WHAT IS CANCER ?
Most normal cells are differentiated, that is, they have a specific appearance and function. Different cells in the body do different things. Cancers derive from transformation of a single precursor cell which grows and divides to form a clone. All cells in the tumor clone usually share some particular features of the original precancer cell. Despite the presence of such shared characteristics, the cells are not all necessarily identical: indeed, the cells in most tumors are quite heterogeneous with respect to many properties, suggesting that cancer cells continuously modify their properties and adapt during growth and development of tumor.
Cancer cells often loose some of the specific characteristics that the cells of origin usually possess. This process is called dedifferentiation. Considerable resemblance to the tissue of origin may persist, however, allowing the pathologist to recognize the tissue of origin. Thus, cancers that arise from glial cells are called glioblastomas, from ependymal cells are called ependymomas, from meningeal cells are called meningeomas, from lymphoid cells are called lymphomas, etc.
A characteristic of cancer cells is that they tend to have a blunted response to normal feedback mechanisms that limit growth. Cells of a normal tissue are controlled by the surrounding cells via substances called cytokines, as well as by substances that are secreted by distant glands, hormones. Cancer cells loose much of responsiveness to these agents They may grow faster or slower than surrounding tissues. Cancer cells tend to tolerate injury less well than normal tissue and recover poorly from damage due to chemotherapy or radiation.
WHAT IS CHEMOTHERAPY ?
Chemotherapy works by killing dividing cells. Cell division is preceded by duplication and recombination of DNA. During this process chemotherapy may introduce errors into the DNA of tumor cells and lead to their death. Chemotherapy injury can be caused by several mechanisms: the cells may not be able to complete DNA recombination or might end up missing a part of the DNA that is crucial to continued life and function, the cells may become unable to further divide and produce progeny, or may become quiescent. The damage to the DNA, which controls all of cell function and structure, may cause the cancer cell to become nonviable and susceptible to damage by the normal stress of daily functioning. In addition, a recently identified mechanism called apoptosis, which is analogous to normal aging, may be triggered by chemotherapy, leading to cell death. Chemotherapy can also affect production of hormones or cytokines retarding or preventing tumor growth. Anticancer drugs are classified into several families based on their origin or their activity. These families include the alkylating agents, antimetabolites and natural products that have anticancer activity. The first documented clinical use of chemotherapy was in 1942 when the alkylating agent nitrogen mustard was used to obtain a brief clinical remission in a patient with lymphoma. There are currently over 40 chemotherapeutic agents licensed for use in North America.
OTHER EFFECTS OF CHEMOTHERAPY
Because chemotherapy kills all dividing cells, it may affect normal tissue. Depending on the mechanism of action of a particular drug, the tissues most affected may vary, thus causing different side effects. Adult tissues that maintain a high growth rate include the bone marrow, intestinal cells, hair follicles, and reproductive organs. Damage to the bone marrow often causes a fall in the granulocyte counts, a subtype of a white cells that is most involved with fighting infection. If you think of bone marrow as the shore of the sea, with waves crushing on the shore one after another, chemotherapy may take out 1 to 2 waves of white cells that are being newly produced. This usually results in decrease in white cell blood counts 7 to 14 days after administration of chemotherapy, when the newly formed white cells mature and become available in the peripheral blood. When the next wave of cells matures, the granulocyte count rises, usually within several days. The effect of different agents on the bone marrow varies reflecting different effects on the DNA. Some chemotherapeutic agents such as BCNU, which is commonly used in brain tumors, can damage stem cells and deplete bone marrow reserves after prolong use. When granulocytes fall you may be more susceptible to infection. Any fever during the vulnerable period requires an immediate evaluation by your physician. If granulocyte counts are below an acceptable number, usually 1,000x103 /ml, immediate hospitalization and intravenous antibiotics are recommended. Importance of this cannot be overemphasized as severe illness and death can be almost completely prevented by prompt institution of antibiotic therapy.
A cytokine called Neupogen is now available to speed up recovery of white cells and is often used to attenuate this toxicity of chemotherapy. Chemotherapeutic agents cast be classified into those that cause great deal of nausea, those that have moderate nausea producing effects, and those that almost never produce nausea. Cisplatin, dacarbazine, bleomycin and nitrogen mustard are examples of the first group while 5 fluorouracil and methotrexate, in standard doses, rarely cause nausea. There has been a great deal of progress in the past 10 years in managing this particular side effect and with currently available therapies, no patient need to suffer from severe nausea and vomiting due to chemotherapy.
Mucositis, ulcerations of the lining of mouth and intestine, is a common effect of chemotherapy particularly of 5 fluorouracil and methotrexate. This is usually an uncomfortable but self limited toxicity that can be alleviated with special mouth rinses.
Diarrhea that sometimes occurs can also be treated with widely available and effective symptomatic agents.
Hair loss is common with many anticancer drugs and usually begins two weeks after treatment. This is specific to certain agents and does not occur in all patients. Some patients' hair may begin to regrow despite continue treatment with the offending agent. Full recovery occurs after cessation of treatment.
Production of sperm in men and of eggs in women is susceptible to toxic effects of many anticancer agents. Many agents cause temporary effects that are filly reversible; while others can cause sterility. Patients contemplating having children should discuss their chemotherapeutic regimen and its effect on fertility with their physicians.
Many anticancer agents are carcinogens. Patients who are long term survivors of chemotherapy may be at increased risk for developing a second malignancy. This effect became apparent when prolonged survival began to be obtained in malignant disease. Acute leukemias can rarely occur one to four years after initiation of chemotherapy. Depending on the type of chemotherapy, solid tumors can also occur with the delay of 5 to 20 years. Of course, the benefit of being cured is usually considered to far outweigh the risk of developing future malignancies.
IMMUNOTHERAPY AND HORMONAL THERAPY
As previously mentioned, cancer cells may retain some sensitivity to inhibition by cytokines, substances secreted by adjacent cells, and hormones, substances produced by glands and carried through the blood. While I will not discuss these agents, alpha interferon would be an example of a biologic agent and tamoxifen would be an example of a hormone (although is higher doses, Tamoxifen may act through other than hormonal mechanisms). Much research is ongoing into combining these agents with chemotherapy.
ROLE OF CHEMOTHERAPY IN BRAIN CANCER
There are serious impediments to effective delivery of chemotherapy to primary brain cancers. Blood brain barrier is a mechanism by which the brain is protected from toxic chemicals. It results in keeping out toxins from the brain. While it is a very useful mechanism for healthy individuals, it does affect the ability of many chemotherapeutic agents to penetrate into the brain. Diffusion of chemotherapeutic drugs within the brain is also fairly poor.
Notwithstanding this fact, many drugs do readily cross blood brain barrier. These include BCNU, CCNU, procarbazine, thiotepa and high dose methotrexate. A number of investigational approaches involves disruption of blood brain barrier by various agents such as mannitol and bypassing the barrier by infusion of chemotherapeutic agents directly through carotid and vestibular arteries or their installation into the cerebrospinal fluid. Intratumoral injection has also been investigated in the past.
Astrocytomas and high grade glioblastomas have been extensively treated with chemotherapy. There have been 11 controlled clinical trials of chemotherapy combined with radiation after resection. Effectiveness has been shown for BCNU, CCNU, procarbazine, streptozocin, and combination therapies. Combination therapies that include nitrogen mustard type drugs appear to be superior to treatment with single agent. A study using procarbazine, CCNU, and vincristine ('PCV') showed doubling of time to tumor progression and doubling of survival in patients with anaplastic glioma. Patients with high grade glioblastomas appeared to be benefit also, although the results did not reach statistical significance.. Another study compared PCV chemotherapy with or without radiotherapy in patients with anaplastic astrocytoma or glioblastoma multiforme. Patients who received PCV and radiotherapy had a significantly longer time to tumor progression and survival time. A number of other studies have also been published. There is a general consensus at this time that some form of chemotherapy with radiation appears to be of benefit after resection of primary glioblastoma of high grade histology.
A newer agent that has recently been extensively used is
TEMODAR (temozolomide). Capsules by mouth have been FDA approved for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. Despite the fairly restrictive indication, the drug is used in many other settings because of its ability to penetrate the blood-brain barrier, a line of defense against toxins that keeps most chemotherapeutic agents out of the brain. Ongoing trials are attempting to determine the extent of a clinical benefit resulting from treatment in other settings.
Dosage of TEMODAR must be adjusted according to white cell and platelet counts in the previous cycle and at the time of initiating the next cycle. The initial dose is 150 mg/m2 orally once daily for 5 consecutive days per 28 day treatment cycle.
TEMODAR therapy can be continued until disease progression, although the optimum duration of therapy is not known.
WHAT IS COMBINATION CHEMOTHERAPY
Since chemotherapy first began to be used, it became appreciated that combinations of drugs lead to better results. The rationale for this is twofold: first of all, different agents may have different effects on subpopulations of cells within the tumor, each killing a different population. Secondly, two or more agents may have synergistic effects, being able to kill some cells that would otherwise not respond to either of the single agents. In addition, combining drugs with disparate and different side effects allows one to give a higher total dose of effective therapy while causing less toxicity that would be obtained by simply increasing the dose of a single agent.
DECADRON
Although, decadron is not a strictly speaking a chemotherapeutic agent, it is extensively used in brain cancers. We will briefly discuss how this agent fits into the spectrum of therapy.
Decadron or other steroid drugs are used to decrease edema, that is swelling, of the brain. Because the brain is enclosed in a hard structure, the skull, any pressure within the brain, tends to cause swelling, both in the surrounding area and in the other areas of the brain. Decadron is extremely effective in reducing this swelling and in relieving many of the symptoms associated with brain tumors. It is also used to decrease swelling associated with tumor necrosis. When tumors are destroyed by therapy (tumor necrosis),
the dead tissue that remains within the brain often causes an inflammatory reaction that leads to brain swelling.
Unfortunately, this extremely useful agent has many side effects. These can be divided into those effects that can be seen within the first days or weeks of use, and those that tend to only occur after prolonged use. The first group includes alteration of mood (euphoria or depression), elevation of blood sugar and development of clinical diabetes in susceptible individuals, and fluid retention. Patients who take the medication for longer period of time may develop cataracts or glaucoma, muscle weakness and loss of muscle mass, osteoporosis and fractures, damage to the head of long bones of arm and leg, stomach or duodenal ulcers with associated complications, and pancreatitis. After prolonged use, decadron can cause impaired wound healing, thin fragile skin with black and blue marks and discoloration, menstrual irregularities, and increase in body hair A particularly troublesome complication of prolonged decadron use is the development of a Cushingoid state. This refers to weight gain, with the peculiar distribution of newly gained fat around the face and neck leading to what has been termed 'moon facies' and 'buffalo hump', a pad of fat in the back of the neck.
When decadron is used for greater than 1 to 2 weeks, production of steroid hormones by the body may be decreased. If decadron is rapidly stopped, a deficiency of steroids in the body may result, leading to life threatening complications. Of course, as in general, no medication should ever be stopped without consultation with a physician.
| For questions or comments, contact: |
| Mark Levin, MD |
| Co-Director - Division of Medical Oncology and Hematology |
| The Brookdale University Hospital And Medical Center |
| One Brookdale Plaza |
| Brooklyn, NY 11212 USA |
| Voice: (718)240-6147 |
| Fax: (718)240-6634 |
| Email: mlvmd@aol.com |
