Treatment Modalities: Drug Therapy Part II · welcome you to the second part of Treatment Modalities: Drug Therapy. Olá, eu sou Jeffrey Bryan. Sou especialista em ... Os interferons,

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Professional Oncology Education Treatment Modalities: Drug Therapy, Part 2 Time: 18:16

Educação Profissional em Oncologia

Modalidades de Tratamento: Terapia Medicamentosa, 2a Parte Duração: 18:16

Jeffrey Bryan, Pharm.D. Clinical Pharmacy Specialist Pharmacy Clinical Programs The University of Texas MD Anderson Cancer Center

Jeffrey Bryan, Pharm.D. Especialista em Farmácia Clínica Programas de Farmácia Clínica MD Anderson Cancer Center – Universidade do Texas

Treatment Modalities: Treatment Modalities: Treatment Modalities: Treatment Modalities:

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.

Olá, eu sou Jeffrey Bryan. Sou especialista em farmácia clínica no MD Anderson Cancer Center da Universidade do Texas. Gostaria de dar-lhes as boas-vindas à segunda parte das Modalidades de Tratamentos: Terapia Medicamentosa.

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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.

Na conclusão desta apresentação, os participantes devem ser capazes de discutir os objetivos e as funções da terapia medicamentosa, de identificar as classificações da quimioterapia e de diferenciar a quimioterapia, hormonoterapia, imunoterapia e terapia alvo, além de identificar as toxicidades comuns associadas aos agentes quimioterápicos.



Immune-based Therapy and

Targeted Therapy

At first, we will start off with immune-based therapy, then discuss targeted therapy.

Primeiro, começaremos com a imunoterapia; depois, discutiremos a terapia alvo.

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ImmuneImmuneImmuneImmune----based Therapybased Therapybased Therapybased Therapy

• Treatment with agents from biologic sources

and/or agents able to affect biologic responses

• Stimulates host’s immune system to fight

against cancer

• A means to deliver systemic anticancer therapy

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.

A ideia de estimular ou reforçar o sistema imunológico do organismo para combater ou impedir o câncer levou ao desenvolvimento de imunoterapias. Hoje, muitos se referem a essa ideia como sendo a quarta modalidade de tratamento antineoplásico. A ideia é utilizar várias citocinas e outros modificadores da resposta biológica, como o interferon, anticorpos monoclonais e vacinas, para estimular o sistema imunológico do hospedeiro e atacar tumores.


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.

Os interferons, as interleucinas, formam parte de uma família de citocinas e proteínas normalmente produzidas no corpo em resposta ao estresse ou à inflamação. O interferon e a interleucina geneticamente modificados demonstraram ter efeitos antineoplásicos em diversos cânceres. Embora sua toxicidade seja diferente da quimioterapia convencional, está associada a uma constelação de sintomas, como febre, calafrios, mialgias, depressão e, às vezes, mielossupressão.

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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.

Nos últimos anos, foram desenvolvidos diversos anticorpos monoclonais para o tratamento de pacientes com diferentes cânceres. Esses agentes atacam proteínas ou antígenos específicos expressos nas células tumorais. Além disso, podem ser administrados sozinhos ou em combinação com a quimioterapia convencional sem sobreposição ou aumento da toxicidade.



• Four Types of MoAbs

Murine (100% Murine)

Chimeric (30% Murine, 70% human)

Humanized (5% Murine, 95% human)

Human (100% human)

Monoclonal Antibodies (MoAbs)Monoclonal Antibodies (MoAbs)Monoclonal Antibodies (MoAbs)Monoclonal Antibodies (MoAbs)

Mouse

Human

(Murine = Mouse)

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.

Os anticorpos monoclonais são sintetizados de diferentes fontes. A maioria dos anticorpos monoclonais é quimérica; isto é, têm uma região variável murina ligada a uma região constante humana ou humanizada, que significa serem de origem predominantemente humana.

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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.

Além disso, os anticorpos monoclonais podem ser conjugados ou não conjugados. Os anticorpos monoclonais conjugados têm uma toxina ou um radionucleotídio ligado ao anticorpo que permite que a toxina seja entregue ao tumor. Em comparação, os anticorpos não conjugados contam com a ativação do sistema imunológico, que, por sua vez, ataca o 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.

Esta é uma lista de alguns anticorpos monoclonais aprovados pela FDA com suas principais características e indicações. Vocês podem ver que cada anticorpo monoclonal tem como alvo um agente bem específico. Por exemplo, o alvo do rituximabe é o CD20 em células B e o alvo do gemtuzumab é o CD33 em células mieloides.

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Targeted TherapyTargeted TherapyTargeted TherapyTargeted Therapy

• 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.

Já discutimos a quimioterapia convencional, a hormonoterapia e a imunoterapia. Agora, dedicaremos parte do nosso tempo discutindo o que se conhece como terapia alvo e as implicações no tratamento do câncer. A principal limitação da terapia citotóxica atual é a falta de sensibilidade nas células malignas. A quimioterapia pode afetar qualquer célula que se divida rapidamente, seja normal ou maligna. Com o aumento do conhecimento sobre a biologia dos tumores, surgem novas estratégias terapêuticas, como a terapia alvo. O aspecto singular da terapia alvo [é] ser dirigida aos processos. A terapia alvo bloqueia o crescimento das células tumorais interferindo em moléculas específicas, um processo muito diferente do da quimioterapia convencional, hormonoterapia e imunoterapia.



Targeted Therapy (continued)Targeted Therapy (continued)Targeted Therapy (continued)Targeted Therapy (continued)

• Systemic-like chemotherapy designed to target

cancer cells

• Optimal targets vary widely between cancers

• Effectiveness depends on the expression of

target antigen, receptor, or other molecules

• Different toxicity profile from conventional

cytotoxic agents

• Intravenous and oral formulations

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.

À semelhança da quimioterapia convencional, a terapia alvo é considerada uma modalidade sistêmica, mas projetada para afetar principalmente as células tumorais. Por essa razão, esses fármacos estão associados a efeitos secundários bastante diferentes e, às vezes, a um menor número deles. Frequentemente, a eficácia desses fármacos depende da expressão do receptor do antígeno alvo e outras moléculas nas células tumorais. Um benefício da terapia alvo é que, frequentemente, é oferecida em formulações orais.

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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.

Este diagrama mostra os diferentes alvos da terapia medicamentosa. Vocês podem ver que na parte externa da célula, ou na sua superfície, há fatores de crescimento que se ligam aos receptores. A ligação desencadeia uma cascata de eventos intracelulares nas quais participam muitas tirosino-quinases. Isso resulta no aumento do crescimento, proliferação e diferenciação celular, juntamente com a angiogênese. Ao inibir uma dessas proteínas, pode-se impedir os efeitos posteriores.



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.

Esta é outra ilustração dos alvos para alguns dos anticorpos monoclonais e/ou inibidores da tirosino-quinase. Por exemplo, o alvo do gemtuzumab é o CD33. O gemtuzumab forma um complexo com uma toxina denominada calicheamicina. Após ligar-se ao CD33, a calicheamicina é engolfada pela célula, causando sua morte. Na parte inferior desta foto, muitos destes anticorpos monoclonais são utilizados para tumores sólidos, mas seus alvos são processos celulares. E, internamente, os alvos de muitas das tirosino-quinases, como imatinibe e dasatinibe, são as rotas responsáveis pela diferenciação e sobrevivência das células.

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Targeted Therapy Targeted Therapy Targeted Therapy Targeted Therapy ---- Summary of AgentsSummary of AgentsSummary of AgentsSummary of Agents

Vascular endothelial growth factor = VEGFEpidermal growth factor receptor = EGFRTyrosine kinase inhibitor = TKIPlatelet-derived growth factor receptor = PDGFR

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.

Esta lista relaciona... esta tabela relaciona muitas terapias alvo aprovadas pela FDA e resume seus mecanismos de ação, alvos e indicações. Por exemplo, o alvo do bevacizumabe é o VGEF, que é o fator de crescimento endotelial vascular. E o cetuximabe cobre... o cetuximabe liga-se ao receptor do fator de crescimento epidérmico. E temos toda uma lista de inibidores da tirosino-quinase, cujos alvos são os processos celulares dentro da célula, por exemplo, imatinibe, dasatinibe e erlotinibe.


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.

Resumindo, a imunoterapia e a terapia alvo bloqueiam o crescimento de células tumorais ao interferir com moléculas alvo específicas necessárias para o crescimento do tumor. Essas terapias desempenham um importante papel na monoterapia e em combinação na quimioterapia para o tratamento do câncer. E este é o futuro do desenvolvimento de antineoplásicos.

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Dosing and Toxicity

Now we are going to switch gears a little bit and talk about dosing and toxicity.

Agora, mudaremos um pouco de assunto e falaremos sobre doses e toxicidade.



Dosing StrategiesDosing StrategiesDosing StrategiesDosing Strategies

• Body Surface Area (BSA)

– BSA(m2) =

• Single Agent Chemotherapy

– Less toxicity to normal tissue BUT

less toxicity to cancer cells

– Palliative role

• Combination Chemotherapy

– Different mechanisms of action

– Greater cell kill

– Fewer resistant cell lines

height (cm) x weight (kg)

3600√

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/m2 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.

Geralmente, na quimioterapia convencional, a dose é obtida levando em conta a superfície corporal, que é calculada utilizando a altura e o peso do paciente. Por exemplo, a dose de 20 mg/m2 na superfície corporal de um paciente é 2, a dose será de 40 mg. Com frequência, a quimioterapia de um único agente é utilizada na função paliativa, mas é geralmente menos tóxica e menos tóxica para as células tumorais, enquanto que a quimioterapia administrada em combinação capitaliza diferentes mecanismos de ação da quimioterapia por alcançar uma grande morte celular e impedir linhagens celulares resistentes.

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Dosing Strategies (continued)Dosing Strategies (continued)Dosing Strategies (continued)Dosing Strategies (continued)

• 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.

Agora que nos familiarizamos com a dose na quimioterapia, a dose eficaz pode ser um fator limitante da capacidade de a quimioterapia alcançar a cura. Em geral, existem dois tipos de estratégias para as doses: intensidade da dose e densidade da dose. Por exemplo, a intensidade da dose é a quantidade total do fármaco administrada uma vez ou durante uma semana cada 28 dias. Pode haver uma relação positiva entre a intensidade da dose e a taxa de resposta. No entanto, também existe uma correlação entre esquemas com doses intensas e aumento da toxicidade. Por outro lado, quanto à densidade, a dose é administrada em pequenas quantidades e com mais frequência; por exemplo, uma vez por semana ou cada duas semanas.



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.

O medicamento quimioterápico ideal destrói as células tumorais e preserva as células normais. Infelizmente, não é o caso da maioria das quimioterapias. As toxicidades da quimioterapia pode afetar qualquer órgão do corpo e, consequentemente, a qualidade de vida e os resultados do tratamento do paciente. Dedicarei parte do nosso tempo à discussão de algumas toxicidades da quimioterapia.

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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.

Mas, antes disso, existem muitos fatores que afetam a toxicidade do tratamento, por exemplo, a dose da quimioterapia, o horário do tratamento, se a quimioterapia for administrada em combinação ou como agente único, além de fatores específicos dos pacientes, como a idade. Os pacientes idosos são menos tolerantes à quimioterapia, frequentemente por causa do mau funcionamento dos órgãos ou outras comorbidades. Além disso, o método de administração, se for contínuo ou em bolus, pode afetar a toxicidade do fármaco. E temos que considerar outros fármacos e produtos à base de ervas quando a quimioterapia for administrada.



Gastrointestinal ToxicityGastrointestinal ToxicityGastrointestinal ToxicityGastrointestinal Toxicity

• Nausea and vomiting

– Most common early manifestation of toxicity

– Mechanisms

• Stimulation of chemoreceptor zones

• Damage to gastrointestinal mucosa

• Alterations in taste and smell

• Five distinct clinical syndromes

– Acute: < 24 hours after chemotherapy

– Delayed: ≥ 24 hours after chemotherapy

– Breakthrough: Symptoms despite prophylaxis

– Refractory: Ineffective treatment

– Anticipatory: Symptoms prior to therapy

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.

Náuseas e vômitos são efeitos colaterais comuns da quimioterapia e temidos pela maioria dos pacientes. No ambiente de quimioterapia, são conhecidos clinicamente como náuseas e vômitos induzidos por quimioterapia. Com frequência, é o primeiro efeito colateral que os pacientes apresentam. As náuseas e os vômitos podem ser caracterizados como agudos, quando ocorrem nas primeiras 24 horas do início da quimioterapia, ou tardios, quando ocorrem nas 24 horas após a quimioterapia. As náuseas e os vômitos incidentais são aqueles que ocorrem mesmo tomando medicamentos para evitá-los. As náuseas e os vômitos refratários são os que não respondem ao tratamento. Finalmente, as náuseas e os vômitos antecipatórios ocorrem quando o paciente experimenta sintomas antes de iniciar o próximo ciclo de quimioterapia.

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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.

Curiosamente, nem todos os agentes quimioterápicos causam o mesmo grau de náuseas e vômitos. Existem vários sistemas de classificação que definem a emetogenicidade da quimioterapia. Essa informação facilita a escolha do regime antiemético que usaremos. Embora esta tabela não seja completamente abrangente, mostra exemplos de agentes quimioterápicos que supostamente são de alto risco emetogênico e estão associados a mínimos riscos emetogênicos. Como podem ter observado, o potencial emetogênico... algumas quimioterapias são dependentes da dose.



Gastrointestinal ToxicityGastrointestinal ToxicityGastrointestinal ToxicityGastrointestinal Toxicity

• Mucositis

– Inflammatory reaction and ulcerative lesions

of mucosal surfaces

– Most commonly caused by methotrexate,

5-fluorouracil, vinca alkaloids

• Diarrhea

– Common adverse effect of irinotecan

• Constipation

– Common adverse effect of vincristine

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.

E, como se não bastassem as náuseas e os vômitos, alguns agentes também destroem a mucosa que reveste todo o trato gastrointestinal. O tecido que reveste o trato gastrointestinal é constituído por células que se dividem rapidamente. Por isso, essas células são suscetíveis aos efeitos da quimioterapia. Agentes, como o metotrexato e o 5-flurouracilo, podem causar mucosite e reações inflamatórias na mucosa. O irinotecano, utilizado para o tratamento do câncer de cólon, quase sempre causa diarreia, embora a vincristina cause o oposto, constipação.

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CardiotoxicityCardiotoxicityCardiotoxicityCardiotoxicity

• Rare but serious complication of cancer therapy

• Incidence and severity depends on agent, dose,

schedule, patient factors, and other treatments

• Cardiomyopathy

– Anthracyclines, interferon

• Ischemia

– Fluorouracil, sorafenib

• Arryhthmias

– Anthracyclines, arsenic, taxanes

• Hypertension

– Bevacizumab, sorafenib

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.

Uma complicação rara, mas grave, com alguns agentes quimioterápicos é a cardiotoxicidade. A cardiotoxicidade pode se manifestar como cardiomiopatia, insuficiência cardíaca congestiva, isquemia, arritmias ou hipertensão. As antraciclinas são bem reconhecidas como agentes que causam cardiomiopatias e insuficiência cardíaca congestiva quando certas doses cumulativas de antraciclina são atingidas.



NeurotoxicityNeurotoxicityNeurotoxicityNeurotoxicity

• Cerebellar toxicity

– 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.

Os efeitos neurotóxicos da quimioterapia ocorrem com bastante frequência e, muitas vezes, são razões para limitar a dose ou adiar a terapia. Alguns agentes causam neurotoxicidade central e periférica. Por exemplo, altas doses de citarabina, ifosfamida e nelarabina são bastante conhecidas pelos seus efeitos colaterais neurotóxicos do sistema nervoso central.

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Neurotoxicity (continued)Neurotoxicity (continued)Neurotoxicity (continued)Neurotoxicity (continued)

• Peripheral neuropathy

– Manifest as stocking-glove like distribution,

pain, tingling

– Vinca Alkaloids

• Vincristine

– Platinum Analogs

• Cisplatin and oxaliplatin

– Taxanes

• Paclitaxel > Docetaxel

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.

A quimioterapia também pode induzir a neuropatia periférica relacionada à dose cumulativa e ao tipo de fármaco utilizado. Os alcaloides da vinca, os análogos da platina e os taxanos são conhecidos por induzirem a neuropatia periférica. Os sinais e sintomas precoces são dor ou formigamento nas mãos e nos pés e, às vezes, perda dos reflexos. E, geralmente, isso é razão para adiar ou reduzir a dose no próximo ciclo.



Neurotoxicity (continued)Neurotoxicity (continued)Neurotoxicity (continued)Neurotoxicity (continued)

• Constipation, Bowel obstructions

– Vinca alkaloids, cisplatin

• Ocular Toxicity

– Chemical conjuctivitis

– High dose cytarabine

• Ototoxicity

– Loss of high frequency ranges,

acute tinnitus, chronic hearing loss

– Cisplatin

And some --- additional neurotoxic effects can involve the bowel system, the eyes, and the ears.

E outros efeitos neurotóxicos podem afetar o sistema intestinal, os olhos e os ouvidos.

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HepatotoxicityHepatotoxicityHepatotoxicityHepatotoxicity

• Hepatotoxicity manifests in a variety of patterns

– Hepatocellular necrosis - acute toxicity

– Cholestasis - impaired flow of bile from liver to duodenum

– Steatosis - fatty liver

– Veno-occlusive disease (VOD) - injury to hepatic venous

endothelium

• Hepatocellular injury is generally reversible and nonfatal

• Many drugs require dose reduction or avoidance in the

setting of hepatic insufficiency

• Hepatotoxic agents include: vinca alkaloids, cytarabine,

methotrexate, clofarabine, gemtuzumab, imatinib,

L-asparaginase

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.

A quimioterapia também pode causar hepatotoxicidade que se manifesta como resultados elevados dos exames de função hepática, colestase e doença veno-oclusiva, que é a lesão do endotélio venoso hepático. Muitos desses medicamentos são metabolizados pelo fígado. Por conseguinte, haverá necessidade de ajustar a dose quando de lesões hepatocelulares ou redução da função hepática. Relacionei uma lista de fármacos que são caracteristicamente hepatotóxicos ou metabolizados pelo fígado. Alguns deles incluem: alcaloides da vinca, citarabina, metotrexato, clofarabina, imatinibe e L-asparaginases.



NephrotoxicityNephrotoxicityNephrotoxicityNephrotoxicity

• Chemotherapy can impair kidney function

• Impairment can range from asymptomatic elevations

of serum creatinine to renal failure requiring dialysis

– Methotrexate and cisplatin are well-known nephrotoxins

• Impaired renal function can increase systemic

toxicities

• Many drugs require dose reduction or avoidance in

the setting of renal insufficiency

– Cytarabine, methotrexate, cisplatin, carboplatin, etoposide

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.

E não podem esquecer a nefrotoxicidade. Muitos dos agentes quimioterápicos são metabolizados pelos rins. Dois agentes comuns são o metotrexato e a cisplatina. Ambos são eliminados pelos rins e causam... podem causar insuficiência renal. O comprometimento da função renal pode aumentar as toxicidades sistêmicas. Por isso, em caso de insuficiência renal, é necessário reduzir a dose de alguns fármacos ou evitá-los.

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Dermatologic ToxicityDermatologic ToxicityDermatologic ToxicityDermatologic Toxicity

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.

Não é estranho que alguns desses medicamentos causem problemas na pele. A boa notícia é que muitos desses agentes... muitos desses problemas são reversíveis. A perda de cabelo é um efeito colateral comum de alguns desses agentes. O extravasamento ocorre quando o fármaco se infiltra na pele através dos vasos e causa sua necrose. Às vezes, para isso é necessário uma intervenção cirúrgica. Curiosamente, algumas terapias alvo causam erupção cutânea tipo acne no rosto, tronco e membros.



MyelotoxicityMyelotoxicityMyelotoxicityMyelotoxicity

• Neutropenia

– 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.

Efeitos adversos na produção da medula óssea, denominada mielossupressão, é uma toxicidade grave que pode se manifestar como neutropenia, anemia ou trombocitopenia. Muitas vezes, a mielossupressão é ditada pela dose, o horário [das doses] e o tipo de agente utilizado. As características do paciente, bem como a idade, a função renal, etc., podem afetar a dose e a toxicidade desses fármacos. A neutropenia é um efeito colateral muito grave por causa do risco de infecção. Frequentemente, a neutropenia febril exige hospitalização e antibióticos por via IV. Muitas vezes, a anemia causa fadiga e trombocitopenia e aumenta o risco de hemorragia. Estas complicações podem ser impedidas por transfusões.

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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.

Resumindo, quanto à dose e toxicidade, os fármacos podem afetar qualquer sistema de órgãos do corpo. E os fatores que muitas vezes influenciam a toxicidade do tratamento podem abranger o fármaco, a dose do fármaco, a função do órgão, a idade e o método de administração. Além disso, o monitoramento e o tratamento da toxicidade induzida por fármacos exigem uma abordagem multidisciplinar.



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.

Em resumo, o objetivo da quimioterapia pode variar dependendo de fatores específicos do paciente, como idade, comorbidade, estágio do tumor e tipo de câncer. O principal suporte da terapia oncológica ainda implica o uso de agentes citotóxicos que destroem indiscriminadamente as células que se dividem rapidamente. Terapias originais, como imunoterapia e terapia alvo, são dirigidas a moléculas e processos específicos do tumor e, ao mesmo tempo, preservam o tecido normal. Muitas vezes, a terapia alvo é combinada com a quimioterapia convencional.

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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.

E, finalmente, gostaria de terminar com este slide que mostra uma lista de recursos com mais informações sobre câncer e quimioterapia. Espero que tenham gostado da apresentação e agradeceríamos suas opiniões e comentários. Obrigado.

Treatment Modalities: Drug Therapy Part II · welcome you to the second part of Treatment Modalities: Drug Therapy. Olá, eu sou Jeffrey Bryan. Sou especialista em ... Os interferons,

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