Drugs

Cancer ChemotherapyOUTLINE

Introduction Cell cycle Definition of terms Commonly used cytotoxic drugs Routes of administration Pre-chemotherapy assessment Response & Resistance to Chemo. Complications & Management

Introduction

Cancer chemotherapy is a branch of cancer treatment that involve the use of chemical agents to destroy cancer cells. Other modalities of cancer Rx include surgery, radiation, immune modulation, & marrow transplants.

Introduction

The aim of cancer chemotherapy is to cure where possible and palliate where cure is impossible. The effective use of cancer chemotherapy requires an understanding of the principles of tumor biology, cellular kinetics, pharmacology, and drug resistance.

Cell Cycle

A constantly proliferating cell (normal or malignant) repeats a cycle of events that eventually end with cell division

Cell Cycle

The progression of a cell through this cycle is promoted by cycline dependent kinases which when complexed with cyclines drives the cell through cell cycle.


* , the cell cycle consists of: G1 = growth and preparation of the chromosomes for replication; S = synthesis of DNA and duplication of the centrosome; G2 = preparation for M = mitosis.


Definition of terms
Induction: chemotherapy given with the intent of inducing complete remission when initiating a curative regimen. usually applied to hematologic malignancies. Consolidation: Repetition of the induction regimen in a patient who has achieved a complete remission after induction, with the intent of increasing cure rate or prolonging remission.

Definition of terms

Intensification: Chemotherapy after complete remission with higher doses of the same agents used for induction or with different agents at high doses with the intent of increasing cure rate or remission duration.

Definition of terms

Maintenance: Long-term, low-dose, single or combination chemotherapy in a patient who has achieved a complete remission, with the intent of delaying the regrowth of residual tumor cells.

Definition of terms

Adjuvant: A short course of high-dose, usually combination chemotherapy in a patient with no evidence of residual cancer after surgery or radiotherapy, given with the intent of destroying a low number of residual tumor cells. Neoadjuvant: Adjuvant chemotherapy given in the preoperative or perioperative period.

Definition of terms

Palliative: Chemotherapy given to control symptoms or prolong life in a patient in whom cure is unlikely. Salvage: A potentially curative, high-dose, usually combination, regimen given in a patient who has failed or recurred following a different curative regimen.

Routes of Administration

IntravenousOralIntrathecal / Intraventricular – used in meningeal metastasis.Intrapericardial – used in malignant pericardial effusion.


Routes of Administration
Intraperitoneal – used in ovarian cancer, colorectal cancer, mesothelioma.Intra-arterial – used in Liver cancer

chemotherapy dosage

Based on Body Surface Area( BSA) or weightBSA gives more accurate measure of fluid and tissue proportionsUse normogram or BSA conversion calculatorBSA (mІ) = √ ht(cm) Ч w(kg) 3600

Pre-Chemotherapy Assessment

Detailed Hx - Age Occupation Duration of symptoms Weight loss PMHx

Pre-Chemotherapy Assessment

Physical Examination Lymphadenopathy Organomegaly States of the heart & lungs Bone involvement Ht, Wt, BSA

Pre-Chemotherapy Assessment

Performance status Popular instrument used in oncology includeKarnofsky performance index : Normal – 100% Death – 0%Eastern Cooperative Oncology Grp ECOG : 0 – Asymptomatic 5 - Death

Pre-Chemotherapy Assessment

InvestigationsHematologic – FBC, ESR, BM biopsyBiochemical – LFT, RFTImaging – CXR, USS, Bone scan, CT, MRITumour markers – gene products expressed in some cancers & may be used as diagnostic & monitoring tools. E.g. a-feto protein, PSA

Response to Chemotherapy

Complete response (CR) Disappearance of all known disease, confirmed at ≥ 4 weeksPartial response (PR) ≥ 50% decrease from baseline, confirmed at ≥ 4weeks


Response to Chemotherapy
Progressive disease (PD) ≥ 25% increase in one or more lesions or appearance of new lesionsStable disease (SD) Neither PR nor PD criteria met (no change)

Resistance to Chemotherapy

Primary Resistance When the cancer does not respond to standard chemotherapy from the very first exposure. Acquired Resistance When the tumour initially responds to chemotherapy then becomes resistant.

Resistance to Chemotherapy

Cancer cells may mutate & develop pathways that are independent of those blocked by cytotoxic drugs. Gene amplification may lead to overproduction of proteins that are blocked by anticancer drugs.

Resistance to Chemotherapy

Cancer cells may develop mechanism that inactivate anticancer drugs. They may learn to repair the DNA & protein damages induced by anticancer drugs. Resistant clones of cancer cells may develop

Complications of Chemotherapy

Skin Alopecia Darkening of the skin & Nails Noticeable with 5FU Hematological - Anaemia, Leucopaenia, Thrombocytopenia - Almost all cytotoxic drugs

Complications of Chemotherapy

Gastrointestinal Nausea, Vomiting, Mucositis, GIT infection Almost all drugs Endocrine Infertility, Amenorrhea, Irregular menses Almost all drugs

Complications of Chemotherapy

Neurological Peripheral neuropathy Loss of interest Confusion Common with plant alkaloids

Complications of Chemotherapy

OthersOtotoxicity – Platinum compoundsSecond tumors – Alkylating agentsCardiac toxicity – AnthracyclinesPulmonary toxicity – BleomycinBladder toxicity – CyclophosphamideNephrotoxicity – Platinum compoundTumour lysis syndrome

Prevention & Management of Complications

Nausea & Vomiting 5-HT3 receptor antagonist Ondasetron, Ganisetron Secondary tumors - Careful follow-up

Prevention & Management of Complications

Anaemia Erythropoietin Blood transfusion Immunosupression: Colony stimulating factor BM transplant Broad-spectrum antibiotics

Prevention & Management of Complications

Supportive Rx Leucovorin (folinic acid) is added when a very high dose Antimetabolites are given Colony stimulating factor & Erythropoietin can be used to supplement high dose chemotherapy

* Classification

* Alkylating agents
Cyclophosphamide Cisplatin Procarbazine Busulfan Mechlorethamine

Mechanism Of Action (MOA)

They are highly reactive drugs that restrict the action of biological molecules such as proteins and DNA by binding to them They add alkyl groups to the electro negative groups in cancer cells
Alkylating agents

* Alkylating Agents- Used in wide variety of hematologic and solid tumors

Thiotepa – ovarian cancerBusulfan – DOC in CML (***Important ADR-Pulmonary fibrosis).***Nitrosoureas (Carmustine and lomustine ) - brain tumorsHighly lipid soluble drugs hence reach high concentration in the brain and CSF. Streptozocin – insulin-secreting islet cell carcinoma of the pancreasMechlorethamine – Prodrug. Component of MOPP regimen for Hodgkin’s disease. It is a highly irritant drug so care should be taken to avoid extravasation during IV administrationChlorambucil (Leukeran): for CLL. Slow acting and least toxic nitrogen mustard.

* Cyclophosphamide

It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard The active drug alkylates nucleophilic groups on DNA bases Particularly at the N-7 position of guanine This leads to cross linking of bases, abnormal base pairing and DNA strand breakage


*

*

Mechanism of resistance

*** The mechanisms mentioned below are common for all the alkylyting agentsIncreased DNA repairDecreased drug permeabilityProduction of “trapping” agents (thiols)


Uses
Non-Hodgkin’s lymphomaBreast CaOvarian CaNeuroblastoma

* Adverse effect (ADR)

Acrolein is the metabolite Responsible for causing hemorrhagic cystitis Suprapubic pain Hematuria Cyctoscopic findings ***This is prevented/treated by MESNA (mercaptoethanesulfonate) Rarely cyclophosphamide can cause SIADH and pulmonary toxicity


*

Cisplatin

Platinum analog Same MOA as cyclophosphamide **Used in testicular carcinoma Also used for Ca of bladder, lung and ovary Carboplatin is new drug with better safety profile ADR Nephrotoxicity (prevented by Amifostine***) ***Ototoxicity (acoustic nerve damage) Peripheral neuritis Severe nausea and vomiting

Procarbazine

MOA: forms hydrogen peroxide, which generates free radicals that cause DNA damageImportant component of regimens especially for Hodgkin’s lymphomaADR***Disulfiram like reactions

Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage. During alcohol metabolism after disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body.

Disulfiram plus even small amounts of alcohol produces flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions, there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. The intensity of the reaction may vary with each individual but is generally proportional to the amount of disulfiram and alcohol ingested. In the sensitive individual, mild reactions may occur when the blood alcohol concentration is increased to as little as 5 to 10 mg/100 mL. At a concentration of 50 mg/100 mL symptoms are usually fully developed, and when the concentration reaches 125 to 150 mg/100 mL unconsciousness may occur.

Blood in the urine!!!

A 30-year-old man is seen at the ER complaining about severe suprapubic pain, fever and signs of passing blood in the urine. He is currently in treatment for non-Hodgkin’s lymphoma (four drug regimen).What is your preliminary diagnosis?If it is drug induced, who is “the culprit”?What is the mechanism behind the latest complication?How to treat the complication?Which drug we covered until now has serious nephrotoxic effects?How to prevent that particular drug induced renal damage?


* Antimetabolites
Folic Acid Analogs
Purine Analogs
Pyrimidine Analogs
Methotrexate
Mercaptoguanine
Fluorouracil
Trimetrexate Pemetrexed
Thioguanine Fludarabine Phosphate Cladribine
Cytarabine Gemcitabine Capecitabine

Antimetabolites

They are structurally similar to endogenous compounds They act as antagonists of: Folic acid (methotrexate) Purines (Mercaptopurine and thioguanine) Pyrimidine (fluorouracil, cytarabine)

* Antimetabolits: sites of drug action

Methotrexate


* Methotrexate (MTX)
MTX is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR) Thus it interferes with the synthesis of tetrahydrofolate (THF) THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins.

* Mechanism of Resistance

1. Decreased drug transport 2. Altered DHFR 3. Decreased polyglutamate formation 4. Increased levels of DHFR

* Contd..

Most commonly used anticancer drug. Cell cycle specific (CCS) drug and acts during S phase of the cell cycle. Antineoplastic, immunosuppressant and antiinflammatory Used in RA, psoriasis Well absorbed orally; can also be given IM, IV or intrathecally**. It is bound to plasma proteins, does not cross the BBB and most of the drug is excreted unchanged in urine. It is a weak acid and so is excreted better at high urine pH. Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTX

* ADR

Bone marrow suppression (BMS) Mucositis Folic acid deficiency The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin) This is called leucovorin rescue **** Higher the dose of MTX more the leucovorin you give**

* Leucovorin Rescue

Mechanism of action of methotrexate and the effect of administration of leucovorin. FH2 = dihydrofolate FH4 = tetrahydrofolate dTMP = deoxythymidine monophosphate dUMP = deoxyuridine mono phosphate.

* 6-Mercaptopurine (6-MP) & Thioguanine

Both 6-MP and Thioguanine are activated by hypoxanthine guanine phosphoribosyl transferase(HGPRT) to toxic nucleotides that inhibit several enzymes involved in purine metabolism***Resistance is due to cancer cells having d activity of HGPRTCancer cells also es alkaline phosphatase that inactivate toxic nucleotides

* 6-MP & Allopurinol

6-MP is metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine ***Allopurinol is used frequently to treat/prevent hyperuricemia caused by many anticancer drugs. If Allopurinol is used with 6-MP then the dose of 6-MP is reduced by more than 75% Why??

* Cytarabine (Ara-C)

Cytarabine arabinoside is a pyrimidine antimetabolite The drug is activated by kinases This acts as an inhibitor of DNA polymerase ***of all antimetabolites, this is the most specific for S phase of tumor cell cycle It is an important component in acute leukaemia regimens ADR: at high doses cause neurotoxicity (cerebellar dysfunction and peripheral neuritis) Hand-foot syndrome

* 5-FU

Mechanism of the cytotoxic action of 5-FU 5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase. 5-FU = 5-fluorouracil 5-FUR = 5-fluorouridine 5-FUMP = 5-fluorouridine monophosphate 5-FUDP = 5-fluorouridine diphosphate 5-FUTP = 5-fluorouridine triphosphate dUMP = deoxyuridine monophosphate dTMP = deoxythymidine monophosphate 5-FdUMP = 5-fluorodeoxyuridine monophosphate.

* Contd..

5-FU causes, “thymidineless death” of cellsResistance is due to d activation of 5-FU and d thymidylate synthase activityUses and ADRMetastatic carcinomas of the breast and the GI tract, hepatomaCarcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areasCombined with levamisole for Rx of colon cancer ADR: nausea, mucositis, diarrhea, ***hand and foot syndrome, Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression

* Hand –foot syndrome is a side effect of some chemotherapy drugs that results when a small amount of drug leaks out of the blood vessels, damaging tissues. This tends to happen in the hands and the feet because of the increased friction and heat that the extremities are exposed to through daily activities. Symptoms can be prevented by avoiding friction and heat. Treatment consists of reducing or stopping treatment with the drug that caused the syndrome. prevent symptoms by avoiding friction or heat. Symptoms of hand-foot syndrome include:Tingling or burningRednessFlakingSwellingSmall blistersSmall sores on the palms of the hands or soles of the feet

* A 50-year-old man is undergoing chemotherapy with a multi-drug regimen after being diagnosed to have a malignant tumor. Soon after the first cycle of chemotherapy, he develops symptoms of severe fatigue and pallor. His Hb is very low and the peripheral smear shows presence of macrocytes What is your prelim. Diagnosis? Which of the drugs we discussed can be most likely responsible for this complication? Which compound (and how) administered soon after chemotherapy could have prevented the toxicity? Which are the anticancer drugs which can cause tingling, feeling of warmth, redness, flaking and blisters (what is this)?

* Plant Alkaloids

Vinca Alkaloids
Podophyllotoxins
Camptothecins
Taxanes
Vinblastine
Etoposide
Topotecan
Paclitaxel
Vinblastine Vincristine Vinorelbine
Teniposide
Irinotecan
Docetaxel

* Vinka alkaloids (Vinblastine, vincristine)

These drugs block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules***They act primarily on the M phase of cancer cell cycleResistance is due to d efflux of drugs from tumor cells