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 NORMAL 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 coordinatedgrowth factor secretion

Presence of tumor suppressorgenes

FrequentFrequentmitosesmitoses

NucleusNucleus

BloodBlood vesselvessel

AbnormalAbnormalheterogeneousheterogeneous cells cells

NormalNormalcellcell

FewFewmitosesmitoses

Cancer Cells and Normal Cells

Many definitions for the word cancer: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 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

DEATHDEATH

DIFFERENTIATIONDIFFERENTIATION

DNA content = 2nDNA content = 2n

MitosisMitosis

MM

SSDNA synthesisDNA synthesis

GG22

GG11

GG00

DNA content = 4nDNA content = 4n

The Cell Cycle

Cycle-Specific 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)

Alkylating Agents

AntibioticsCell 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)

– IV administration– Myelosuppression, alopecia, cardiotoxicity, local

vesicant, nausea/vomiting, mucosal ulcerations• Anthracyclines

• Mitomycin • Mithramycin

Antimetabolites

• 5-Fluorouracil (5-FU, fluorouracil)– 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

1986

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European Yew: Taxus baccata

Pacific Yew: Taxus brevifolia

Miscellaneous

• Cisplatin - IV administration

- Side effects include nephrotoxicity, tinnitus, hearingloss, and nausea/vomiting

• Carboplatin - IV administration - 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• Intraventricular• 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 tumorsAll, 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 doxorubicinor 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)