CANCER CHEMOTHERAPY Principles & Clinical Evaluation

Presenter: Dr. Jyotiman Nath

The term “Chemotherapy” was coined by Paul Ehrlich in early 20th century – ‘magic bullets’ in the treatment of bacterial infections

Sidney Farber – father of ‘modern chemotherapy’

The origin of cancer chemotherapy.....

WW (I) exposure of military to mustard gas led to the observation that alkylating agents caused marrow and lymphoid hypoplasia wich is further studied during WW(II)

This observation led to the direct application of such agents to patients with Hodgkin’s disease and lymphocytic lymphomas at Yale Cancer Center in 1943

Luis Goodman and Alfred Gillmen demonstrated it for the first time.

1948, Sydney Farber successfully used Antifolates to induce remission in children with ALL.

1955, National chemotherapy program begins at National cancer institute, a systematic programme for drug screening.

1958, Roy Hertz and Min Chiu Li demonstrated Methotrexate as a single best agent for choriocarcinoma, the first solid tumour that can be cured by chemotherapy.

1959, FDA approved the alkylating agent, Cyclophosphamide

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.

• Neoadjuvant chemotherapy (primary or induction): given before definitive surgical therapy (in the context of locally extensive disease with a risk of distant micrometastatic disease)

• Adjuvant chemotherapy: used to treat tumors with high risk of recurrence after initial local therapy (surgery and RT) has removed all evidence of disease

Modalities of Cancer Chemotherapy

• Multimodality therapy: chemotherapy and/or radiation therapy after a tumor has been incompletely removed

Concurrent Chemoradiation Chemotherapy and Hormonal therapy Biochemotherapy (Chemotherapy and Immunotherapy) Chemotherapy and Targeted therapy

• Palliative chemotherapy Zoledronic acid for skeletal metastasis

Presently used in 4 clinical setting....Primary induction treatment for advance disease or cancers for which no other effective treatment available

As primary or neoadjuvant treatment for patients with localized disease for which local forms of therapy is ineffective

Adjuvant treatment for early stage disease following local forms of treatment

Direct instillation into tumour site

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

Rationale for combination chemotherapy•Different drugs exert their effect through different mechanisms and at different stages of the cell cycle, thus maximize cell kill

•Decease the chance of drug resistance

Principles........

For classical chemotherapy to be effective, cell proliferation is required. Indolent (slowly growing) cancers are typically resistant.

It is better to treat micrometastatic disease

Maximum Tolerated Dose - this may not equate to the Maximum Therapeutic Dose

The only principle regarding dosage is that, dose must be adjusted to the

individual patient, and that nothing can or will supersede clinical experience, and

careful study, combined with good judgement.

PRINCIPLES FOR COMBINATION CHEMOTHERAPEUTIC REGIMENS....

All drugs must have single-agent activity

Drugs should have no overlapping toxicity

Drugs should have different mechanisms of action

Drugs should have different mechanisms or patterns of resistance Drugs should be given in optimum dose and schedule to optimize dose intensity/dose density

Drugs should be individually titrated in individual patients to end-organ toxicity to optimize adherence to schedule

Primary chemotherapy: cancers for which chemo is primary treatment modality

Acute LeukemiaNHLHLGerm cell tumourPrimary CNS lymphomaOvarian CarcinomaSmall cell lung CAWilms tumourEmbryonal rhabdomyosarcoma

Neoadjuvant Chemotherapy: Cancers for which Neoadjuvant chemo is usefull for locally advanced disease...........

Anal CancerBladder CancerBreast CancerCervical CancerGastroesophageal CANon Small Cell lung CA

Head and Neck CAOvarian CAOsteogenic SarcomaRectal CASoft tissu Sarcoma

Chemosensitivity of tumors

► highALLHodgkin’s

diseaseNHLtesticular cancerSCLCWilms’ tumor

medium ovarian cancer breast cancer osteosarcoma head & neck

cancer multiple myeloma bladder cancer colorectal cancer

low NSCLC cervical cancer endometrial

cancer adult soft

tissue sarcoma malignant

melanoma liver cancer pancreatic

cancer

THE CELL CYCLE

Phases of cell cycle

G1 - primary growth phaseS – synthesis; DNA replicatedG2 - secondary growth phasecollectively these 3 stages are called interphase

M - mitosisC - cytokinesis

Cell cycle

G0 phase (resting stage): The cell has not yet started to divide. Depending on the type of cell, G0 can last from a few hours to a few years. When the cell gets a signal to reproduce, it moves into the G1 phase:

G1 phase During this phase, the cell starts making more proteins and growing larger, so the new cells will be of normal size. This phase lasts about 18 to 30 hours.

S phase: In the S phase, the chromosomes containing the genetic code (DNA) are copied so that both of the new cells formed will have matching strands of DNA. It lasts about 18 to 20 hours.

G2 phase: The cell checks the DNA and gets ready to start splitting into 2 cells. This phase lasts from 2 to 10 hours.

M phase (mitosis): In this phase, which lasts only 30 to 60 minutes, the cell actually splits into 2 new cells

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Daughter Cells

DNA Copied

Cells Mature

Cells prepare for Division

Cell Divides into Identical cells

Control of cell cycle- by special proteins and enzymes that act as switches

G1 checkpoint- stop, pause or go into S phase some cells stop permanently

G2 checkpoint- will cell divide?

M checkpoint- formation of new cells

G1 checkpointsRb prevents cell moving into S phase by binding to a transcription factor

When Rb is phoshporylated it cannot bind so cell can move into S phase

p53 prevents damaged from dividing (by inhibiting Rb pathway)

Abnormalities in both genes are associated with hereditary forms of cancer

Action of chemotherapy drugs

• Cell cycle dependent

• Cell cycle independent

Cell cycle non-selective agents: Introduces mutations into resting DNA 1. Alkylating agents 2. DNA intercalating agents (spindle poisons - interferes with tubulin polymerization)

Cell cycle selective agents: Antimetabolites of DNA synthesis

DNA synthesis

Antimetabolites

DNA

DNA transcription DNA duplication

Mitosis

Alkylating agents

Spindle poisons & Microtuble Stablizers

Intercalating agents

Sites of Action of Cytotoxic Agents at Cellular Level

Other classes of Anticancer Drugs

Antitumor antibioticsAntimicrotubule agents Topoisomerase Interacting AgentsTargeted therapies

• Tyrosine kinase inhibitors

Monoclonal antibodiesMiscellaneous agentsHormonal agents

Alkylating agents

They directly damage DNA to prevent the cancer cell from reproducing

Cell cycle-specific, but not phase-specific

kills a fixed percentage of cells at a given dose

•First chemotherapyeutic agent used in man•Prototype alkylating agent•Main toxicity comes from DNA cross linkage

Nitrogen Mustard

Cyclophosphamide Mechlorethamine Uramustine Melphalan Chlorambucil Ifosfamide

Cyclophosphamide

alkylation of DNA through the formation of reactive intermediatesoral bioavailability 100%T1/2 3-10 hrs metabolism: microsomal hydroxylation hydrolysis to phosphoramide mustard and acrolein

Main side effect is myelosupression

Mesna is used to prevent Toxicity

PLATINUM ANALOGUES

Cisplatin, carboplatin, oxaliplatin

Cisplatin is the cornerstone drug in the modern management of head and neck cancer

Carboplatin is superior to cisplatin due to less vomitting,renal and less otologic complication, BUT it is more marrow suppressive agent than Cisplatin

They interfere with DNA and RNA growth bysubstituting for the normal building blocks of RNA and DNA.

These agents damage cells during the S phase

Commonly used to treat...... •leukemias, •cancers of the breast•ovary, •intestinal tract, as well as other types of cancer.

Antimetabolites

• Antifolate analogues: Methotrexate (DHFR inhibitor) Pemetrexed (multi targeted antifolate)

• 5-Fluoropyrimidines:

5-FUCapecitabine

S-1 (Uracil/Tegafur) Gemcitabine

• Cytarabine

Purine analogues: 6-mercaptopurine (6-MP) 6-thioguanine (6-TG) Fludarabine Cladribine Clofarabine PentostatinPyrimidine analogues: Azacitidine Hydroxyurea (analogue of urea)

Antimetabolites..........

Antitumor Antibiotics

Cell cycle non-specific agentsVariety of mechanisms: prevents DNA replication,

RNA production,or both

Anthracyclines AnthracenedionesActinomycin D (dactinomycin) – DNA intercalator, inhibits topoisomerase II alsoBleomycin – inhibits DNA synthesis, G2-phase specificMitomycin C – functions as alkylator

Interfere with enzymes involved in DNA replication.These drugs work in all phases of the cell cycle

Anthracyclines....

•Daunorubicin•Doxorubicin (Adriamycin)•Epirubicin•Idarubicin

Anti-tumour antibiotics that are not anthracyclines include:

· Actinomycin-D· Bleomycin· Mitomycin-C

Topoisomerase inhibitors

DNA topoisomerase enzymes alters DNA topology by causing and resealing DNA breaks

Topoisomerase I - relaxes supercoilded DNA Topoisomerase II - catalyzes double-stranded

breaking and resealing of DNA

Topoisomerase I inhibitors

• Topotecan • Irinotecan

Topoisomerase II inhibitors

•Etoposide •Teniposide.•Mitoxantrone

Epipodophylotoxins

Antimicrotubule (Mitotic spindle) Agents

Vinca Alkaloids• Vincristine• Vinblastine• Vinorelbine• Vindesine

Plant alkaloids and other compounds derived from natural products.

They can stop mitosis or inhibit enzymes from making proteins needed for cell reproduction.

Work during the M phase of the cell cycle but can damage cells in all phases.

Taxanes

• Paclitaxel• Docetaxel

Estramustine (combination of estradiol and non-nitrogen mustard)

Newer antitubular drug Dolastatin

Miscellaneous agents

• Bleomycin – inhibits DNA synthesis, G2- phase specific

• Asparaginase – purified from E. coli &/or Erwinia, hydrolyses asparagine, inhibits protein synthesis

• Interferons – antitumor, antiproliferative, inhibits angiogenesis, regulated differentiation, NK cell activation

• Interleukins – IL2 stimulates growth of activated T cells

Drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression.

Targeted Therapy

The primary goal of targeted therapy is to fight cancer cells with more precision and

potentially fewer side effects.

Dual (EGFR and HER2) inhibitor: Lapatinib

VEGF inhibitors: Sorafenib (multi kinase inhibitor) Sunitinib (multiple TK inhibitor) Pazopanib (multi kinase inhibitor) Afitinib

BCR-ABL inhibitors: Imatinib (inhibitors of bcr-abl, PDGFR, c-kit) – CML, GIST Dasatinib (multiple TK inhibitor) Nilotinib (multiple TK inhibitor)EGFR inhibitors: Gefitinib Erlotinib

Monoclonal antibodies

• Relative selectivity for tumor tissue

• Relative lack of toxicity

• Various radioactive and chemotherapeutic agents can be conjugated to monoclones

Drugs-Immunoconjugates - Plant toxins,

Bacterial toxins Radioconjugates –Tositomumab,

Ibritumumab

Monoclonal Antibodies in OncologyMonoclonal Antibody Construct Isotype Target

Rituximab Chimeric IgG1 CD20

Cetuximab Chimeric IgG1 EGFR

Panitumumab Human IgG2 EGFR

Trastuzumab Humanized IgG1 HER-2

Gemtuzumab ozogamicin Humanized IgG4 CD33

Alemtuzumab Humanized IgG1 CD52

Ibritumomab tiuxetan Mouse IgG1 CD20

Bevacizumab Humanized IgG1 VEGF

Hormonal therapy is one of the major modalities of medical treatment for cancer

Hormonal therapy

It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones

Used for several types of cancers derived from hormonally responsive tissues, including the breast, prostate, endometrium, and adrenal cortex.

May also be used in the treatment of paraneoplastic syndromes.

Most familiar example of hormonal therapy in oncology is the use of the selective estrogen-response modulator tamoxifen for the treatment of breast cancer, although another class of hormonal agents, aromatase inhibitors, now have an expanding role in that disease.

Adrenocorticosteroids: Methylprednisolone, DexamethasoneAndrogens: Methyltestosterone, FluoxymesteroneAntiandrogens: Bicalutamide Flutamide Nilutamide

Hormonal therapy..........

Estrogens: DiethylstilbestrolAntiestrogens: Tamoxifen, Raloxifen Fulvistrant – only antagonist effect

Aromatase inhibitors: (non steroidal)• Aminoglutethimide (1st generation)• Exemestane (2nd generation)• Anastrazole (3rd generation)• Letrozole (3rd generation)

LHRH agonists: Leuprolide GoserelinProgestins: Megestrol Medroxyprogesterone acetateAdrenal inhibitors: Mitotane

Hormonal therapy..........

breast cancerprostate cancerendometrial cancerrenal cancerovarin cancercancer cachexia

Hormonal therapy – indications

Dosage calculation in oncology

• Body surface area– derived in 1916 by Du Bois – reduce the interpatient variability of drug

exposure and, hence, sideeffects • AUC (carboplatin)

– Dose (mg) = Target AUC (mg/mL/min) x [GFR (mL/min) + 25]

• Fix dosing

Dosages of drugs should be adjusted for people who:

· Are elderly· Have poor nutritional status· Are obese· Have already taken taking other medicines · Have already receiving radiation therapy · Have low blood cell counts· Have liver or kidney diseases

Chemotherapy is generally given at regular intervals called cycles.

A cycle may involve a dose of one or more drugs followed by several days or weeks without treatment

This gives normal cells time to recover from the drug’s side effects.

Planning Chemo shedules

CHEMOTHERAPY TOXICITY

IMMEDIATE (Hours to days)•Local tissue necrosis / Extravasation•Nausea and Vomiting•Phlebitis, Skin rash•Anaphylaxis

EARLY (Days to weeks)• Mucositis• Leucopenia• Thrombocytopenia• Alopecia

Myelosupression

DELAYED (Weeks to months)

• Anemia• Neurotoxicity• Pulmonary fibrosis• Nephrotoxicity• Cardiotoxicity• Hepatotoxicity

LONG TERM(Over Years)• Sterility • Second malignancy - Leukemias & MDS

EXTRAVASATION• Some of the cytotoxic drugs are

vesicants and if any leakage into the tissue occurs will cause severe ulceration and necrosis.

EXTRAVASATIONBASIC GUIDELINES

• Doubtful venepuncture

• High index of suspicion

• Early detection and management

Chemo induced Nosea and Vommiting

Anticipatory Acute Delayed

Chemo 16 - 24 hoursAnticipatory (24 hrs before chemotherapy) - Psychological Mechanism -Antiemetics ineffective - Behavioural therapy helpfull

Acute onset (day 1) – Serotonin dependent mechanisms (peripheral)

Delayed onset (day 2-5) – substance P dependent mechanisms (central)

Visceral Stimuli Chemoreceptor trigger zone

Vestibilar input

Dopamine and serotonin released

Dopamine and serotonin released

Histamin and acetylcholine released

Medullary vommiting center stimulated

Nousea and vommiting

Proposed Pathways for CINV

Increased afferent input to the chemoreceptor trigger zone and vomiting center

Chemotherapy

Cell damage

Higher CNS centers

Release of neuroactive agents

Activation of vagusand splanchnic nerves

Smallintestine

Chemoreceptor trigger zone

Medulla oblongata

Vomiting center

Emetogenic Risk of different drugs

High risk(>90%)•CISPLATIN•CARMUSTINE•CYCLOPHOSPHAMIDE (>1.5 gm/m2)•STREPTOZOCIN•DOCARBAZINE•MECHLORETHAMINE

Moderate risk(30-90%)•CARBOPLATIN•CYCLOPHOSPHAMIDE (< 1.5 gm/m2)•DOXORUBICIN•DANORUBICIN•IFOSFAMIDE•IRINOTECAN •OXALIPLATIN

Antiemetics5-HT3 Antagonists Ondensetron Palonosetron Granisetron Ramosetron

Aprepitant Approved in the US in 2003

MOA selective, high affinity antagonist of human substance P at neurokinin 1 (NK1) receptors interferes with the substance P pathway that produces N/V

Aprepitant Administration*Given for three days as part of a regimen that

includes a 5-HT3 antagonist and a corticosteroid

*Recommended dose125 mg po 1 hour prior to chemotherapy80 mg daily in the morning on days 2 and 3

*Supplied in 125- and 80-mg capsules

MUCOSITIS

Alkylating AgentsBusulfanCyclophosphamideProcarbazine

AnthracyclinesDaunorubicinDoxorubicinEpirubicin

AntibioticsActinomycinBleomycinMitomycin

AntimetabolitesCytosine Arabinoside5-FlurouracilHydroxyureaMethotrexate6-Mercaptopure

TaxanesDocetaxelPaclitaxel

Vinca AlkaloidsVinblastineVincristineVinorelbine

MUCOSITIS MANAGEMENT

PROPHYLAXIS : Maintain oral hygiene Chlorhexedine oral rinse

TREATMENT : Clotrimazole Xylocaine viscous

Fluconazole Acyclovir

Palifermin

ALOPECIA* Psychologically distressing -

Negative body image, Altered interpersonal relations

* Rejection of curative treatment* Starts 1-2 weeks after initiation of

therapy - maximum at 2 months after initiation of therapy

DRUGS : Doxorubicin, Cyclophosphamide, Nitrosoureas PREVENTION: Prevent drug circulation to hair follicle

1. Scalp tourniquet 2. Scalp hypothermia (ice turban)

Hand foot syndrome

First described in 1984 at the New England, Deaconess Hospital during 5-fluorouracil (5-FU) continuous infusion.

Hand-Foot syndrome…..

• Common in high dose therapy, prolonged infusion, liposomal forms

• Management– Stop dosing– Topical wound care &

cold cream base– Pain management– Steroid creams– Pyridoxine– Avoid heat and

pressure

AgentsCapecitabineCytarabineDocetaxelDaunorubicinDoxorubicin5-FU (infusion)MTX

DIARRHEA...

Cisplatin,Dactinomycin, Docetaxel , Irinotecan capecitabine,Erlotinib,Gefitinib,Imatinib,Bortezomib

Organ toxicity

• Nephrotoxicity• Cardiotoxicity • Hepatotoxicity • Pulmonary toxicity• CNS toxicity • PNS toxicity

Nephrotoxicity

Patients must be hydrated before, during, and post drug

administration. Usual approach is to give at least 1 liter before and 1 liter

post drug treatment of 0.9% sodium chloride with 20 mEq of KCl and 4 cc MgS04

With higher doses of drug, more aggressive hydration should be considered with at least 2 liters of fluid administered before drug

In this setting, urine output should be greater than 100 cc/hr.

Furosemide diuresis may be used after every 2 liters of fluid

HEPATOTOXICITYHIGH POTENTIAL LOW POTENTIALAsparaginase HydroxyureaCytarabine MercaptopurineInterferon PentostainMethotrexate Vincristine

IRREVERSIBLE Azathioprine Busulphan

Carmustine Cytarabine Methotrexate Mitomycin

PULMONARY TOXICITY• Early-Onset Chemotherapy-Induced Lung Injury Inflammatory Interstitial Pneumonitis Pulmonary Edema [Cytarabine, all-trans-

retinoic acid, interleukin-2, and bleomycin ] Bronchospasm Pleural Effusions• Late-Onset Chemotherapy-Induced Lung Injury pulmonary fibrosis. [bleomycin, busulfan,

carmustine (BCNU), and mitomycin ]

Peripheral Neuropathy

• Platinum compounds • Vinca alkaloides • Taxenes • Bortezomib • Thalidomide

Cisplatin: Significant peripheral neurotoxicity

Carboplatin: Carboplatin is less neurotoxic More importantly, when used in combination with paclitaxelOxaliplatin: Acute, transient neurotoxicity

CNS TOXICITY • CISPLATIN: posterior leucoencephalopahty, seizures • CARBOPLATIN: thrombotic microangiopathy, optic

neuropathy, seizures • 5- FU: acute cerebellar syndrome • BUSULPHAN: seizures • FLUDARABINE: delayed progressive

encephalopathy • CYCLOPHOSPHAMIDE: reversible visual blurring ,

dizziness • DACARBAZINE: mild encephalopathy

• RETINOIDS: benign intracranial hypertension

DELAYED EFFECCTS

Sterility in Men

• Procarbazine most toxic • Cyclophosphamide [ 9 gm ] generally reversible• Chlorambucil [ 400 mg ]• Methotrexate • Vincristine or vinblastine• Doxorubicin• MOPP-like regimens infertility is universal by the third

cycle• Only 5% to 15% ever regain effective spermatogenesis

Teratogenic effects• Both men and women should be strongly

counseled to avoid pregnancy during active cancer treatment, when the risks of both teratogenesis and mutagenesis are highest

• 5-fluorouracil, cyclophosphamide, busulfan, and chlorambucil anthracyclines . Cis-retinoic acid thalidomide

Tumor Lysis Syndrome• Large numbers of tumor cells are destroyed rapidly,

resulting in intracellular contents being released into the bloodstream faster than the body can eliminate them.

• Hyperkalemia is a common finding• Collaborative management includes:

– Prevention– Hydration– Drug therapy (Allopurinol)

Drug Resistance

• The main obstacle to the clinical efficacy of chemotherapy is the development of drug resistance.

• Complex and multifactorial, but main causes of drug resistance are probably now understood

• Inadequacy of tumor vasculature, leading to poor exposure to chemotherapeutic agents

Clinical Endpoints in Evaluating Response to Chemotherapy

• Complete Response (CR)– Relapse-free survival after stopping treatment

• Partial Response (PR)– At least a 50% reduction in measurable tumor mass

• Progressive Disease (PD)– > 25% increase in one or more lesions

• Stable Disease (SD)– Neither PR nor PD (no changes)

• MRI is commonly used to see the response after chemotherapy in solid malignancy

• MRI does not always reflect tumour response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumour response for the subsequent clinical determination about radiotherapy or radical surgery

• In such cases PET Scan Plays a important role in clinical evaluation: 18FDG- PET

Monitoring of serial biomarker for evaluating response in certain cancers like

*CA 125 for Ovarian Carcinoma*PSA for Prostate CA*hCG and AFP for Testicular CA

CT based Tumour density assesment gained some support in evaluating treatment response in cases of GIST

Besides all these……..

•Routine clinical evaluation for known side effects of specific dugs•Routine check up of LFT,RFT, Serum Electrolytes etc.

are of paramount important during the course of Chemotherapy treatment

It is easy to kill cancer cells, but the challenge is keeping the

patient alive with less morbidity at the same time…..!

Thanks