1 PowerPoint Slides English Text Mandarin Chinese Translation Treatment Modalities: Drug Therapy, Part 2 VideoTranscript 2 Professional Oncology Education Treatment Modalities: Drug Therapy, Part 2 Time: 18:16 2 18:16 Jeffrey Bryan, Pharm.D. Clinical Pharmacy Specialist Pharmacy Clinical Programs The University of Texas MD Anderson Cancer Center MD Anderson Jeffrey Bryan, Pharm.D. Treatment Modalities: Treatment Modalities: Treatment Modalities: Treatment Modalities: Drug Therapy Part II Drug Therapy Part II Drug Therapy Part II Drug Therapy Part II Treatment Modalities: Treatment Modalities: Drug Therapy Drug Therapy – – Part II Part II Jeffrey Bryan, Pharm.D. Clinical Pharmacy Specialist Pharmacy Clinical Programs Hello, my name is Jeffrey Bryan. I am a Clinical Pharmacy Specialist with The University of Texas MD Anderson Cancer Center. I would like to welcome you to the second part of Treatment Modalities: Drug Therapy. Jeffrey Bryan MD Anderson
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PowerPoint Slides English Text Mandarin Chinese Translation
Treatment Modalities: Drug Therapy, Part 2 VideoTranscript
治疗方法:药物疗法,第 2 部分 视频文本
Professional Oncology Education Treatment Modalities: Drug Therapy, Part 2 Time: 18:16
专业人员肿瘤教学讲座 治疗方法:药物疗法,第 2 部分 时间: 18:16
Jeffrey Bryan, Pharm.D. Clinical Pharmacy Specialist Pharmacy Clinical Programs The University of Texas MD Anderson Cancer Center
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Treatment Modalities: Treatment Modalities:
Drug Therapy Drug Therapy –– Part II Part II
Jeffrey Bryan, Pharm.D.
Clinical Pharmacy Specialist
Pharmacy Clinical Programs
Hello, my name is Jeffrey Bryan. I am a Clinical Pharmacy Specialist with The University of Texas MD Anderson Cancer Center. I would like to welcome you to the second part of Treatment Modalities: Drug Therapy.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
ObjectivesObjectivesObjectivesObjectives
Upon completion of this lesson, participants will
be able to:
• Discuss the goals and roles of drug therapy
• Identify classifications of chemotherapy
• Differentiate between chemotherapy, hormone,
immune-based, and targeted therapy
• Identify common toxicities of drug treatment
Upon completion of this lesson, participants should be able to discuss the goals and roles of drug therapy; identify classifications of chemotherapy; differentiate between chemotherapy, hormone therapy, immune-based therapy, and targeted therapy; and identify some common toxicities associated with chemotherapeutic agents.
The idea of stimulating or augmenting the body’s own immune system to fight or prevent cancer led to the development of immune-based therapies. This is now referred to by many as the fourth cancer treatment modality. The idea is to use various cytokines and other biologic response modifiers, such as interferon, monoclonal antibodies, and vaccines, to stimulate the host immune system to attack the tumors.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIImmuneImmuneImmuneImmune----based Therapy based Therapy based Therapy based Therapy ----Interferons/InterleukinsInterferons/InterleukinsInterferons/InterleukinsInterferons/Interleukins
• Cytokines - proteins that are normally produced in
the body in response to stress
• Act as chemical signals to:
– Directly slow tumor growth
– Slow angiogenesis (formation of new blood vessels)
– Stimulate cancer cells to produce antigens
– Stimulate immune system cells to attack cancer cells
• Interferon-alfa: CML, melanoma, lymphoma
• Interleukin-2 (IL-2): melanoma, renal cell
Interferons, interleukins are part of a family of cytokines and proteins that are normally produced in the body in response to stress or inflammation. Genetically-engineered interferon and interleukin have been shown to have anti-tumor effects in several malignancies. Although their toxicities differ from conventional chemotherapy, they are associated with a constellation of symptoms, such as fever, chills, myalgias, depression, and sometimes myelosuppression.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIImmuneImmuneImmuneImmune----based Therapy based Therapy based Therapy based Therapy ----Monoclonal Antibodies (MoAb)Monoclonal Antibodies (MoAb)Monoclonal Antibodies (MoAb)Monoclonal Antibodies (MoAb)
• Developed to target specific proteins/antigens
involved in the development and progression
of cancer
• High specificity to tumor-specific targets
• Different toxicity profile from conventional
cytotoxic agents
• Synergy with chemotherapy agents
In recent years, a number of monoclonal antibodies have been developed for the treatment of patients with a variety of cancers. These agents target specific proteins or antigens that are expressed on tumor cells. Additionally, these agents can be given as a single agent or in combination with conventional chemotherapy without overlapping or increasing toxicity.
Monoclonal antibodies are synthesized from different sources. The majority of monoclonal antibodies are chimeric, meaning that they have a murine variable region fused to a human constant region or humanized, meaning they are predominantly of human origin.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIMonoclonal Antibodies Monoclonal Antibodies Monoclonal Antibodies Monoclonal Antibodies ----Conjugated vs. UnconjugatedConjugated vs. UnconjugatedConjugated vs. UnconjugatedConjugated vs. Unconjugated
Additionally, monoclonal antibodies can be conjugated or unconjugated. Conjugated monoclonal antibodies have a toxin or a radionucleotide attached to the antibody that allows the toxin to be delivered to the tumor. Whereas unconjugated monoclonal antibodies rely on activating the host immune system, which in turn attacks the tumor.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIImmuneImmuneImmuneImmune----based Therapy based Therapy based Therapy based Therapy ----Monoclonal AntibodiesMonoclonal AntibodiesMonoclonal AntibodiesMonoclonal Antibodies
This is a list of some of the FDA-approved monoclonal antibodies along with their main characteristics and indications. You can see that each monoclonal antibody has a very specific antigen it targets. For example, rituximab targets CD20 on B-cells and gemtuzumab target CD33 on myeloid cells.
这份表格列出了 FDA 批准的部分单克隆抗体及其主要特征和适应症。可以看到每种单克隆抗体都有特异性极强的靶的抗原。例如,利妥昔单抗的靶的是 B 细胞的 CD20,而吉妥单抗是针对髓系细胞的
• Agents that specifically target cell processes that
are aberrant or more abundant in malignant cells
than normal cells
• Target cellular processes and signaling pathways
that affect:
– Cell growth and differentiation
– Angiogenesis (new blood vessel formation)
– Apoptosis (programmed cell death)
– Cell motility
We have discussed conventional chemotherapy, hormone therapy, and immune-based therapy. Now, I will spend some time discussing what is called targeted therapy and the implications on the treatment of cancer. A major limitation of current cytotoxic therapy is the lack of sensitivity on malignant cells. Chemotherapy can affect any cell that is rapidly dividing whether it be normal or malignant. As our knowledge of tumor biology increases, novel therapeutic strategies, such as targeted therapy have evolved. What is unique about targeted therapy [is] that it targets processes. Targeted therapy blocks growth of cancer cells by interfering with specific molecules, a process very different from conventional chemotherapy, hormone therapy, and immune-based therapy.
Similar to conventional chemotherapy, targeted therapy is considered systemic therapy, but designed to affect predominantly cancer cells. For this reason, these drugs are associated with very different and sometimes less side effects. The effectiveness of these drugs often depends on the expression of the target antigen receptor and other molecules on the cancer cells. A benefit of targeted therapy is that they often come in oral formulations.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Targeted Therapy Targeted Therapy Targeted Therapy Targeted Therapy ---- Mechanism of ActionMechanism of ActionMechanism of ActionMechanism of Action
This diagram shows the different targets for drug therapy. You can see that outside of the cell, or on the cell surface, there are growth factors that bind to the receptors. The binding triggers a cascade of intracellular events involving many tyrosine kinases. This results in increasing cell growth, proliferation, and differentiation along with angiogenesis. By inhibiting one of these proteins, you can prevent the downstream effects.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Targeted Therapy Targeted Therapy Targeted Therapy Targeted Therapy ---- Mechanism of ActionMechanism of ActionMechanism of ActionMechanism of Action
This is another depiction of the targets for some of our monoclonal antibodies and/or tyrosine kinase inhibitors. For instance, gemtuzumab targets the CD33. Gemtuzumab is complexed with a toxin called calicheamicin. Upon binding the CD33, the calicheamicin is engulfed by the cell, which causes ultimate cell death. On the bottom half of this picture, a lot of these monoclonal antibodies are used for solid tumors. But these target cell processes. And internally a lot of the tyrosine kinases such as imatinib and dasatinib target pathways that are responsible for cell differentiation and cell survival.
This list lists --- this table lists many FDA-approved targeted therapies and summarizes their mechanisms of action, targets, and indications. For example, bevacizumab targets VGEF, which is the vascular endothelial growth factor. And cetuximab covers --- cetuximab binds to the epidermal growth factor receptor. And we get a whole list of tyrosine kinase inhibitors, which target the cell processes within the cell, for instance, imatinib, dasatinib and erlotinib.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIImmuneImmuneImmuneImmune----based and Targeted Therapy based and Targeted Therapy based and Targeted Therapy based and Targeted Therapy ----SummarySummarySummarySummary
• Blocks the growth of cancer cells by interfering with
specific targeted molecules needed for tumor growth
• Important role as monotherapy or in combination with
chemotherapy for the treatment of cancers
• Future of cancer drug development
In summary, immune-based therapy and targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for tumor growth. These play an important role for monotherapy and in combination in chemotherapy for the treatment of cancers. And this is the future of cancer drug development.
Conventional chemotherapy is generally dosed off of BSA, which is calculated off the height and weight of the patient. For instance, a dose of 20 mg/m
2 in
the BSA of a patient is 2, the dose will be 40 mg. Oftentimes, single-agent chemotherapy is used in the palliative role, but it is generally less toxic and less toxic to cancer cells, whereas chemotherapy given in combination capitalizes on different mechanisms of action of the chemotherapy for achieving greater cell kill and preventing resistant cell lines.
• Dose Intensity - dose delivered over a specified
period of time (mg/m2/week)
– ⇑ dose intensity = ⇑ response rate
– Leukemias, lymphomas, breast, ovarian
• Dose Density - shortening the usual interval between
doses; designed to maximize the drug’s effects on
tumor growth kinetics
– May require growth factor support
Now that we are familiar with dosing chemotherapy, effecting --- effective dosing can be a factor limiting the ability of chemotherapy to achieve a cure. There are generally two types of dosing strategies: dose intensity and dose density. Dose intensity is the total amount of drug administered at one time or over a week, every 28 days for instance. There can be a positive relationship between dose intensity and response rate. However, there is also a correlation with increased toxicity with dose intense regimens. Dose density, on the other hand - you give the drug, give smaller doses of the drug more often, for instance, once a week or every two weeks.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Common Drug Therapy ToxicitiesCommon Drug Therapy ToxicitiesCommon Drug Therapy ToxicitiesCommon Drug Therapy Toxicities
• Gastrointestinal toxicity
• Cardiotoxicity
• Neurotoxicity
• Hepatotoxicity
• Nephrotoxicity
• Dermatologic toxicity
• Myelotoxicity
The ideal chemotherapeutic medication will kill tumor cells and spare normal cells. Unfortunately, this is not the case when it comes to most --- most chemotherapy. Toxicities from chemotherapy can potentially affect any organ in the body and result in affecting both the patient’s quality of life and treatment outcomes. I will spend some time going over some of the toxicities of chemotherapy.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Drug Therapy ToxicityDrug Therapy ToxicityDrug Therapy ToxicityDrug Therapy Toxicity
• Factors that may influence treatment toxicity
– Dose of chemotherapy
• High dose vs. low dose
– Treatment schedule
• Weekly vs. biweekly vs. monthly
– Combination therapy
• Anthracycline with antimetabolite
– Patient specific factors
• Age, BSA, organ function, comorbidities,
response to prior therapies
– Method of administration
• Continuous vs. bolus
– Drug-drug and drug-herbal interactions
But, before we do this, there are many factors that influence treatment toxicity, for instance the dose of chemotherapy, the treatment schedule, whether the chemotherapy is given in combination or as a single agent, and patient-specific factors, such as age. Elderly patients have less --- are less tolerable of chemotherapy, oftentimes because they might have poor organ function or other comorbidities. Additionally, the method of administration, whether it is given continuous versus bolus, can affect the toxicity of the drug. And you have to consider other drugs and herbal products when giving chemotherapy as well.
Nausea and vomiting are common side effects of chemotherapy and are feared by most patients. In the setting of chemotherapy, nausea and vomiting is medically known as chemotherapy-induced nausea and vomiting. It is often the first side effect of patients that --- it is often the first side effect patients experience. Nausea and vomiting can be characterized as acute, occurring within the first 24 hours of starting chemotherapy, or delayed nausea and vomiting occurs within 24 hours after chemotherapy. Breakthrough nausea and vomiting is that which occurs despite being on medication to preventive it. Refractory nausea and vomiting is that that does not respond at all to treatment. Finally, anticipatory nausea and vomiting is when a patient experiences symptoms prior to starting their next cycle of chemotherapy.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIEmetogenic Potential of Commonly Emetogenic Potential of Commonly Emetogenic Potential of Commonly Emetogenic Potential of Commonly used Agents used Agents used Agents used Agents
NCCN v.1.2010 Antiemesis Practice Guidelineshttp://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf
Interestingly, not all chemotherapeutic agents cause the same degree of nausea or vomiting. There are several classification systems that define emetogenicity of chemotherapy. And this helps us choose what kind of antiemesis regimen we will use. Although this table is not all inclusive, it shows examples of chemotherapeutic agents that are thought to be of high emetogenic risk and associated with minimal emetogenic risk. As you may have noticed, the emetogenic potential - some chemotherapy is dose --- dose-dependent.
And, if nausea and vomiting is not enough, certain agents also destroy the mucosal lining throughout the gastrointestinal tract. Tissue lining this gastrointestinal tract is usually rapidly dividing cells. Hence, these cells are susceptible to the actions of chemotherapy. Agents, such as methotrexate and 5-fluorouracil, can cause mucositis and inflammatory reactions of the mucosal lining. Irinotecan, used for the treatment of colon cancer, almost always causes diarrhea, whereas vincristine does the opposite, causes constipation.
A rare, but serious, complication with some chemotherapy agents is cardiotoxicity. Cardiotox --- Cardiotoxicity can manifest as cardiomyopathy, congestive heart failure, ischemia, arrhythmias, or hypertension. Anthracyclines are well recognized as the agents that cause cardiomyopathies and congestive heart failure when certain cumulative doses of the anthracycline have been reached.
– Ataxia, nystagmus, gait and coordination abnormalities
– High dose cytarabine (> 1 gm/m2)
• Encephalopathy
– Confusion, aphasia, headache
– Methotrexate, ifosfamide
• Arachnoiditis
– Headache, nausea/vomiting, fever, photophobia
– Intrathecal methotrexate and cytarabine
• Seizures
– Nelarabine
Neurotoxic effects of chemotherapy occur fairly frequently and are often reasons to limit the dose or delay therapy. Some agents cause both central and peripheral neurotoxicity. For example, high-dose cytarabine, ifosfamide, and nelarabine are commonly known for their central neurotoxic side effects.
Chemotherapy can also induce peripheral neuropathy that is related to the cumulative dose and the type of drug used. The vinca alkaloids, the platinum analogs, and the taxanes are notorious for inducing peripheral neuropathy. The early signs and symptoms are pain or tingling in the hands and feet and sometimes loss of reflexes. And this is usually a reason for delaying or reducing the dose of the next cycle.
Chemotherapy can also cause hepatotoxicity that can manifest as elevated liver function tests, cholestasis, and veno-occlusive disease, which is injury to the hepatic venous endothelium. Many of these drugs are cleared through the liver, hence, will require dose adjustment in the setting of hepatocellular injury or reduced liver function. I’ve provided a list of drugs that are typically hepatotoxic or hepatically-cleared agents. Some of them include vinca alkaloids, cytarabine, methotrexate, clofarabine, imatinib, and L-asparaginase.
And you cannot forget about nephrotoxicity. Many of the chemotherapy agents are renally cleared through the kidneys. Two common agents are methotrexate and cisplatin. They are both renally eliminated and cause --- can cause renal insufficiency or renal failure. Impaired renal function can increase systemic toxicities. Hence many drugs require dose reduction or avoidance in the setting of renal insufficiency.
It is not surprising that some of these medications cause problems with the skin. The good news is that many of these agents --- many of these problems are reversible. Hair loss is a common side effect of some of these agents. Extravasation occurs when the drug leaks through the tubing into the skin and causes skin necrosis. Occasionally, this may require surgical intervention. Interesting --- interestingly, some targeted therapies cause acne-like rash on the face, trunk, and extremities.
– Decrease in the number of circulating neutrophils
– Single most important predisposing factor to infection
• Anemia
– Decrease in hemoglobin or circulating erythrocytes
• Thrombocytopenia
– Decrease in the number of circulating platelets
Adverse effects on the bone marrow production called myelosuppression is a serious toxicity that can manifest as neutropenia, anemia, or thrombocytopenia. Myelosuppression is often dictated by the dose, schedule, and type of agent being used. Patient characteristics as well, the age, renal function, liver function, etc., can affect the dosing and the toxicity of these drugs. Neutropenia is a very serious side effect due to the risk of infection. Febrile neutropenia often requires hospitalization and IV antibiotics. Anemia is --- often causes fatigue and thrombocytopenia, increases your risk for bleeding. These complications can be thwarted by transfusions.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Dosing and Toxicity SummaryDosing and Toxicity SummaryDosing and Toxicity SummaryDosing and Toxicity Summary
• Drug therapy can affect any organ system in
the body
• Factors that influence treatment toxicity may
include drug dose, organ function, age and method
of administration
• Monitoring and management of drug-induced toxicity
plays an important role in caring for cancer patients
So, in summary of dosing and toxicity, drugs can affect any organ system in the body. And factors that often influence treatment toxicity can include the drug, the drug dose, organ function, age, and method of administration. And monitoring and management of drug-induced toxicity requires a multidisciplinary approach.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
ConclusionsConclusionsConclusionsConclusions
• Drug therapy may be used for various goals in
cancer treatment depending on a patient’s disease
and prognosis
• Chemotherapy drugs are classified by mechanisms
of action and differ in cytotoxic mechanisms of action
• Newer immune-based and targeted therapies are
emerging and serve an important role in cancer
care
• Drug therapy may result in a wide variety
of side effects
In summary, the purpose of chemotherapy may vary depending on patient-specific factors, such as age, comorbidity, tumor stage, and type of malignancies. The mainstay of oncology therapy still involves cytotoxic agents that indiscriminately kill rapidly dividing cells. Novel therapies, such as immunotherapy and targeted therapy, targets tumor-specific molecules and processes while hopefully preserving normal tissue. Often targeted therapy is combined with conventional chemotherapy.
Drug Therapy Part IIDrug Therapy Part IIDrug Therapy Part IIDrug Therapy Part II
Cancer ResourcesCancer ResourcesCancer ResourcesCancer Resources
And lastly, I would like to leave you with this slide with a list of resources for additional cancer and chemotherapy information. I hope you have enjoyed this lecture and we welcome your feedback. Thank you.