Chemotherapy is the use of drugs to fight cancer. It is one of the major therapeutic options available for cancer treatment and many of the great success stories in the recent fight against the disease are due to improvements in the efficacy of chemotherapy agents. To understand how these drugs work, one must first understand the basic nature of cancer, so before we discuss chemotherapy, we must first provide an introduction to cancer.
Chemotherapy: Introduction to Cancer
Cancer is the name of a family of diseases whose fundamental behavior involves the uncontrolled division of cells and the subsequent invasion of these cells into other parts of the body. Although people often speak of cancer as if it were a single entity, it is in fact a number of highly-individualized diseases that all work along these same two principles. For our discussion of chemotherapy, the nature of cell division and replication is the most important area to understand about cancer because this is the domain that chemotherapy targets for treatment.
All cancers begin from the same basic process: the breakdown of the regulatory mechanisms that govern the cell cycle leads to the uncontrolled division and replication of malignant (harmful) cells. This unrestrained division of cells is cancer and it represents such a serious threat to the patient’s life because the body is, in some sense, losing control of itself that is, the processes that normally function to preserve life become processes which threaten it. To better understand this, we need to understand the relationship between the body’s internal processes and its regulation of these processes.
The human body is an amazingly complex organism whose health and well-being emerge from a large number of biophysical processes and the regulatory mechanisms that govern them. The cell cycle is essential to these processes: it is responsible for the creation, maintenance and replication of the individual cells that make up our body. It is normally a tightly-regulated affair that has evolved multiple mechanisms to analyze cells for their overall health and to repair damaged cells if they are identified. In those cases where cells cannot be repaired, they are removed from the body through a process known as apoptosis, which is a form of programmed cell death. This is done to ensure that only the healthiest cells are reproduced. Sometimes, however, these regulatory processes breakdown and become dysfunctional, so instead of damaged cells being removed from the body, they are allowed to replicate. Mutations in their structure are then passed on to each successive generation, which can lead to a situation where the body loses all control of the replication process. This is cancer. The longer this malignant situation continues, the more likely it is that these cells will invade other tissue structures and the cancer will spread throughout the body. Metastasis is the term used to describe the spread of cancer to distant parts of the body. The discovery of metastases is a very serious situation, as it indicates that the cancer has spread beyond its local point of origin.
If an individual develops a cancer, physicians can treat it in a number of ways, with chemotherapy being one of the most effective treatments for most forms of the disease.
Mesothelioma is a rare form of cancer typically affecting the lining of the lungs that is highly aggressive and is resistant to many standard cancer treatments. The prognosis for mesothelioma patients is usually grim: the average survival time varies from 4 – 18 months after diagnosis. However, through the use of chemotherapy, radiation, and sometimes surgical treatment, the patients’ symptoms will ease, their lungs may clear, and their prognosis could improve.
As we said above, chemotherapy refers to the use of drugs and other chemical (“chemo” is a derivative of “chemical”) agents to fight cancer. Most traditional chemotherapy drugs fight cancer by inhibiting the process of cell division (mitosis) among rapidly dividing cells, although some drugs may work along a different framework. There are drugs which enhance the apoptotic process by which malformed cells are removed from the body and others that target different phases in the cell cycle.
Recent advances in the creation of anticancer drugs have also come from fields outside of traditional chemotherapy. These new agents, such as those based on monoclonal antibody therapy, may also be considered chemotherapy drugs, even though their mechanisms of action differ from traditional chemo agents. For example, monoclonal antibody therapy works by targeting tumor-specific antigens in a cell or specific molecular abnormalities that have been shown to lead to certain cancers.
In all cases though, successful chemotherapy cures the body of cancer by arresting the production of new cancer cells and killing off whatever malignant structures remain. As such, chemotherapy drugs are considered cytotoxic agents (i.e., drugs that kill cells-cyto is the scientific prefix for discussions of cells).
One of the major problems associated with chemotherapy is its lack-of-specificity for cancer cells. Chemotherapy is considered a broad-scope treatment because it attacks all rapidly dividing cells, not just cancer cells. This is the primary reason for the side effects that are commonly associated with it, such as anemia, digestive disorders and hair loss. The natural activity of bone marrow cells, as is also the case with the cells that control the growth of hair follicles and those that line the digestive track, is also characterized by rapid division, so they, too, are affected by chemotherapy. Science is only now beginning to map the different internal structures between normal cells and cancerous ones, so traditional cancer treatments, such as chemotherapy, have been unable to distinguish between these cell types in meaningful ways. Even as recent years have shown a great increase in the overall efficacy of many chemotherapy agents, as well as a reduction in the severity of many of the side effects associated with treatment, chemotherapy is still considered a systemic therapy because of the wide scope of cells that are subject to its cytotoxic effects.
As in every specialized practice, cancer treatment and chemotherapy have their own highly structured vocabularies that may not be fully understandable to those without experience in the field. This vocabulary is often full of highly technical words from medicine and science, but it also includes specialized uses of a number of commonly used words. When learning about chemotherapy, it’s important to understand the meaning of these words when used within this context. Three of the most important of these words for treatment purposes are regimen, cycle and course and they are often prefaced with chemotherapy to distinguish the context in which they are used. There are a number of other terms that are important for an understanding of chemotherapy treatment and they will be introduced in the following sections as well.
A chemotherapy regimen refers to the overall treatment plan that governs a patient’s chemotherapy. It will identify, at least, the following information:
- The particular chemotherapy agent (or, more likely, agents) to be administered, as well as the dosage levels and the duration of delivery for the selected agent(s).
- The vitamins or other secondarily-administered substances that will be used to mitigate the toxicity and other side effects of the actual chemo agents administered, should this be required. Not all chemotherapy regimens require this step, but many of them do. The most commonly deployed chemotherapy for malignant mesothelioma, pemetrexed and cisplatin combination therapy, is much better tolerated when folic acid and vitamin B12 are also administered to patients.
- The overall schedule of administrations and the number of chemotherapy cycles that the patient will receive.
A chemotherapy cycle refers to one complete administration of the drug delivery regimen and a resting period which follows the administration. Different chemotherapy regimens will specify a different number of cycles. Chemotherapy is not simply given at one time, like a flu shot, or even over a few days, as antibiotics are generally given. Chemotherapy is delivered over time, usually over months, because this allows the drugs the greatest likelihood of attacking all of the malignant cells. As chemotherapy specifically targets cells that are dividing, it will be most effective on those parts of the malignancy that are currently undergoing mitosis and less effective on the parts of the cancer that are not dividing.
Another important reason why chemotherapy is given in cycles has to do with patient health. After the drugs are delivered, there is always a waiting period before their next administration. This is done to give the body time to recover from any side effects associated with the individual agents. Normally, the specified waiting period is enough to give a patient’s immune system time to recover, but in some cases, the chemo may be too toxic or the side effects a little too strong for a particular individual, so adjustments will be made. For example, neutropenia, a blood condition that features an abnormally low number of neutrophils (a specific type of white blood cell), is a common side effect of certain chemotherapy regimens, so if a patient develops it, his or her oncologist may delay the beginning of the next cycle until the body has more time to recover. Adjustments may be made for a number of other side effects as well.
When a patient has completed all of the chemo cycles, he or she is said to have completed the chemotherapy course. It is always preferable to complete the full course of chemotherapy than it is to only complete a portion of it. Chemotherapy regimens have been developed through detailed studies and clinical trials, so the proscribed courses have been identified as the most effective. It is not always possible to complete the full course, but it is the goal at the start of every chemotherapy treatment.
Chemotherapy regimens are generally considered either first-line therapies or second-line therapies. First-line chemotherapy is a term that describes the standard chemotherapy regimen for any particular cancer. In the case of mesothelioma, combination therapy using pemetrexed and cisplatin is considered the chemotherapy standard of care, so it is also referred to as first-line chemotherapy. However, not every patient responds to first-line therapy; these patients will then be treated with second-line chemotherapy, which refers to a chemotherapy regimen that is regularly deployed when a patient fails first-line therapy. In the case of pleural mesothelioma, there is not yet a standard second-line therapy, but there is active research into this question.
As in most forms of cancer treatment, chemotherapy can be deployed with curative intent or for palliative purposes. When it is employed with curative intent, the goal of chemotherapy will be the removal of all signs and symptoms of cancer from the persons body. This is known as remission and is what everyone being treated for cancer is hoping for. In this situation, the chemotherapy regimen will likely stipulate an intense treatment course. Cancer is a complex and difficult disorder to treat, so the goal of chemotherapy with curative intent will be to overpower the malignancy and this strategy requires a strong treatment regimen.
When employed for palliative purposes, chemotherapy will be used to extend life and control symptoms. However, because many forms of chemotherapy are often associated with a high toxicity profile, its benefits for palliation must be balanced against the side effects of the actual treatment.
Chemotherapy is often used as part of a multi-modal treatment plan that attempts to maximize patient outcome through the deployment of multiple treatment mechanisms. In these cases, it is most often combined with surgery and radiation; sometimes it’s used with both and other times with just one of them. A number of studies have identified trimodal therapy, consisting of surgery, chemotherapy and radiation, as the most effective treatment strategy for mesothelioma patients who are eligible for curative treatment.
When chemotherapy is combined with other treatment modalities, the sequential order in which the treatments are conducted has a strategic component to it and the chemotherapy is described differently based on this order. The two major strategies employed for curative chemotherapy are adjuvant chemotherapy and neoadjuvant chemotherapy. Adjuvant chemotherapy refers to the use of chemotherapy after surgery and is conducted to kill whatever cancerous cells remain after the operation. In many cases, the surgery will appear to have removed all of the cancerous tissues, but will, in fact, only have removed the visible malignant cells leaving microscopic cancer cells that will continue to grow and possibly spread. Doctors use the term occult disease to describe diseased cells that live in the body but which does not show up on physical or laboratory tests. Adjuvant chemotherapy is performed to minimize the likelihood of the cancer returning/spreading due to microscopic or occult cancer cells that remain after surgery. This is especially true for mesothelioma patients, because the diffuse nature of mesothelioma’s invasion pattern makes complete surgical extraction very difficult, if not impossible, to perform.
Neoadjuvant chemotherapy refers to the use of chemotherapy before surgery and is used to shrink the size of the tumor(s) or overall malignant area to make surgical extraction easier and less extensive. Multimodal therapies utilizing neoadjuvant chemotherapy are also under investigation for the treatment of mesothelioma. One of the major questions in mesothelioma treatment research is whether treatment regimens featuring adjuvant chemotherapy are more effective for the overall treatment of the disease than are protocols that feature neoadjuvant chemotherapy.
Chemotherapy can be conducted with a single chemo agent or with a combination of agents. Combination chemotherapy is probably the contemporary standard for most forms of treatment, but the choice of which protocol to deploy will be based on the nature of the individual cancer as presented.
Single agent therapy refers to the use of one drug for the full course of a patient’s chemotherapy. This was the original manner in which chemotherapy was used and it is still the basic protocol used to treat a number of cancers. However, single agent therapy presents a number of possible issues that can complicate a patient’s treatment.
One potential problem with single agent therapy is a build-up of resistance to the particular agent that is used. Certain classes of drugs may be more susceptible than others to this phenomenon, but the adaptive nature of our immune system means that the body can develop a resistance to any drug given over time. The other possible problem with single agent therapy is its potential for side effects. If the use of a drug as a single agent requires a heavy dosage level to guarantee its efficacy, the dose level may also be responsible for significant side effects. This means that even if it’s effective at treating the cancer, it may not considered appropriate for treatment especially if studies involving combination therapy demonstrate similar effectiveness and less severe side effects.
Combination chemotherapy refers to the use of multiple agents for the treatment of cancer and is the preferred protocol for most cancers these days, because it mitigates many of the problems that are associated with single agent therapy. Combination therapy makes it more difficult to develop a drug resistance because the cancer is being treated in multiple ways by multiple agents, so the immune system is less likely to organize resistance to any one agent. Combination therapies also have benefits regarding side effects, as using two agents to treat the cancer may be easier to tolerate if both agents have minimal toxicity profiles, as compared to the use of a single agent with an extensive profile. The last major benefit to combination chemotherapy is its potential for greater treatment efficacy due to a synergistic effect of the agents being used in concert. In some cases, using multiple agents together amplifies the effectiveness of the overall treatment. This is not always the case, but it is a potential benefit to combination therapy.
In the case of mesothelioma, cisplatin had originally been studied in single agent therapy, but studies revealed limited success and serious side effects when it was used this way. There were, however, indications that cisplatin would be more effective when used in combination therapy, which subsequent research has confirmed. When the FDA approved the use of pemetrexed and cisplatin for pleural mesothelioma in 2004, they did so because of the enhanced effectiveness of two drugs used together.
The most common method of chemotherapy delivery is through an IV-drip. For patients who are presently in the hospital, their chemotherapy will be delivered in their hospital room. For patients who are home and receiving chemotherapy on an outpatient basis, they will go to the doctors office and will receive the chemo through intravenous delivery and will then return home after the administration.
Even though intravenous administration is the standard method of delivery, there are other delivery methods as well. Some agents can be given through direct injection, while others are in pill form and can be delivered orally. The delivery method for a given drug is usually decided upon with a view to maximizing its effectiveness. Some agents can even be repurposed and used in different forms.
An alternative method of delivery that is being studied more often in the treatment of mesothelioma is isolated perfusion chemotherapy (IPC), where the chemotherapy agents are delivered into a particular area of the body. Because IPC is administered to specific regions, it is not associated with the same side effects as are most other forms of chemotherapy. Another benefit to the treatment is that it allows the chemotherapy agents to be heated up, which enhances their ability to be absorbed by malignant tissues.
IPC is important because it allows oncologists to specifically treat malignant areas that are not treatable through surgical resection. IPC has been used in the treatment of a number of other cancers besides mesothelioma, and it is because of its successes with those cancers that its use for mesothelioma treatment is now being studied. Intrapleural perfusion chemotherapy refers to chemotherapy that is circulated over the pleural surfaces of the body, while intraperitoneal perfusion chemotherapy refers to chemotherapy that is directly delivered to the abdominal areas.
Chemotherapy has long been associated with significant side effects, but, contemporary chemo agents and regimens exhibit less intensive treatment effects than they historically have. Some of these improvements are due to advancements in the agents deployed, such as the development of more targeted drugs or of agents with lesser toxicity profiles, while others are due to the transition to combination chemotherapy and the addition of vitamin supplementation to chemotherapy regimens. However, not all regimens have been equally improved and the experience and severity of side effects are still dependent on the particular agents utilized, as well as the particular patient’s individual reaction to the medications.
The major cause of treatment-related side effects is due to chemotherapy’s cytotoxic effects on all rapidly-dividing cells. Because chemotherapy agents are not generally able to target specifically malignant cells, normally-functioning cells whose regular behavior involves rapid division are also likely to be affected by the treatment. Examples of these cell types include:
- bone marrow and blood cells
- hair follicles
- cells involved with digestion and reproduction
Side effects from each of these cell families have been studied in relation to chemotherapy and progress has been made in mitigating many of them, but the very nature of chemotherapy makes it unlikely that treatment-related side effects will disappear completely.
For more information related to chemotherapy and mesothelioma treatment, please read the following:
- Mesothelioma Treatment: Chemotherapy Agents and Drug Classes