumor cell formation process. Thus, tumor cell death in non-dividing radiated cancer cells is uncommon. It is also true that apoptosis, which is the name for the phenomenon that all cells are pre-programmed to eventually die from “old age”, appears to occur at an accelerated rate once cells are radiated. It ‘ages’ the cancer cells. Cancer cells attempt repair of non-lethal and potentially lethal cellular damage from radiation. This occurs within about 5-6 hours and is probably never complete. Although human cells have a narrow range of tolerance, compared to tumor cells they have a more efficient repair and recovery processes. We try to exploit this phenomenon by the daily or twice daily treatment or fractionation scheme of most radiation.

As one would imagine, there is clearly an array of adverse effects from radiation depending on dose and intervals as well as type and duration. Three-dimensional planning is the biggest advance as regards not only focusing the beam precisely but also avoiding damage to normal tissue. In this technique, similar to a hologram, the radiation team can predict how much beam is going where. Nonetheless, there are both early and late radiation induced reactions. The early reactions occur during or immediately following treatment and are usually self-limiting, although they may last for a few weeks. These may be local or systemic and include loss of appetite, nausea, fatigue, inflammation of the esophagus, diarrhea, (if the G.I. tract is in the beam), skin reactions (redness and peeling), inflammation of the lining of the mouth, loss of hair and low blood counts. The basic mechanism is damage to rapidly dividing cells. These symptoms can be modestly treated and usually resolve well.

Late radiation induced reactions can be clinically important and may be apparent months to years later. They are often progressive and not self limiting. These are typically local and include inflammation of nerves, death of bone, tightening of bowels, scarring of the lung, loss of skin, kidney damage and heart damage. These are usually very infrequent owing to the careful planning discussed earlier. Since these late effects are usually irreversible, careful planning towards prevention is pivotal.

As one would expect, the side effects of radiation therapy influence other treatment methods and vice versa. Certain chemotherapy agents can greatly accentuate skin inflammation during radiation and thus we avoid simultaneous administration. Some may even create a radiation recall effect long after the chemotherapy is over. This is when after the administration of particular types of chemotherapy a previously radiated area may inflame even though the radiation was delivered quite some time previously. Prior abdominal surgery may accentuate both acute and late radiation induced bowel damage if it places bowels in the path or radiation. Radiation can damage small blood vessels and thus may impair healing after surgery. Finally, a more recently recognized complication of radiation is the risk of bone marrow and blood disorders as well as acute leukemia years after the therapy.

The key is teamwork and careful planning. As with any therapy, one must always weigh the goods against the harms while remembering the immense harm of not treating the tumor at all or inadequately. The techniques of radiation are becoming more refined. The field of radiation sensitizers that may increase the vulnerability of tumor cells relative to normal cells is growing. Radiation will continue to have a prominent role not only for symptom control but also as an integral portion of a comprehensive approach to the treatment of many human malignancies as seen in cancers of the lung, colon/rectum, breast and Hodgkin’s disease.

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