BASIC INFORMATION Oncology – the study of the causes, properties, disease progressions and treatments of tumors & cancer Oncologist – physician who specializes in treating cancer Radiation oncologist – oncologist who specializes in using radiation to treat cancer Radiotherapy – use of high energy x-rays, external beams, or radioactive materials placed directly on the tumor

Human body contains 5x10¹³ cells Cells can either be - non dividing and terminally differentiated - continually proliferating - rest but may be recruited into cell cycle Tumour becomes clinically detectable when there is a mass of 10,000,000,000 cells (1g)

Cancer Cells and Normal Cells CANCER CELLS NORMAL CELLS Frequent mitoses Normal cell Few mitoses Nucleus Blood vessel Abnormal heterogeneous cells Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Oncogene expression is rare Intermittent or coordinated growth factor secretion Presence of tumor suppressor genes

Many definitions for the word cancer: Any definition must embody two characteristics: The property of uncontrollable growth of cells originating from normal tissue. The property of killing the host by means of local tissue invasion and/or distant spread (metastasis). Cancer is a group of diseases characterized by uncontrolled cellular growth with local tissue invasion and/or systemic metastasis. Metastasis-spread of cells, from a primary tumor via the lymphatic and circulatory systems to a distant body part, where cells give rise to another cancer. Micro metastasis-metastasis too small to be detected by conventional diagnostic methods. Tumor-abnormal growth that can be benign or malignant.

Chemotherapy Goals - Cure - Control - Palliation

Chemotherapy Systemic treatment. Chemical agents that kill rapidly growing cells. Most act by damaging DNA. Indications: Curative Adjuvant Neo-adjuvant Palliative Radiosensitisation Administration/Cycle: One drug or a combination of drugs. Given monthly, every 3 wks, weekly or daily depending on the disease and drug.

Chemotherapy Strategies of administration Monotherapy Combination chemotherapy Goal: maximize efficacy & minimize toxicity Adjuvant chemotherapy Goal: prevention of recurrence Neoadjuvant chemotherapy As a 2nd line in resistant ds. Combined modality chemotherapy : Chemotherapy + radiotherapy + surgery Goal: obtain higher response rate

How do Cytotoxic Agents Work? Compete with DNA/RNA building blocks Affect enzymes in DNA/RNA synthesis Prevent cells from dividing

Classification of Chemotherapeutic Agents Alkylating Agents - Bind to DNA at N-7 position of Guanine - Interferes with DNA Replications (Nitrosoureas) (Antitumor antibiotics) - Interfere with nucleic acid synthesis and function, inhibits RNA synthesis and DNA synthesis Antimetabolites - Resemble cellular metabolites (folic acid, purine, pyrimidine) - Interfere with DNA precursors & cellular metabolism Plant Alkaloids- arrest or inhibits mitosis Hormonal Therapy Immunotherapeutic Agents Miscellaneous

The Cell Cycle G0 M S G2 G1 DEATH DIFFERENTIATION Mitosis DNA synthesis DNA content = 4n G2 G1 DNA content = 2n

Cycle-Specific Agents

Alkylating Agents Cyclophosphamide (Cytoxan) - Oral or IV administration - Side effects include myelosuppression, cystitis + bladder fibrosis, alopecia, hepatitis, gonadal dysfunction Ifosphamide (Ifex) Dacarbazine (DTIC) Chlorambucil (Leukeran) Melphalan (Alkeran, L-PAM) Triethylenethiophosphoramide (TSPA, Thiotepa)

Antibiotics Cell cycle nonspecific Isolated from natural products from soil fungi Mechanisms of action vary between classes with complex structures Bleomycin causes single and double stranded DNA breaks at sites of guanine IV, IM, SC, or IP administration Fever, dermatologic reactions, pulmonary toxicity, anaphylactic reactions Actinomycin D (Dactinomycin, Cosmegen) IV administration Nausea/vomiting, skin necrosis, mucosal ulceration myelosuppression Doxorubicin (Adriamycin) Myelosuppression, alopecia, cardiotoxicity, local vesicant, nausea/vomiting, mucosal ulcerations Anthracyclines Mitomycin Mithramycin

Antimetabolites 5-Fluorouracil (5-FU, fluorouracil) Methotrexate IV administration, Oral Myelosuppression, nausea/vomiting, anorexia, alopecia Methotrexate IV,IM,intrathecal Mucosal ulceration, myelosuppression, hepatotoxicity, allergic pneumonitis, meningeal irritation Hydroxyurea (Hydrea) Gemcitabine (Gemzar)

Plant Alkaloids Cell cycle specific Taxanes Bind preferentially to the microtubules themselves resulting in polymerization and stabilization Paclitaxel (taxol) Myelosuppression, alopecia, allergic reactions, cardiac arrhythmias Docetaxel (Taxotere) Myelosuppression, alopecia, hypersensitivity reactions Vinorelbine (Navelbine) Myelosuppression, constipation, peripheral neruopathy Epipodophyllotoxins (Etoposide) Interact with DNA to cause single stranded breaks Myelosuppression, alopecia, hypotension Vinca alkaloids Vincristine (Oncovin) Vinblastine (Velban)

Paclitaxel & Docetaxel 1971 Pacific Yew: Taxus brevifolia OH 1986 European Yew: Taxus baccata

Miscellaneous Cisplatin - IV administration Carboplatin Topotecan - Side effects include nephrotoxicity, tinnitus, hearing loss, and nausea/vomiting Carboplatin - Side effects include nephrotoxicity and ototoxicity, although less than with cisplatin Topotecan Irinotecan

Dosage Calculation Remember the Five Rights: medication, time, route, dose, patient Calculate body surface area (BSA) Recalculate drug and dosage against order Check current labs (CBC,KFT,LFT) Review drugs and potential side effects Verify informed consent Pre-medicate if ordered

Routes of Chemo Therapy Administration Oral Intravenous Intra-arterial Isolated limb perfusion Intracavity Intra-peritoneal Intraventricular Intrathecal Intravesical Intraperitoneal intrapleural

Side Effects of Chemotherapy Bone Marrow Suppression - Anemia - Neutropenia - Granulocytopenia - Leukopenia - Thrombocytopenia Gastrointestinal - NVD/Constip - Mucositis/stomatitis Fatigue Alopecia Infection

Anticancer drugs kill fast growing cells blood cells progenitors cells in the digestive tract reproductive system hair follicles Other tissues affected heart and lungs kidney and bladder nerve system Liver

Epithelial Ovarian Cancer Early stage high risk ovarian cancer single or multiagent chemotherapy with varying combinations of cisplatin, carboplatin, cyclophosphamide, and paclitxel Advanced stage ovarian cancer Combination chemotherapy with paclitaxel and carboplatin (Cycloph. / Cisplat) Value of intraperitonal chemotherapy controversial Alternative regimens in topotecan, gemcitabine, and liposomal doxorubicin

Germ Cell Tumors Dysgerminomas Highly sensitive to low dose radiation, but should not used due to decreased fertility Combination chemotherapy with BEP, VBP, or VAC preferable for metastatic disease Recurrence treated with BEP or POMB-ACE Immature teratomas Ia grade 1 do not require adjuvant chemotherapy Higher grades and ANY patient with ascites should receive adjuvant chemotherapy, for which BEP is currently the preferred regimen Endodermal sinus tumors All, regardless of stage, are treated with adjuvant chemotherapy using BEP or POMB-ACE following surgery Embyonal carcinomas Mixed germ cell tumors

Sex Cord Stromal Tumors Granulosa Cell Tumors No evidence chemotherapy has benefit in stage I Late recurrence Stage II/IV: postoperative chemotherapy with BEP may increase Long term survival Metastasis and recurrence: cyclophosphamide, melphalan, VAC, PAC, or BEP Suboptimally debulked benefits from BEP Sertoli-Leydig Tumors Limited data but have shown that measurable disease after surgery may benefit from cisplatin with doxorubicin or ifosphamide

Gestational Trophoblastic Neoplasia Placental site trophoblastic tumors are insensitive to chemotherapy Gestational trophoblastic neoplasia (According to FIGO Score) (low risk <7) Single agent: MTX or Actinomycin-D (high risk >7) combination chemotherapy (EMA-PE/CO)