through the cell cycle. However, how we administer drugs also depends on the combinations that we give and the doses that we give.

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1 Hello and welcome to this lecture. My name is Hillary Prescott. I am a Clinical Pharmacy Specialist at The University of Texas MD Anderson Cancer Center. My colleague, Jeff Bryan and I have prepared this lecture to help you understand the role of drug therapy as a treatment modality for cancer. In this lecture, we ll focus on the role of drug therapy, specifically chemotherapy, hormone therapy, immune-based and targeted therapy as options to treat cancer. During my part of the lecture, I ll discuss the goals and the roles of drug therapy and give an introduction to the different chemotherapy and hormonal agents. Upon completion of this lesson, we hope you re able to discuss the goals and roles of drug therapy; to identify the different types of chemotherapy; and to differentiate between chemotherapy, hormone therapy, immune-based and targeted therapy; and last, to identify the common toxicities associated with the different chemotherapy agents and classes. It s important to understand that the goals of treatment may vary depending on the type and the stage of a patient s cancer. In the best-case scenario, the goal is to cure the cancer or totally eradicate the tumor and all of the cancer cells. If the goal is to control the tumor, the objective then is to arrest or slow the tumor growth. So it may not be possible to eradicate all of the cancer cells, but we at least want to slow the tumor s growth in order to extend and improve the quality of life of the patient. We can use drug therapy in the palliative setting and this is to relieve symptoms caused by the tumor, for example, pain. The main purpose here is to improve the patient s quality of life. Lastly, we can use certain agents, such as hormone therapy, to try to prevent cancer in certain high-risk populations. Along with understanding the different goals of therapy, it s important to know that there are different roles of drug therapy. And they vary depending on the treatment of different types of cancer. The roles of drug therapy in solid tumors can be used at several different time points in the treatment process. Induction therapy refers to the primary treatment given to induce a complete remission. Drug therapy can be given in the neoadjuvant setting, which means it s given before surgical removal of the tumor, usually to shrink the tumor. Adjuvant therapy refers to the administration of drug therapy after surgery and is given to increase the chance of cure. Drug therapy is often used in the salvage setting for treatment of cancers that have failed to respond to prior treatment or that have recurred after being in a complete remission. And in some cases drug therapy can actually be given as -- in -- as palliative treatment with the sole purpose of relieving symptoms, reducing suffering, and improving quality of life. Contrary to the solid tumors, drug therapy or chemotherapy is not used in the adjuvant or the neoadjuvant setting for the treatment of hematologic malignancies like the leukemias or the lymphomas. Generally speaking, when a patient s diagnosed with a hematologic malignancy, induction chemotherapy is administered. This is our primary method to eliminate the tumor or the cancer cells. And again, here is where we want to achieve a complete remission. Following induction chemotherapy, and only if a patient has achieved a complete remission, a second phase of chemotherapy called

2 consolidation or intensification is given to eradicate any undetectable disease. Then maintenance chemotherapy is given in certain malignancies to help prolong the effects of remission and to eradicate any minimal residual disease. Similar to the solid tumors, drug therapy can be used in the salvage and palliative setting as well. Now, once we give chemotherapy, how do we measure or define its response? For solid tumors, there are two sets of criteria, the World Health Organization and the RECIST criteria. These criteria differ slightly, but both are commonly used in practice. A complete remission is universal and is defined as the disappearance of all known cancer. Depending on the criteria, a partial response is when there s a 30 to 50% decrease in the size of the tumor. If the tumor has neither grown nor shrunk, the patient s considered to have stable disease. And finally progressive disease is when the tumor actually grows despite therapy. The criteria for response in hematologic malignancies really depends on the type of malignancy. And there are guidelines with specific criteria for each type of hematologic malignancy. So, when or how did we first discover chemotherapy? Well, Paul Ehrlich is credited with coining the term chemotherapy in the early 1900s, and this was during his search for a chemical that would cure not cancer, but syphilis. It wasn t until 1942, during World War II, that nitrogen mustard was discovered and used for the treatment of cancers. Then, over the next 20 to 30 years, chemotherapy made its introduction into clinical practice. Since 1949, over a hundred -- therapeutic -- chemotherapeutic agents have been approved for oncologic use in the United States and nearly half of these approvals occurred over the last decade. Now, I ll spend some time discussing chemotherapy agents. Chemotherapy agents are cytotoxic in nature, meaning they are able to destroy and kill cells. Most chemotherapy agents work by either modifying or interfering with DNA synthesis and, thus, are therapeutic options for the treatment of malignancy. Chemotherapy is the treatment of choice for most hematologic malignancies and advanced solid tumors. As previously noted, most chemotherapy agents interfere with DNA synthesis. In turn, chemotherapy is able to block or inhibit cell growth and cell replication. In addition, certain chemotherapy agents and classes of chemotherapy are able to initiate apoptosis or programed cell death of the cancer cells. You can see that it s important to find the balance between destroying cancer cells and sparing normal cells. Most of us --- Most of us --- have seen and studied the cell cycle. The cell cycle is important to know because it gives us insight into how different chemotherapy agents work. Chemotherapy agents that are cell-cycle non-specific exert their cytotoxic effects throughout any phase of the cell cycle. Theoretically, the magnitude of cell kill is proportional to the dose given. Whereas chemotherapy agents that are cell-cycle specific exert a majority of their activity or cell kill in a specific phase of the cell cycle, for example the M-phase or the G2- phase. These agents theoretically are best given as a continuous infusion with the idea that we maximize cell kill as the different cells pass

3 through the cell cycle. However, how we administer drugs also depends on the combinations that we give and the doses that we give. To help put this concept into perspective, we have shown some examples of phase specific agents and where they work in the cell cycle. Remember though that not all chemotherapy is cell-cycle phase specific. Now, I ll briefly review the different classes, or biochemical categories of chemotherapy agents. In general, chemotherapy is classified by their mechanism of action. And these include alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antimetabolites, miscellaneous agents, and hormone therapy. The alkylating agents are the oldest and most commonly used agents. They are prodrugs that are converted to reactive compounds that bind to DNA and form covalent bonds or cross-links with DNA. This leads to the inhibition of DNA replication. These agents are cell-cycle phase non-specific. There are many classes of alkylating agents. These include the nitrogen mustards like cyclophosphamide and ifosfamide; the nitrosureas, like carmustine and lomustine. The platinum analogs, like cisplatin and carboplatin as well as many other agents. The alkylating agents differ in their spectrum of activity, their toxicity profiles as well as their pharmacokinetics. Another class of chemotherapy includes the topoisomerase inhibitors. Topoisomerases are enzymes that break and reseal DNA strands. By inhibiting this enzyme, these agents induce DNA damage thereby preventing DNA replication and ultimately protein synthesis. The plant alkaloid camptothecans are Topo I inhibitors and these are S-phase specific. Topo II inhibitors include the epipodophyllotoxins, which are also cell-cycle specific, and drugs from other classes such as the anthracyclines like doxorubicin, idarubicin, daunorubicin, which are cell-cycle non-specific. There are 2 types of mitotic inhibitors, the vinca alkaloids and the taxanes. The vinca alkaloids exert their effect by binding to tubulin and inhibiting the assembly of microtubules. This prevents the formation of DNA synthesis and arrests the cells or tumor growth in the metaphase or the M-phase. The taxanes differ from the vinca alkaloids in that they enhance microtubule formation and prevent the disassembly of the microtubules. This leads to non-functional microtubule formation and the cells arrest in the G2 or the M-phase.

4 The different vinca alkaloids and taxane agents are listed here. Examples include vincristine and vinorelbine as well as paclitaxel and docetaxel. And both of these are derived from plants and trees. If you think back to basic biology, there are a handful of nucleotides that make up DNA and RNA. Anti-metabolites are drugs that --- struct --- structurally resemble these nucleotides and that inhibit the metabolic pathways needed for DNA and RNA synthesis. Anti-metabolites can also work by inhibiting enzymes needed for DNA and RNA synthesis. This leads to cell-cycle arrest thus making these agents S-phase specific. Methotrexate and pemetrexed are anti-metabolites or folate antagonists that work by inhibiting the enzyme needed for DNA synthesis. The other agents are purine and pyrimidine analogs and these are all incorporated into RNA and DNA, opposed to inhibiting an enzyme needed. Then, there are several anti-neoplastic agents that are classified as miscellaneous drugs. And this is because they work through different mechanisms than the ones I have already explained. These include drugs like L-asparaginase, the IMiDs, such as thalidomide and lenalidomide, bortezomib, arsenic among others. Now, we will slightly shift gears and spend some time discussing the role of hormone therapy. Endocrine or hormone therapy is --- is an important and effective means for treating many hormone-sensitive cancers. Just as hormones influence the growth of many normal tissues, many malignant cells retain a degree of hormonal sensitivity depending on their origin. This is particularly true for cancers of the breast, prostate, and endometrium. Although hormonal therapy by itself can t cure cancer, it does play an important role in the treatment of many cancers. As well, hormone therapy has a role in supportive care with many agents being used as appetite stimulants or for the prevention or treatment of -- drug-induce -- chemotherapy-induced nausea and vomiting. High-dose corticosteroids like dexamethasone are used in the treatment of many hematologic malignancies. Dexamethasone appears to work by having a lytic effect on lymphocytes. And so they are considered equally important agents in the treatment of hematologic malignancies to chemotherapy. Dexamethasone also plays an important role in the prevention and treatment of chemotherapy-induced nausea and vomiting and is considered standard of care. Megestrol acetate is a progestin that is often prescribed as an appetite stimulant to patients with cancer. And it has also been used in the actual treatment of certain cancers, metastatic cancers, for example, prostate cancer. As well, estrogens and androgens have also been used in the treatment of certain metastatic cancers. On the contrary, the inhibition of estrogen and androgen is also important. Antiestrogens and anti-progestins are very important means of treatment for certain cancers. Tamoxifen is probably the most famously used anti-estrogen and plays a

5 critical role in the treatment of breast cancer, where its use has been shown to prolong survival in certain patients with breast cancer. The aromatase inhibitors are also important drugs in cancer therapy for patients with breast cancer. Their mechanism and their side-effect profile differ from that of tamoxifen. It s important to remember that these agents only work when the tumor cells are estrogen- or progestin-positive. This slide demonstrates how hormone therapy works in a very different way compared to conventional cytotoxic chemotherapy. Tamoxifen an anti-estrogen binds to the estrogen receptor on the breast cancer cells and prevents the binding of estradiol, whereas the aromatase inhibitors inhibit the conversion of androgens to estrogen in the peripheral tissue, thus depleting the amounts of estradiol that go into circulation. The anti-androgens and the LHRH agonists are also hormone therapy and these are important treatments for patients with prostate cancer. Again, these agents work in a very different mechanism than conventional cytotoxic chemotherapy. The LHRH agonists work via a negative feedback loop to inhibit the -- pro --- production of testosterone in the testes. The anti-androgens actually block the biologic effects of androgens by binding to the androgen receptors inside the prostate cells and prevent the activity of testosterone. We ve now reviewed the goals and the roles of drug therapy in the treatment of cancer and the various classifications of drugs used including chemotherapy and hormone therapy. In part 2 of this module, immune-based and targeted therapies will be discussed as well as the common side effects of drug therapy. Thank you for your attention and we welcome your feedback.

Cancer Chemotherapy. Munir Gharaibeh MD, PhD, MHPE School of Medicine, The University of Jordan December 2018

Cancer Chemotherapy. Munir Gharaibeh MD, PhD, MHPE School of Medicine, The University of Jordan December 2018 Cancer Chemotherapy Munir Gharaibeh MD, PhD, MHPE School of Medicine, The University of Jordan December 2018 االدوية Polyfunctional Alkylating Agents االستخالبية متعددة الوظائف Not cell cycle-specific.