Module No. 8-9 Infectious & Oncologic Disorders PDF

Module No. 8: Management of Infectious Diseases Shane Valerie G. Bautista, RPh INFLUENZA is a contagious viral infection that can cause mild to severe symptoms and life-threatening complications, including death, even in healthy children and adults. The route of transmission: pe...

Module No. 8: Management of Infectious Diseases Shane Valerie G. Bautista, RPh INFLUENZA is a contagious viral infection that can cause mild to severe symptoms and life-threatening complications, including death, even in healthy children and adults. The route of transmission: person-to-person via inhalation of respiratory droplets, which can occur when an infected person coughs or sneezes. CLINICAL PRESENTATION Classic signs and symptoms of influenza include rapid onset of fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis. Nausea, vomiting, and otitis media are also commonly reported in children.  DIAGNOSIS The gold standard for diagnosis of influenza are RT-PCR or viral culture. Rapid influenza diagnostic tests [(RIDTs), also known as point-of-care (POC) tests], direct (DFA) or indirect (IFA) fluorescence antibody tests, and the RT-PCR assay may be used for rapid detection of virus.  PREVENTION Appropriate infection control measures, such as hand hygiene, basic respiratory etiquette (cover your cough and throw tissues away), and contact avoidance, are important in preventing the spread of influenza. Annual vaccination is recommended for all persons age 6 months or older and caregivers (eg, parents, teachers, babysitters, nannies) of children less than 6 months of age. PHARMACOLOGICAL TREATMENT The neuraminidase inhibitors are the only antiviral drugs available for treatment and prophylaxis of influenza and are oseltamivir and zanamivir.  EVALUATION OF THERAPEUTIC OUTCOMES Patients should be monitored daily for resolution of signs and symptoms associated with influenza, such as fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis. These signs and symptoms will typically resolve within ~1 week. If the patient continues to exhibit signs and symptoms of illness beyond 10 days or a worsening of symptoms after 7 days, a physician visit is warranted, as this may be an indication of a secondary bacterial infection.  PNEUMONIA - an infection that inflames the air sacs in one or both lungs. The air sacs may fill with fluid or pus (purulent material), causing cough with phlegm or pus, fever, chills, and difficulty breathing. A variety of organisms, including bacteria, viruses and fungi, can cause pneumonia. CLINICAL PRESENTATION DIAGNOSIS  EVALUATION OF THERAPEUTIC OUTCOMES With community-acquired pneumonia, time for resolution of cough, sputum production, and presence of constitutional symptoms (eg, malaise, nausea or vomiting, and lethargy) should be assessed. Progress should be noted in the first 2 days, with complete resolution in 5 to 7 days. With nosocomial pneumonia, the above parameters should be assessed along with white blood cell counts, chest radiograph, and blood gas determinations.  Module No. 9: Management of Oncologic Disorders Shane Valerie G. Bautista, RPh  TOPIC OUTLINE 01 Breast Cancer 02 Colorectal Cancer 03 Lung Cancer 04 Lymphomas 05 Prostate Cancer  INTRODUCTION How does cancer develop? Types of genes that cause cancer Cancer is a genetic disease—that is, it is caused by The genetic changes that contribute to cancer tend to affect changes to genes that control the way our cells three main types of genes—proto-oncogenes, tumor suppressor function, especially how they grow and divide. genes, and DNA repair genes. These changes are sometimes called “drivers” of cancer. Genetic changes that cause cancer can happen because: of errors that occur as cells divide. of damage to DNA caused by harmful substances in the environment, such as the chemicals in tobacco smoke and ultraviolet rays from the sun. they were inherited from our parents.  ONCOGENES TUMOR SUPPRESSOR GENES Proto-oncogenes are genes that normally help cells Tumor suppressor genes are normal genes that slow down grow and divide to make new cells, or to help cells cell division or tell cells to die at the right time (apoptosis). stay alive. DNA REPAIR GENES DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division. CLINICAL PRESENTATION DIAGNOSIS  TUMOR MARKERS Cannot diagnos tumot cancer  TREATMENT GOALS Cure – Patients are said to be ‘cured’ of cancer when they are completely disease free and have a normal life expectancy. Prolong survival while maintaining patient quality of life Provide palliative care with relief of symptoms such as pain. SURVIVAL Survival depends on the tumor type, the extent of disease, and the therapy received. Although some patients are free of all detectable disease, not all patients are cured. The terms complete response and remission are used to indicate that the patient has no evidence of disease after treatment. This is not a synonym for cure, as several patients who have achieved complete remission may relapse.  CELL GROWTH KINETICS 1. Cell growth fraction is the proportion of cells in the tumor dividing or preparing to divide. As the tumor enlarges, the cell growth fraction decreases because a larger proportion of cells may not be able to obtain adequate nutrients and blood supply for replication. 2. Cell cycle time is the average time for a cell that has just completed mitosis to grow and again divide and again pass through mitosis. Cell cycle time is specific for each individual tumor. 3. Tumor doubling time is the time for the tumor to double in size. As the tumor gets larger, its doubling time gets longer because it contains a smaller proportion of actively dividing cells owing to restrictions of space, nutrient availability, and blood supply. 4. The gompertzian growth curve Tumor cell burden is the number of tumor cells in the body. 1. Because a large number of cells is required to produce symptoms and be clinically detectable (approximately 109 cells), the tumor may be in the plateau phase of the growth curve by the time it is discovered. 2. The cell kill hypothesis states that a certain percentage of tumor cells will be killed with each course of cancer chemotherapy. a. As tumor cells are killed, cells in G0 may be recruited into G1 , resulting in tumor regrowth. b. Thus, repeated cycles of chemotherapy are required to achieve a complete response or remission. c. The percentage of cells killed depends on the chemotherapy dose. 3. In theory, the tumor burden would never reach absolute zero because only a percentage of cells are killed with each cycle. Less than 104 cells may depend on elimination by the host’s immune system. CHEMOTHERAPEUTIC AGENTS 1. Phase-specific agents are most active against cells that are in a specific phase of the cell cycle. These agents are most effective against tumors with a high growth fraction. a. M phase b. G1 phase c. S phase D. G2 phase CHEMOTHERAPEUTIC AGENTS 2. Phase-nonspecific agents are effective while cells are in the active cycle but do not require that the cell be in a particular phase. These agents generally show more activity against slow-growing tumors. 3. Cell cycle–nonspecific agents are effective in all phases, including G0.  OBJECTIVES OF CHEMOTHERAPY 1. For cancers like leukemias and lymphomas, several phases of chemotherapy are necessary. CURATIVE APPROACH: a. Remission induction: therapy given with the intent of maximizing cell kill. b. Consolidation (also known as intensifi cation or post-remission therapy): therapy to eradicate any clinically undetectable disease and to lower the tumor cell burden below 103, at which level host immunological defenses may keep the cells in control. c. Maintenance: therapy given in lower doses with the aim of maintaining or prolonging a remission.  OBJECTIVES OF CHEMOTHERAPY 2. For solid tumors, one or more approaches to chemotherapy may be used when seeking a cure based on the known utility of chemotherapy in line with other modalities, such as surgery or radiation. a. Adjuvant chemotherapy is given after more definitive therapy, such as surgery, to eliminate any remaining disease or undetected micrometastasis. b. Neoadjuvant chemotherapy is given to decrease the tumor burden before definitive therapy, such as surgery or radiation.  OBJECTIVES OF CHEMOTHERAPY 3. Palliative therapy is usually given when complete eradication of the tumor is considered unlikely or the patient refuses aggressive therapy. Palliative chemotherapy may be given to decrease the tumor size, control growth, and reduce symptoms. 4. Salvage chemotherapy is given as an attempt to get a patient into remission, after previous therapies have failed.  CHEMOTHERAPY DOSING AND ADMINISTRATION Chemotherapy dosing may be based on body weight, body surface area (BSA), or area under the concentration versus time curve (AUC). Dosing adjustments may be Textrequired for kidney or liver dysfunction to prevent toxicity. Combination chemotherapy is usually more effective than single-agent therapy. Acronyms often are used to designate chemotherapy regimens. e.g. CMF  CHEMOTHERAPY DOSING AND ADMINISTRATION 1. IV administration is most commonly employed, oral administration of chemotherapy is becoming increasingly more common. 2. Other administration techniques include oral, subcutaneous, intrathecal, intra-arterial, intraperitoneal, intravesical, continuous IV infusion, bolus IV infusion, and hepatic artery infusion. 3. Drugs that may be given intrathecally include methotrexate, cytarabine, and hydrocortisone. Drugs should not be administered by the intrathecal route without specific information supporting intrathecal administration. 4. Products with different formulations, including liposomal or pegylated agents (e.g., liposomal doxorubicin, pegfilgrastim), are being used to decrease frequency of administration and/or reduce toxicities. VARIOUS MISCELLANEOUS AGENTS 1. Retinoid derivatives a. Tretinoin (all-trans-retinoic acid; ATRA) is a retinoic acidderivative th a t is u se d in th e tre a tm e n t of a spe cifi c t y p e o f a c u t e myelogenous leukemia, known as acute promyelocytic leukemia (APL), to help cells differentiate into functionally mature cells. b. Isotretinoin (13-cis-retinoic acid; 13-CRA) is a retinoic acid derivative that is used in the treatment of neuroblastoma, a type of solid tumor seen in young children. c. Bexarotene is a selective retinoid X receptor (RXR) ligand used for cutaneous T-cell lymphoma. Activation of the retinoid receptors leads to regulation of gene expression and apoptosis. VARIOUS MISCELLANEOUS AGENTS 2. Arsenic trioxide is an antineoplastic compound used in the treatment of APL that may induce selective apoptosis of APL cells. 3. Bortezomib is a proteosome inhibitor currently used in patients with multiple myeloma and under investigation for the treatment of several other types of cancer. 4. Thalidomide and lenalidomide are immunomodulatory agents with various mechanisms of action. They work as angiogenesis inhibitors by interfering with the growth of new blood vessels needed for tumor growth and survival. They inhibit the production of tumor necrosis factor (TNF-a) production, induce oxidative damage to DNA, and help stimulate human T cells. They can be used as treatment for multiple myeloma in combination with dexamethasone. BIOLOGICAL RESPONSE MODIFIERS 1. Cytokines 2. Monoclonal antibodies 3. Immunotoxins Denterleukin diffory 4. Tumor vaccines OTHER THERAPEUTIC MODALITIES 1. Surgery (diagnostic/therapeutic) 2. Radiation Therapy 3. Hematopoeitic stem cell transplantation Autologous transplants, stem cells are obtained from the patient, preserved, and later reinfused into the same patient. Allogeneic transplants involve two separate individuals. Cells are obtained from a matched donor and then infused into a separate patient. Syngeneic transplant occurs when both the donor and recipient are identical twins. Treatments: Alkylating agents: Cyclophosphamide: Forms DNA cross-links, resulting in inhibition of DNA synthesis and function Other major alkylating agents: mechlorethamine, procarbazine, busulfan, carmustine, lomustine, dacarbazine Platinum analogs: cisplatin, carboplatin, oxaliplatin Antimetabolites Methotrexate: Dihydrofokate reductase Inhibits DHFR, resulting in inhibition of synthesis of thymidylate, purine nucleotides, serine, and methionine 6-Mercaptopurine Inhibits de novo purine synthesis 5-Fluorouracil: Inhibits thymidylate synthase, and its metabolites are incorporated into RNA and DNA, all resulting in inhibition of DNA synthesis and function and in RNA processing Other antimetabolites: cytarabine, gemcitabine Vinca Alkaloids Vincristine: Periwinkle- catharantus ruseus Interferes with microtubule assembly, resulting in impaired mitosis Other vinca alkaloids: vinblastine, vinorelbine Podophyllotoxins Etoposide: Inhibits topoisomerase II, resulting in DNA damage Other podophyllotoxins: teniposide Podophyllum pentatum- american apple or mandrake Camptothecins Topotecan: Inhibits topoisomerase I, resulting in DNA damage Other camptothecins: irinotecan Taxanes Paclitaxel: Interferes with microtubule disassembly, resulting in impaired mitosis Other taxanes: docetaxel Anthracyclines Doxorubicin: Oxygen free radicals bind to DNA causing strand breakage; inhibits topoisomerase II; intercalates into DNA Other anthracyclines: daunorubicin, idarubicin, epirubicin, mitoxantrone Other antitumor antibiotics: bleomycin, mitomycin Tyrosine kinase inhibitors Imatinib: Inhibits bcr-abl tyrosine kinase and other receptor tyrosine kinases Other tyrosine kinase inhibitors: dasatinib, nilotinib, sorafenib, sunitinib, and pazopanib Growth factor receptor inhibitors Trastuzumab: Inhibits the binding of EGF to the HER-2/neu growth receptor Other growth factor receptor inhibitors: cetuximab, panitumumab, gefitinib, erlotinib Vascular endothelial growth factor (VEGF) inhibitors Bevacizumab: Inhibits binding of VEGF to its receptor, resulting in inhibition of tumor vascularization Proteasome Inhibitors Bortezomib Reversibly inhibits chymotrypsin- like activity of the 26S proteasome Other proteasome inhibitor: carfilzomib  Hormone agonists Prednisone  Hormone antagonists Tamoxifen Other hormonal antagonists: aromatase inhibitors, GnRH agonist and antagonists, androgen receptor antagonists.  BREAST CANCER Breast cancer is a malignancy originating from breast tissue. Disease confined to a localized breast lesion is referred to as early, primary, localized, or curable. Disease detected clinically or radiologically in sites distant from the breast is referred to as advanced or metastatic breast cancer (MBC), which is usually incurable. CLINICAL PRESENTATION DIAGNOSIS  PROGNOSTIC FACTORS Age at diagnosis and ethnicity are patient characteristics that may affect prognosis. Tumor size and presence and number of involved axillary lymph nodes are primary factors in assessing the risk for breast cancer recurrence and subsequent metastatic disease. Hormone receptors [estrogen (ER) and progesterone (PR)] are not strong prognostic markers but are used clinically to predict response to endocrine therapy. HER2/neu (HER2) overexpression is associated with transmission of growth signals that control aspects of normal cell growth and division. Overexpression of HER2 is associated with increased tumor aggressiveness, rates of recurrence, and mortality.  GOALS OF TREATMENT Adjuvant therapy for early and locally advanced breast cancer is administered with curative intent. Neoadjuvant therapy is given to eradicate micrometastatic disease, determine prognosis, and potentially conserve breast tissue for a better cosmetic result. Palliation is the desired therapeutic outcome in the treatment of MBC.  TREATMENT - EARLY BREAST CANCER Ø Local-Regional Therapy § Breast-conserving therapy (BCT) is often primary therapy for stage I and stage II disease; it is preferable to modified radical mastectomy because it produces equivalent survival rates with cosmetically superior results. § Simple or total mastectomy involves removal of the entire breast without dissection of underlying muscle or axillary nodes. This procedure is used for carcinoma in situ where the incidence of axillary node involvement is only 1% or with local recurrence following BCT Ø Systemic Adjuvant Therapy § The administration of systemic therapy following definitive local therapy (surgery, radiation, or in combination) when there is no evidence of metastatic disease but a high likelihood of disease recurrence. The goal of such therapy is cure.  TREATMENT - EARLY BREAST CANCER Ø Adjuvant Chemotherapy  TREATMENT - EARLY BREAST CANCER Ø Adjuvant Biologic Therapy § Trastuzumab in combination with or sequentially after adjuvant chemotherapy is indicated in patients with early stage, HER2-positive breast cancer. The risk of recurrence was reduced up to 50% in clinical trials. Ø Adjuvant Endocrine Therapy § Tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing hormone– releasing hormone (LHRH) agonists, and aromatase inhibitors (AI) are hormonal therapies used in the treatment of primary or early- stage breast cancer.  TREATMENT - LOCALLY ADVANCED BREAST CANCER q Neoadjuvant or primary chemotherapy is the initial treatment of choice. q Primary chemotherapy with an anthracycline- and taxane-containing regimen is recommended. The use of trastuzumab and pertuzumab with chemotherapy is appropriate for patients with HER2-positive tumors. q Surgery followed by chemotherapy and adjuvant RT should be administered to minimize local recurrence. q Cure is the primary goal of therapy for most patients with stage III disease.  TREATMENT - METASTATIC BREAST CANCER v The choice of therapy for MBC is based on the extent of disease involvement and the presence or absence of certain tumor or patient characteristics, as described below. v The most important factors predicting response to therapy are the presence of HER2, estrogen, and progesterone receptors in the primary tumor tissue. v Consider adding bone-modifying agents (eg, pamidronate, zoledronic acid, or denosumab) to treat breast cancer patients with metastases to the bone to decrease rates of skeletal-related events and the need for radiation to the bones or surgery. Selected Regimens for HER2-Positive Metastatic Breast Cancer  EVALUATION OF THERAPEUTIC OUTCOMES v EARLY BREAST CANCER ü The goal of adjuvant therapy in early-stage disease is cure. Because there is no clinical evidence of disease when adjuvant therapy is administered, assessment of this goal cannot be fully evaluated for years after initial diagnosis and treatment. v LOCALLY ADVANCED BREAST CANCER ü The goal of neoadjuvant chemotherapy in locally advanced breast cancer is cure. Complete pathologic response, determined at the time of surgery, is the desired end point. v METASTATIC BREAST CANCER ü Palliation is the therapeutic end point in the treatment of patients with MBC.  COLORECTAL CANCER Colorectal cancer (CRC) is a malignant neoplasm involving the colon, rectum, and anal canal. PATHOPHYSIOLOGY Features of colorectal tumorigenesis include: genomic instability, activation of oncogene pathways, mutational inactivation or silencing of tumor-suppressor genes, DNA mismatch repairs, and activation of growth factor pathways. CLINICAL PRESENTATION DIAGNOSIS  GOALS OF TREATMENT The goals include cure for stages I, II, and III; the intent is to eradicate micrometastatic disease. Most stage IV disease is incurable; palliative treatment is given to control cancer growth, reduce symptoms, improve quality of life, and extend survival. Treatment modalities are surgery, radiation therapy (RT), chemotherapy, and biomodulators.  TREATMENT - OPERABLE DISEASE v SURGERY C om plete s urgic a l r e s e c t i o n o f t h e p r i m a r y t u m o r w i t h r e g i o n a l lymphadenectomy is a curative approach for patients with operable CRC. Common complications of colorectal surgery include infection, anastomotic leakage, obstruction, adhesions, sexual dysfunction, and malabsorption syndromes. ADJUVANT TREATMENT OF COLORECTAL CANCER ADJUVANT TREATMENT OF COLORECTAL CANCER  EVALUATION OF THERAPEUTIC OUTCOMES v Goals of monitoring are to evaluate benefit of treatment and detect recurrence. v Patients who undergo curative surgical resection, with or without adjuvant therapy, require routine follow-up. Consult practice guidelines for specifics. v Evaluate patients for anticipated side effects such as loose stools or diarrhea, nausea or vomiting, mouth sores, fatigue, and fever. v Less than one half of patients develop symptoms of recurrence, such as pain syndromes, changes in bowel habits, rectal or vaginal bleeding, pelvic masses, anorexia, and weight loss. Recurrences in asymptomatic patients may be detected because of increased serum CEA levels. Monitor quality-of-life indices, especially in patients with metastatic disease.  LUNG CANCER Lung cancer is a solid tumor originating from the bronchial epithelial cells. CLINICAL PRESENTATION DIAGNOSIS  TREATMENT - NON-SMALL CELL LUNG CANCER STAGE IA AND IB - Surgery is the mainstay of treatment and may be used alone or with radiation therapy (RT) and/or chemotherapy. STAGE IIA AND IIB - primarily treated with surgery followed by adjuvant chemotherapy. Chemoradiotherapy is recommended for stage II medically inoperable patients. Platinum-based regimens are preferred and should be given concurrently rather than sequentially with RT. STAGE IIIA - achieved with chemotherapy plus either radiation or surgery, depending on patient and tumor features. STAGE IIIB or IV - Chemotherapy is administered to select patients with intent to palliate symptoms, improve quality of life, and increase duration of survival.  Common Chemotherapy Regimens used in the Adjuvant Treatment of Non–Small-Cell Lung Cancer Common Chemotherapy Regimens - Advanced Stage Lung Cancer Common Chemotherapy Regimens - Advanced Stage Lung Cancer  TREATMENT - SMALL CELL LUNG CANCER SCLC is very radiosensitive. Radiation is given concurrently with chemotherapy and the regimen of choice is etoposide and cisplatin (EP regimen). EXTENSIVE DISEASE: EP regimen RECURRENT DISEASE: Topotecan (IV and oral) is the only FDA-approved second- line therapy for SCLC.  EVALUATION OF THERAPEUTIC OUTCOMES v Evaluate tumor response to chemotherapy for NSCLC at the end of the second or third cycle and at the end of every second cycle thereafter. Consider maintenance therapy with pemetrexed in responding patients with nonsquamous histology. v Evaluate efficacy of first-line therapy for SCLC after two or three cycles of chemotherapy. If there is no response or progressive disease, therapy can be discontinued or changed to a non–cross-resistant regimen. If responsive to chemotherapy, the induction regimen should be administered for four to six cycles. Responding patients benefit from the addition of PCI following initial therapy. v Intensive therapeutic monitoring is required for all patients with lung cancer to avoid drug-related and radiotherapy-related toxicities.  LYMPHOMAS - a heterogeneous group of malignancies that arise from malignant transformation of immune cells residing predominantly in lymphoid tissues. The main subtypes are: Hodgkin's lymphoma (formerly called Hodgkin's disease) Non-Hodgkin's lymphoma TREATMENT - HODGKINS LYMPHOMA TREATMENT - NON-HODGKINS LYMPHOMA  EVALUATION OF THERAPEUTIC OUTCOMES v The primary outcome to be identified is tumor response, which is based on physical examination, radiologic evidence, PET/computed tomography (CT) scanning, and other baseline findings. v Patients are evaluated for response at the end of four cycles or, if treatment is shorter, at the end of treatment.  PROSTATE CANCER - a malignant neoplasm that arises from the prostate gland. Prostate cancer has an indolent course; localized prostate cancer is curable by surgery or radiation therapy, but advanced prostate cancer is not yet curable. Hormonal Regulation of the Prostate Gland CHEMOPREVENTION SCREENING CLINICAL PRESENTATION DIAGNOSIS TREATMENT - PROSTATE CANCER  CHEMOTHERAPY - PROSTATE CANCER Docetaxel, 75 mg/m2 every 3 weeks, combined with prednisone, 5 mg twice daily, improves survival in castrate-refractory prostate cancer. The most common adverse events include nausea, alopecia, and myelosuppression. Cabazitaxel 25 mg/m2 every 3 weeks with prednisone 10 mg daily significantly improves progression-free and overall survival. Neutropenia, febrile neutropenia, neuropathy, and diarrhea are the most significant toxicities. IMMUNOTHERAPY - PROSTATE CANCER Sipuleucel-T is a novel autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer. Use is controversial because trials have not been done to compare it to standard second-line hormonal interventions.  EVALUATION OF THERAPEUTIC OUTCOMES v Monitor primary tumor size, involved lymph nodes, and tumor marker response such as PSA with definitive, curative therapy. PSA level is checked every 6 months for the first 5 years, then annually. v With metastatic disease, clinical benefit can be documented by evaluating performance status, weight, quality of life, analgesic requirements, and PSA or DRE at 3-month intervals.