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Chemotherapy

First off, what are our goals of chemotherapy treatment? Whenever we begin any type of intervention, it’s important to have a framework for why we are giving that treatment, and there can be one of many different goals for the use of cytotoxic therapy. First, chemotherapy treatment could be a sole treatment modality with curative intent, as an example, that would be a patient with choriocarcinoma receiving a multi-agent regimen such as EMACO, no surgery or radiation required with a great chance of cure. Second week we administer chemotherapy with the goal of prolonging life after local therapy. As an example, a patient with a local ovarian cancer, stage IC ovarian cancer that has been completely resected at the time of surgery, might receive chemotherapy after surgery with the goal of reducing the risk of future recurrence. Third, we might use chemotherapy.

Let’s focus more on combined modality therapy using more than one therapeutic approach, chemotherapy plus radiation or chemotherapy plus surgery. This can be as part of primary cancer treatment, and again I will go back to the cervix cancer example that I just gave you. Second could be the use of neoadjuvant chemotherapy. Neoadjuvant therapy is that where a drug is given before local therapy to hopefully improve the potential for local control. For example, a patient with advanced ovary cancer that we think has a low likelihood for having extensive disease resected, we might give chemotherapy up front in a neoadjuvant setting followed by surgery. Finally, we could give chemotherapy after surgery, known as adjuvant treatment, again, hoping to improve the chance of cure after local therapy. Combination chemotherapy is commonly used in gynecologic cancer and by this I mean using more than one cytotoxic agent. There are three basic principals that we will use in defining a given combination regimen. First we hope to use multiple drugs with the hope of overcoming resistance by tumor cells, namely picking drugs which have different mechanisms of action. Second, we would hope to use agents that have different mechanisms of action and not overlapping toxicities and by that I mean different side effect profiles, so one drug that mainly focuses on hematologic toxicity and then another drug.

Well, the way we develop chemotherapy trials are usually in phases and often we’ll hear a different regimen referred to as developed in a phase I or a phase II clinical trial, and let’s talk briefly about what phase trials are. A phase I trial is usually a limited single arm study with a small number of patient’s 10 to 20 or so participants that simply looks to evaluate a drug that might be promising, but the final goal is to evaluate toxicity, and in doing so, the dose of the drug is consecutively escalated until we determine the maximum tolerate dose. This is usually employed in patient’s with an advanced cancer of which there is no curative therapy. After a drug has been evaluated in a phase I setting, we move to a phase II clinical trial, and here in a phase II setting, we wish to determine the effectiveness in a drug. Does it work in this given cancer? In actual practice, phase I, phase II studies may often be combined in a single trial. Once we have determined the maximum dose and if a drug is effective, it will be moved into a phase III setting and that goal is to compare our new treatment to standard therapy, and a classic phase III trial in gynecologic cancer patient’s is the use of Taxol and platinum chemotherapy and ovary cancer, compared to the then standard trial of Cytoxan and platinum and that phase III trial taught us that Taxol and platinum.

So as an example, if we look back at our cell cycle, mitotic spindle apparatus toxins such as vincristine and paclitaxel tend to be imphase cell cycle specific, the antimetabolites methotrexate and 5FU tend to be cell cycle specific for the S phase. Finally we must always account for drug elimination. After we have given the drug, it’s important to see how it’s going to be eliminated for the body and make certain that that part of the body is functioning properly so that we don’t run into toxicity concerns . Some agents are primarily renal eliminated and we must make certain the patient has an adequate creatinine and this includes the platinum compounds, bleomycins, cyclophosphamide and methotrexate. Other agents are primarily eliminated through the hepatobiliary system. It’s important to make certain the patient has relatively normal liver function and a normal bilirubin and this includes dactinomycin. We normally administer most chemotherapy agents in the gynecology cancer setting based upon body surface area, mg per meter squared if you well.

Let’s change gears now and talk about classes of chemotherapy drugs of mechanism of action. First, let me recognize that many of the agents we’ll talk about have different and overlapping mechanisms of action. However, I think by looking at chemotherapy drugs in this manner, it does give us a framework from which to kind of think about the drugs in terms of how they work and also gives us some guides into their toxicity. The agents we will talk about are the alkylating agents, platinum compounds, taxanes, antimetabolites, plant alkaloids and antitumor antibiotics.

Examples of alkylating agents pertinent to the care of gynecology cancer includes cyclophosphamide, ifosfamide and melfalan, each of these having a similar mechanism of action. The side effects of alkylating agents include myelosuppression and in fact, this is usually the dose limiting toxicity. Hair loss and alopecia is common but present to varying degrees, depending upon the individual agent present and nausea and vomiting can be problematic. This profile we’ll see repeated over and over in many of the chemotherapy agents we are going to talk about. Fortunately, we have agents today that can reduce, if not eliminate vomiting and greatly reduce nausea. In the class of alkylating agents, I think it’s important to emphasize one agent ifosfamide which has some unique toxicities. One of the alkylating metabolites of ifosfamide known as Acrilan is concentrated into the urine and in the bladder, and has the potential to do damage to bladder mucosa, therefore, hemorrhagic cystitis is an important toxicity of ifosfamide. We must administer mesna each time with ifosfamide which is a uroprotector binding with Acrilan and eliminating it from the bladder. Another toxic metabolite of ifosfamide can result in CNS depression and this can result from confusion decreased level of consciousness, all the way to coma and although there is no direct treatment for this, one must monitor for this side effect and discontinue the drug if any change in consciousness is noted.

The platinum compounds have mechanisms similar to alkylating agents in that they result in DNA cross liking again, preventing DNA replication, DNA, RNA and protein synthesis. The common examples of the platinum compounds that we use each day are cisplatin and carboplatin. In most gynecologic cancers we feel that these medications can be used with similar efficacy, they are essentially interchangable. The way we decide upon which drug to use is based upon toxicity profiles. Cisplatin primarily is toxic to the renal system, is very highly emetogenic, one of the most nausea/vomiting causing drugs that we give and results in a significant peripheral neuropathy, particularly when high accumulative doses are utilized. In contrast, carboplatin tends to be more hematologic toxic, resulting in anemia and thrombocytopenia. For this reason, carboplatin is used more favorably in most gynecologic cancer regimens. I would say that one exception would be in germ cell tumors where we tend to use cisplatin over carboplatin. The antimetabolites are a large family of chemotherapy drugs which tend to interrupt normal cellular enzyme function, and therefore disrupt normal cell function. Methotrexate is probably the most common antimetabolite that is utilized in gynecologic tumors, methotrexate works by binding the enzyme dihydrofolate reductase in preventing the synthesis of tetrahydrofolate. Tetrahydrofolate is a very important cofactor needed for purine nucleotide synthesis. In some methotrexate regimens, will actually give back tetrahydrofolate in the form of leucovorin, we have often heard of leucovorin rescue that will administer to patient’s 12 hours and 24 hours after the methotrexate dose.

Next, I want to mention the taxane compounds, one of the great advances in gynecologic cancer care in the last 10 years, taxane compounds bind the protein tubulin and stabilize the microtubule apparatus of the mitotic spindle, and for this reason, it is cell cycle specific within the imphase. Only recently have the pharmaceutical industry been able to do a semisynthetic manufacture of paclitaxel making it available to the general public. The toxicity profile of paclitaxel includes hematology toxicity, neutropenia being the dose limiting toxicity, complete alopecia, nausea and vomiting, and important to paclitaxel use, is a peripheral neuropathy which can be progressive during paclitaxel treatment and can be quite disabling in some patient’s.

Moving on to the plant alkaloids, vincristine and vinblastine are important family of agents used, namely in germ cell tumors. These work similarly to paclitaxel and the microtubule apparatus, but instead of stabilizing, it actually inhibits microtubular assembly and therefore again, these alkaloids are in cycle specific and vincristine and vinblastine having some of the other toxicities we mentioned also are worrisome because of neuropathy and very important risk for extravasation injury should the compound leak outside of the IV into surrounding tissues. Another plant alkaloid that has come on the scene in the past 10 years is topotecan which is a topoisomerase II inhibitor, which are an important family of enzymes that result in temporary breaks in the DNA strand to relieve torsional strain to allow for DNA replication. The presence of topotecan interrupts that mechanism resulting in freezing of DNA replication and ultimate toxicity.

Now we will talk about the antitumor antibiotics, these work by a number of various mechanisms including interactions with DNA, inducing breaks in DNA, and again prevention of DNA and RNA synthesis. I think one of the more important antitumor antibiotics that we should mention would be doxorubicin, dactinomycin and bleomycin. Let’s focus on doxorubicin for a moment. Doxorubicin actually has multiple mechanisms of cellular cytotoxicity including DNA binding inducing breaks, free radical cell injury and it’s also a topoisomerase inhibitor. The free radical injury also has a very important toxic component to normal tissues, namely cardiac toxicity, and we know that large cumulative doses of doxorubicin can result in an irreversible and life threatening cardiomyopathy and the risk of that cardiac toxicity is 10% for accumulative life time dose of doxorubicin greater than 500 mg per meter squared. The second antitumor antibiotic that I want to talk about is bleomycin. This is a unique agent that results in free radical formation resulting in DNA strand breaks, and unique to bleomycin from pretty much all the other chemotherapy agents and gynecology cancer, it’s not myelosuppressive. However, important toxicities to consider include pulmonary fibrosis which appears at an increased risk in patient’s with accumulative life time dose of bleomycin greater than 400 units, bleomycin also results in skin hyperpigmentation, we see darkening of nail beds and darkening of the skin, and dermatographia in which patient’s have permanent scarring in areas where there is injury to the skin such as scratching.