What is chemotherapy?
This may seem like a simple question to answer. However, there has been a veritable explosion of new drugs and new methods of administering these drugs that were not available or even imaginable ten years ago. Hence, the content of this chapter must now include a variety of treatments that for most of the public may not come to mind when they hear the term “chemotherapy.” For the purposes of this chapter, we will define chemotherapy as any medication, administered by mouth, intravenously, or directly into the brain, which prevents tumor growth or spread. As will become apparent in the following sections, this definition includes a large and diverse list of medications, and this list will in all likelihood continue to rapidly expand as progress in the treatment of brain tumors continues to advance. Indeed, new treatments for brain tumors are now appearing every six to 12 months—a rate of progress that was unimaginable one decade ago.
How does chemotherapy work?
Most of the drugs that typically come to mind when one hears the term “chemotherapy” work by a similar mechanism. They damage important cellular machinery and thereby induce the cells to undergo a process called “apoptosis.” Apoptosis occurs in normal cells when their DNA—which is the cells’ genetic “blueprint”—is severely damaged (“mutated”). Under these conditions, cells activate a series of processes that ultimately lead to their death, so they do not pass on their damaged DNA to their progeny cells, and do not interfere with normal bodily function. In other words, apoptosis is a form of cellular “suicide” designed to protect our bodies from the dangerous effects of harboring mutant DNA. By damaging DNA or interfering with the duplication of DNA that occurs when cells multiply, these chemotherapeutic drugs induce the tumor cells to undergo apoptosis—leading ultimately to the death of the tumor.
Signal transduction inhibitors:
Although classical chemotherapy has a role in the treatment of brain tumors, there has been much interest recently in examining newer anti-cancer drugs that work by other mechanisms. Most of these interfere with another important cellular function called “signal transduction.” Signal transduction refers to the process by which cells regulate their internal functioning. This functioning includes cell growth, cell division, cell migration, as well as the synthesis of important cellular components. In many types of cancers, including any brain tumors, the process of signal transduction is abnormal. In some instances, signal transduction components are abnormally active—causing cancer cells to multiply inappropriately and in an uncontrolled manner. Because abnormalities in the signal transduction process are so common in cancer, many drug companies have invested considerable effort in developing medications that block these abnormalities, and the resulting drugs have had a major impact on the treatment of a variety of cancers, including cancers of the breast, lung, colon, and kidney. The role of these drugs in treating brain tumors is under very active investigation.
In order for tumors to grow, they need to develop a blood supply to provide them with nourishment. Many tumors, including most brain tumors, are quite adept at producing their own blood supply. This observation has led to a great deal of effort at finding ways of blocking the production of new blood vessels (“angiogenesis”). Several of these are in clinical trial now, and one (Avastin®) is routinely used by many neuro-oncologists.
One of the major problems with classical chemotherapies, and one that applies as well to signal transduction inhibitors, is that they can have significant side effects. Classical chemotherapies are completely incapable of distinguishing normal brain tissue from tumor tissue. These drugs are used only because tumor tissue is generally more sensitive and less able to repair the damage that classical chemotherapies produce. Likewise, since signal transduction is a process found in normal tissue, as well as in cancerous cells, drugs that interfere with signal transduction are expected to have some side effects (although these are generally much milder than those produced by classical chemotherapies). An alternative approach would be to identify some cellular component that is expressed in tumor cells but not normal cells. Drugs that target such a component might therefore kill tumor cells selectively, and leave normal cells alone. This “magic bullet” approach has always been an ideal for brain tumor researchers, but in recent years, we have come to learn that brain tumors have unique targets not found in normal brain tissue, and in several cases, new drugs that attack these unique targets have been developed. This approach is referred to as “targeted therapeutics,” and specific examples will be included in the following sections.
These treatments use cells to attack the tumor, either by delivering toxic chemicals to the tumor or by directly attacking tumor cells through the immune system. Examples include bone marrow or neural stem cells, as well as dendritic cells. The latter are a form of immune system cell that can be programmed to recognize tumors as foreign and destroy them. Each of these therapies is still experimental, but clinical trials utilizing stem cells and dendritic cells are currently open, and you should ask your physician if any are available in your vicinity.
How can we make chemotherapy work better?
A major problem in the use of any of these chemotherapies is that they do not always work, and do not work indefinitely. This is the major reason why glioblastoma multiforme, anaplastic astrocytoma, and other aggressive brain tumors are so difficult to treat. However, in the last several years, we have learned a great deal about how brain tumor cells become resistant to chemotherapy, and have developed new methods of predicting which tumors are likely to be resistant and how to overcome this resistance.
Classical chemotherapy resistance:
Brain tumor cells have evolved several mechanisms to overcome the damage that classical chemotherapy produces. The most significant of these is an enzyme called “methylguanine methyltransferase” (MGMT for short), which undoes the damage produced by classical chemotherapy drugs like temozolomide (Temodar®), BCNU, CCNU, and procarbazine. We now know from several recently-published studies that brain tumors which express high levels of MGMT are likely to be resistant to these classical chemotherapies. It is likely that before too long, testing your tumor for MGMT expression will become routine and will be used to determine which type of chemotherapy will be most useful against your tumor. Furthermore, there are now ways of getting around the problem of MGMT expression, two of which are being actively investigated. The first is through the use of a drug that blocks MGMT, which renders tumor cells sensitive to Temodar® and other classical chemotherapies. One of these, O6-benzylguanine (O6BG for short) is in clinical trials at several institutions, and you should ask your physician if any institutions in your vicinity are using this agent. The second method is to administer chemotherapy in small doses on a daily basis. This type of chemotherapy administration is called “metronomic dosing,” and it appears to also be effective at inactivating MGMT and enhancing the chance that your tumor will respond to drugs like Temodar®.
Concurrent chemotherapy and radiation therapy:
We now know that there is a positive interaction (“synergy”) between Temodar® and radiation therapy, due to a large multi-institutional clinical trial that was conducted several years ago in Canada and Europe. The study found that patients who received a course of Temodar® during their six weeks of radiation therapy did better than those patients who received radiation therapy alone, and this has now become the standard of care for patients with glioblastoma multiforme and anaplastic astrocytoma.
Signal transduction inhibitor resistance:
Although signal transduction inhibitors have great promise for enhancing the treatment of brain tumors, not every tumor is sensitive to this class of drugs. It is now possible to characterize brain tumors on the basis of their “gene expression profiling.” This technique allows scientists to characterize brain tumors based on which of the tumor’s 50,000+ genes are abnormally “turned on” and which are abnormally “turned off.” Although this technology is too complex to discuss in detail in this chapter, it does have the potential of providing a “tumor fingerprint” that will eventually give doctors a way of tailoring treatment to a particular tumor’s gene expression. In general, this technology is still investigational. However, it has already yielded practical information in one specific situation. In a recent study, scientists utilized gene expression profiling to see if they could predict which patients with brain tumors responded to a specific class of signal transduction inhibitors—those which target the epidermal growth factor receptor. These drugs, which include Tarceva® and Iressa®, were found to produce responses in only some patients with brain tumors. Gene expression profiling determined why. Those patients who responded were by and large the ones whose tumors expressed two genes—a mutant epidermal growth factor receptor called EGFRvIII; and PTEN, which is a component of the signal transduction process. It is likely that future gene expression profiling studies will identify other predictors of signal transduction inhibitor responsiveness. Although gene expression profiling is still a research tool, it may eventually become a standard test that will allow the physician to tailor the treatment of a brain tumor to its specific characteristics.
Blood-brain barrier resistance:
The brain is insulated from many of the molecules that circulate in the blood, due to a structure called the “blood-brain barrier.” This prevents the normal brain from being damaged by molecules that are toxic to the brain and which are routinely found in the bloodstream. However, the blood-brain barrier presents a problem for treating brain tumors. This is because it prevents the delivery of chemotherapies that would be effective if they could only get into the brain. Two methods have been developed to get around this problem. The first is a technique called “blood-brain barrier disruption.” In this method, the patient is given a medication that temporarily opens up the blood-brain barrier, and chemotherapy is then administered while the blood-brain barrier is open. The second is a technique called “convection-enhanced delivery” in which the chemotherapy is directly pumped into the brain by means of one or more small tubes that are inserted into the tumor by a neurosurgeon, and removed once the treatment has stopped (usually several days). Both of these techniques are investigational and you should discuss these with your physician if you are interested in considering these.
What chemotherapies are currently available for treating brain tumors?
Some of the classical chemotherapies chemically damage DNA and ultimately lead to apoptosis. These include the following:
Others prevent DNA from being replicated, which occurs as cancer cells try to multiply. These include the following:
- Irinotecan (also known as “CPT 11”)
As a group, these drugs will tend to depress the number of blood cells in your bloodstream. Lowering your white blood cell count increases your risk of getting an infection, while lowering your platelet count increases your risk of bleeding. A drop in your red blood cell count (“anemia”) is less common, but can occasionally occur, and can reduce the oxygen carrying capacity of your blood. By and large, these potential complications are treatable if diagnosed early. Hence, it is very important that you work closely with your physician so any potentially dangerous change in your blood counts can be anticipated and treated effectively.
Nausea is a common side effect of many of these drugs. However, there are now several medications that are generally quite effective in preventing nausea. Chemotherapies that damage DNA have the potential of causing changes in the DNA structure (“mutations”) in normal cells that can cause these cells to eventually become cancerous. These “secondary malignancies” are fortunately rare, and the risk of developing one of these is related to the duration of exposure to chemotherapy—the longer you receive these types of chemotherapies, the greater the risk. This is why a patient will not use drugs like Temodar® indefinitely.
Signal transduction inhibitors
As noted above, these include a number of drugs that have only recently been available for patients with brain tumors. Several of the more common of these include the following:
Generally, the side effects of these drugs are milder than those for the classical chemotherapies, and they vary from one signal transduction inhibitor to another. The most common of these include rash, diarrhea, blood clots, bleeding, high blood pressure (“hypertension”), and swelling of the ankles. Most of these side effects are readily manageable with regular visits to your physician. What role these and related drugs will play in the management of brain tumors is a subject of intensive investigation, and you should check regularly with your physician as new information comes in. In addition, newer signal transduction inhibitors are being studied in both brain tumors as
well as other cancers, and you should check with your physician about the status of clinical trials in your vicinity for which you may be eligible.
Drugs that target the process of angiogenesis have received a great deal of attention recently, as they have shown activity against recurrent brain tumors—the hardest tumors to treat. As noted above, these drugs interfere with the tumor’s ability to create its own blood supply. Several antiangiogenic drugs are FDA-approved for other cancers, and others are being actively investigated in clinical trials for patients with brain tumors. These include the following:
- VEGF Trap
Avastin®, Sutent®, and Gleevec® are FDA-approved, while Cilengitide and VEGF Trap (among others) are in late-phase clinical trials. Avastin® has shown particular promise in patients with recurrent brain tumors, and is now used by many neurooncologists for patients for whom Temodar® no longer works. It is administered intravenously, and its side effects include high blood pressure (“hypertension”), blood clots, bleeding within the tumor, protein in the urine (“proteinuria”), and congestive heart failure. In general, as with the signal transduction inhibitors, these side effects are either rare or manageable.
Drugs that fall within this category are all investigational at the present time. These chemotherapies target unique molecules that are expressed in tumor cells but not, or only to a very small degree, in normal brain tissue. This approach kills tumor cells by one of several mechanisms. One approach involves the formation of a hybrid drug that has two functions—one part binds the tumor cell specifically and the other part kills the cell once contact has been made. These molecules have been investigated in several clinical trials and are referred to as “immunotoxins”. Another approach involves using the immune system to recognize a target found only on tumor cells through the use of a tumor-specific vaccine. A third utilizes “monoclonal antibodies”—protein molecules made by the immune system that recognize unique targets on the tumor and which interfere with tumor growth by blocking this target function.
What are clinical trials and why should I care about them?
It should be apparent from this chapter that much of the progress over the last decade in the development of effective chemotherapies for brain tumors has occurred as a result of research by many scientists. Most of these new treatments are based on findings in the laboratory that were eventually shown in animal studies to be effective in killing brain tumor cells. However, humans are not laboratory rats, and just because a drug looks promising in a rat or mouse with a tumor does not mean it will work in humans. The only way to know is to test promising chemotherapies in real people who are afflicted by real brain tumors, in a process called a “clinical trial.” Before a chemotherapy drug can be approved by the Food and Drug Administration (FDA), it needs to be investigated in a series of clinical trials. Clinical trials are highly regulated and closely monitored in order to protect patients from harm and in order to ensure that their care is not compromised.
There are at least two reasons to consider participating in a clinical trial. The first is altruistic. As is apparent from the above, the only way we will make progress in treating brain tumors is if courageous individuals who are afflicted by this disease volunteer to participate in a clinical trial. While every effort is taken to assure patients of their safety and while a clinical trial on a drug is not initiated unless there is compelling evidence that the drug may be effective, there is no guarantee that the drug will work in humans—hence the need to conduct the trial. The second reason is more out of self interest. As is apparent from this chapter, there are many new promising approaches for the treatment of brain tumors. However, getting these new drugs approved by the FDA can take years, and therefore, the only way to be treated by them now is to enroll in a clinical trial.