CHEMOTHERAPY IN CANCER

MODERATOR DR SHEHTAJ KHAN

COMODERATOR PROF S A SIDDIQUI

PRESENTED BY : DR.YASHVEER SINGH

DATED 07/09/2015

CHEMOTHERAPY

• Systemic chemotherapy is the main treatment available for disseminated malignant diseases.

• Progress in chemotherapy resulted in cure for several tumors.

• Chemotherapy usually require multiple cycles.

Paul Ehrlich 1854 - 1915

• Father of Chemotherapy

• Nobel Prize 1908

HISTORICAL PERSPECTIVE

• Nitrogen mustards were a product of the secret war gas programs in both world wars

• In WWII, an explosion at Bar Harbor exposed seamen to mustard gas - they developed severe marrow and lymphoid hypoplasia

• Led to the use of these agents to treat Hodgkins and non-Hodgkins lymphomas at Yale in 1943

1965, The era of combination chemotherapy begins.

# POMP(Methotrexate,Vincristine,6MP,Prednisolone) regimen was able to induce long term remission in children with ALL# MOPP(Nitrogen Mustard,Vincristine,Procarbazine,Prednisolone) regimen successfully cured HL and NHL used by

Vincent DeVita and collegues in 1970

Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously, called combination chemotherapy or polychemotherapy.

The concept adjuvent Chemotherapy came out in 1972 when Emil Frei and collegues demonstrated chemotherapy given after surgical removal of osteosarcoma improves the cure rate.

In 1992 FDA approved Paclitaxal which become the blockbuster of Oncology drugs in present scenario

2004, FDA approved Bevacizumab, the first clinically proven antiangiogenic agent for colon cancer.

ANTICANCER DRUGS

• Cell Cycle Specific Drugs:

• Antimetabolites• Bleomycin peptide antibiotics• Vinca alkaloids

• Cell Cycle non-Specific Drugs:

• Alkylating agents• Antibiotics (Dactinomycin)• Cisplatin

Chemotherapeutic Agents

Effective for high growth-fraction-malignancies, such as hematologic cancers.

Effective for both low-growth (solid tumors) and high growth fraction malignancies

1. Alkylating agents:

• Major interaction: Alkylation of DNA

• Binds to nucleophilic groups on various cell constituents. Including DNA

• Primary DNA alkylation site: N7 position of

guanine (other sites as well) • Major Toxicity: bone marrow suppression

Chemotherapeutic Agents

CyclophosphamaideCarboplatinCisplatinOxaliplatinDacarbazine

Chemotherapeutic Agents2. Antimetabolites:

•Structurally related to normal compounds that exist within the cell.

•Interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis.

•Their maximal cytotoxic effects are in S-phase and therefore are cell-cycle specific.

5-FluoroUracilGemcitabineCyterabineMethotrexate

3. Microtubule Inhibitors:

• These are plant-derived substances .

• Cause cytotoxicity by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules.

• Vinca alkaloids inhibit microtubule polymerization and increase microtubule disassembly. The mitotic spindle apparatus is disrupted, and segregation of chromosomes in metaphase is arrested.

Chemotherapeutic Agents

Vinca AlkaloidsVincristine VinblastineVinorelbine

TaxanesPaclitaxelDocetaxel

4. Antineoplastic Antibiotics:

• Interacts with DNA, leading to disruption of DNA function.

• Also Inhibit topoisomerases (I and II) and produce free radicals.

• Cell-cycle nonspecific.

• Eg: Actinomycin D binds with double-stranded DNA and blocks the action of RNA polymerase, which prevents DNA transcription.

Chemotherapeutic Agents

BleomycinDoxorubicinDactinomycinDaunorubicin

5. Hormonal Agents:

• Commonly involves the use of glucocorticoids.• Direct antitumor effects are related to their

lympholytic properties;.• Glucocorticoids can inhibit mitosis, RNA synthesis,

and protein synthesis in sensitive lymphocytes.

• Considered cell-cycle nonspecific . • Resistance to a given glucocorticoid may develop

rapidly and typically extends to other glucocorticoids.

Chemotherapeutic Agents

PrednisoneTamoxifenEstrogensFlutamideNilutamideBicalutamide

• Antibodies that are made in the lab rather than by a person's own immune system.

• Directed at specific targets and often have fewer adverse effects.

• Designed to recognise and find specific abnormal proteins on cancer cells.

• Each monoclonal antibody recognizes one particular protein.

Chemotherapeutic Agents

Rituximab TrastuzumabCetuximabBevacizumab

6. Monoclonal Antibodies:

ETIOLOGY OF CANCER

• Carcinogenesis

– A cancer, is thought to develop from a cell in which the normal mechanisms for control of growth and proliferation are altered.

– Current evidence supports the concept of carcinogenesis as a multistage process that is genetically regulated

ETIOLOGY OF CANCER

Genetic and Molecular Basis of Cancer

• Two major classes of genes are involved in carcinogenesis: oncogenes and tumor suppressor genes

GOMPERTZIAN GROWTH• Growth rates are exponential at early stages of development

and slower at later stages of development

Biological growth follows this characteristic curve.Biological growth follows this characteristic curve.

GOMPERTZIAN GROWTH MODEL

Initial tumour growth is first order, with later growth being much slower

Smaller tumour grows slowly but large % of cell dividing

Medium size tumour grows more quickly but with smaller growth fraction

Large tumour has small growth rate and growth fraction

Log kill hypothesis• According to the log-kill hypothesis, chemotherapeutic

agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells, after each dose

1. Solid cancer tumors - generally have a low growth fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgery

2. Disseminated cancers- generally have a high growth fraction & generally respond well to chemotherapy

Log kill hypothesis:

Clinical Implications of Fractional Cell Kill

Pre chemo asssesment

• HISTORY• EXAMINATION• ROUTINE INVESTIGATIONS

CBC

RFT BS SE

LFT

ECG

URINE (R/M)

GOALS

Goals of treatment must be clearly defined

1.cure vs. palliation

2.acceptable toxicity

3.quality of life

MODES OF CHEMOTHERAPY• PRIMARY CHEMOTHERAPY - chemotherapy is used as the sole

anti-cancer treatment in a highly sensitive tumor types– Example – CHOP for Non-Hodgkins lymphoma

• ADJUVANT CHEMOTHERAPY – treatment is given after surgery to “mop up” microscopic residual disease– Example – Adriamycin, cyclophosphamide for breast cancer

• NEOADJUVANT CHEMOTHERAPY – treatment is given before surgery to shrink tumor and increase chance of successful resection– Example – Adriamycin, ifosfamide for osteosarcoma

MODES OF CHEMOTHERAPY

CONCURRENT CHEMOTHERAPY

Treatment is given simultaneous to radiation to increase sensitivity of cancer cells to radiation– Example – Cisplatin, 5-fluourouracil, XRT for head and

neck tumors

PALLIATIVE OR CURATIVE CHEMOTHERAPY

– metastatic cancers

Routes of administration of chemotherapy

Intrathecal, intraventricular in meningeal metastases from leukemia, lymphoma, breast cancer etc.

Intrapericardial — in malignant pericardial effusions

Intraperitoneal in ovarian cancer, colorectal cancer, mesothelioma.

Intra-arterial in liver cancer Isolated limb perfusion in melanoma Intravenous most common routeOral

Repeated intravenousadministration may lead toperipheral thrombo-phlebitisand venous inaccessibility. Inorder to avoid repeated venu‑puncture, increased accessand permit patient mobilityparticularly in continuousinfusion regimes, Port-a-cathwas developed forimplantation under the skinand central venous access

There is a wide variation in sensitivity of various cancers to chemotherapy

HighHigh IntermediateIntermediate LowLow

LymphomaLymphoma BreastBreast Head and neckHead and neck

LeukemiaLeukemia ColonColon ProstateProstate

Small Cell Lung cancerSmall Cell Lung cancer Non-small cell lung Non-small cell lung cancercancer

GastricGastric

Testicular cancerTesticular cancer PancreaticPancreatic

CANCER CHEMOTHERAPY: PRINCIPLES

1. Conventional chemotherapy targets have been the cell cycle, microtubules and DNA.

2. Combination chemotherapy improves responses over single agent, but dose intensity must be maintained.

PRINCIPLES FOR COMBINATION CHEMOTHERAPEUTIC REGIMENS

• Rationale:– minimize resistanceminimize resistance

– maximize synergy/additivitymaximize synergy/additivity

– avoid drugs of overlapping toxicityavoid drugs of overlapping toxicity

– biochemical considerationsbiochemical considerations

• Rationale:

– biochemical considerations:• addition of an agent to overcome drug resistance (eg

MDR inhibitor & vinca alkaloid)• cooperative inhibition (eg leucovorin & 5FU)• inhibition of drug breakdown (eg DPD inhibitor & 5FU)• rescue host from toxic effects of drug (eg leucovorin

following high-dose methotrexate)

CANCER CHEMOTHERAPY: PRINCIPLES

More is better, to a point!

ABVD

FFP: 81%

MOPP/ABV

FFP: 67%

ABVD

FFP: 65%

MOPP

FFP: 63%

SINGLE

AGENT

FFP: 20%

Advanced Hodgkin’s Disease

Careful Sequencing is CriticalDocetaxel Doxorubicin

Doc Dox

40 mg/m2 50 mg/m2

Dox Doc

50 mg/m2 70 mg/m2

Itoh et al. Study of Sequence Switching of AdministrationClin. Cancer Res 6:4082-4090, 2000

PLANNING DRUG DOSES AND SCHEDULES

• Doses - based on body surface area

- differ between children and adults

- adjusted for people who are elderly, have poor

nutritional status, have already taken or taking other medications, have already received or are currently receiving radiation therapy, have low blood cell counts, or have liver or kidney diseases

PLANNING DRUG DOSES AND SCHEDULES

• Schedule (Cycles)

- A cycle = one dose followed by several days or weeks without treatment for normal tissues to recover from the drug’s side effects

The number of cycles = based on the type and stage of cancer, and side effects

HEMATOLOGICAL CONSIDERATIONS FOR DOSE

SCHEDULING• Lifespan

– Platelet - 7-10 days

– Red blood cell - 120 days

– Neutrophils - 6-12 hours

• Time from Stem Cell to Mature Neutrophil

– ~7-10 days

DECIDING ON TREATMENT INTERVALS

• As short as possible

• Recovery of bone marrow

– Supplies mature cells for 8-10 days

– Onset 9-10th days

– Lowest (nadir) 14-18th days

– Recovery by day 21-28.

• Usual schedule is q21-28 days.

COMPLICATION OF CHEMOTHERAPY

• Every chemotherapeutic will have some deleterious side effect on normal tissue .

• E.G; Myelosuppression,nausea&vomiting,

Stomatitis,and alopecia are the most frequently observed side effects.

SIDE EFFECTS OF CHEMOTHERAPY

Mucositis

Nausea/vomiting

Diarrhea

Cystitis

Sterility

Myalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

Distinctive Toxicities of Some Anticancer DrugsToxicity Drug(s)

Renal Cisplatin,* methotrexate

Hepatic 6-MP, busulfan, cyclophosphamide

Pulmonary Bleomycin,* busulfan, procarbazine

Cardiac Doxorubicin, daunorubicin

Neurologic Vincristine,* cisplatin, paclitaxel

Immunosuppressive Cyclophosphamide, cytarabine, dactinomycin, methotrexate

Other Cyclophosphamide (hemorrhagic cystitis); procarbazine (leukemia); asparaginase* (pancreatitis)

*Less Bone marrow suppression – “marrow sparing”

Prevention or Management of Drug Induced toxicities

• The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving proper medications

E.g.

1.mesna is given to prevent hemorrhagic cystitis by cyclophosphamide

2.Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy

CRITERIA USED TO DESCRIBE RESPONSE ARE

• Complete response (complete remission)is the disappearance of all detectable malignant disease.

• Partial response : is decrease by more than 50% in the sum of the products of the perpendicular diameters of all measurable lesions.

• Stable disease : no increase in size of any lesion nor the appearance of any new lesions.

• Progressive disease : means an increase by at least 25% in the sum of the products of the perpendicular diameters of measurable lesions or the appearance of new lesions.