CHEMOTHERAPY -NITI SARAWGI

CONTENTS

• History• Classification of anticancer drug• Mechanism of action• Chemotherapy in oral cancer

- Definitive Chemotherapy– Neo-adjuvant / induction chemotherapy– Adjuvant / Maintenance chemotherapy– Concomitant / simultaneous chemotherapy.

• Chemoprevention of Cancer

• Complications in chemotherapy

History

• Chemotherapy began during the world war ii after the observation of autopsy of soldiers who died due to the use of nitrogen mustard

– Aplasia of bone marrow– Dissolution of lymphoid tissue– Ulceration of the GIT

• The traditional role of systemic chemotherapy as palliative therapy for recurrent/ metastatic head and neck cancer has changed in recent times with realization of appropriate combination modality with loco regional treatment can result in improved outcomes.

• Chemotherapeutic agents act by various

mechanisms

CLASSIFICATIONDrugs acting directly on cells

(Cytotoxic drug)

1. Alkylating agents

Nitrogen mustards (Cyclophosphamide, melphalan)Ethylenimine (Thio-TEPA)Alkyl sulfonates (Busulphan)Nitrosoureas (carmustin)Triazine (Decarbazine)

2.Antimetabolites Folate antagonist (Methotrexate) Purine antagonist (Mercaptopurine) Pyrimidine antagonist (Fluorouracil)

3.Platinum compoundsCisplastin, carboplatin, oxaliplatin

4.Alkaloids (vincristin,vinblastin)5.Antibiotics (Actinomycin,doxorubicin)6.Miscellaneous (Hydroxyurea,Procarbzine)

Drugs altering hormonal milieu:

1.Glucocorticoids (Psrednisolone)2.Estrogen (Diethylstilbestrol)3.Antiestrogen (Tamoxifen)4.Androgens (Testosterone)5.Progestins (Hydroxyprogestrone)

MODE OF ACTIONChemotherapy targets rapidly dividing cells and the two most susceptible stages are the M-phase and S-phase of the cell cycle.

The cell cycle

Interphase

ProphaseDaughter cells

Telophase

Anaphase

Metaphase

The mitosis stages

DNA

Alkylating agents

• are cell cycle non specific, ie act on dividing as well as resting cells.

• Alkylate nucleophilic groups on DNA bases• Position 7 of guanine residues in DNA is

specially susceptible, but other molecular sites are also involved.

• Leads to cross linking of bases, abnormal base pairing and DNA strand breakage

1.Nitrogen mustards-Mustard gas (HN2) ( mechlorethamine, cyclophosphamide, melphalan etc) • Mechlorethamine- use in hodgkins disease• melphalan – multiple myeloma

2. Nitosoureas:(lomustine) lipid soluble and crosses blood brain barrier, used in brain tumour

TOXICITIES OF ALKYLATING AGENT

– ALOPECIA– HEMORRHAGIC CYSTITIS- ONE OF ITS

DEGRADATION PRODUCT ACROLEIN, (MESNA)– SIADH– PULMONARY FIBROSIS– SECONDARY LEUKEMIAS– CNS DEPRESSION

Antimetabolites

• These drugs act in the s phase of cell cycle• Thus only dividing cells are responsive

– Folate antagonists - Methotrexate (40mg/m2 )

– Purine antagonists - 6-Mercaptopurine - 6-Azathioprine (3-5 mg/Kg/day) - 6-Thioguanine

– Pyrimidine antagonists - 5-Flurouracil (12 mg/Kg/day) - Cytarabine

MethotrexateFolic acid

Tetrahydro folic acid

Purine synthesis

-

DRUG CLASS: Antemetabolite

Folate antagonist

Dihydro folic acid

Dihydro folate reductase

DNA synthesis

Cell cycle specific: S phase

AICAR

TS

• Intermittent IV administration • Start with 40 mg/m2 - 100 mg/m2 body surface • area every 2-3 weeks. (Escalate the dose till • toxicity like mucositis appears)• It can also be given :

IMorallyRegional intra-arterial infusion

(into the superficial temporal or superior thyroid artery)

Side-effects are• mucositis and mucosal ulceration• myelosuppression.• Hepatotoxicity

Mercaptopurine:purine antagonist

Mechanism of action:

Inhibits the formation of nucleotides from adenine & guanine ( purine)

Highly effective antineoplastic drugs.

Common side effects: Bone marrow depression Nausea and vomiting Hyperurecemia

DOSE

Active Phase: 2.5 mg/Kg/day I.V.

Maintenance Phase: ½ Dose

5-Fluorouracil :Pyrimidine antagonist

• Mechanism of action: disrupts Pyrimidine synthesisCapecitabine is an oral pro-drug

• Route of administration: Intravenously orally continuous IV infusion

• Even resting cells are affected (Though rapidly multiplying cells are more susceptible) – Particularly useful for many solid tumors.

• Dose: 1gm orally on alternate days(6 doses)

then 1gm weekly 12 mg/kg/day i.v. for 4 days Topical 5% FU cream (Cutaneous basal cell CA)

• Side-effects: myelosuppression Hand and foot syndrome mucosal ulceration/mucositis nausea and vomiting alopecia.

Mitotic spindle inhibitor

• VINCA ALKALOIDS (Vincristine, Vineblastine)

• Inhibits microtubule formation (Mitotic inhibitor)• Cell cycle specific (M phase)• Vincristine 1.5-2 mg/m2 BSA i.v. weekly• Vinblastine 0.1-2 mg/kg i.v. weekly X 3 doses• TAXANES• Prevent disassembly of microtubules

Antitumor Antibiotics(Actinomycin, Bleomycin)

Mechanism of action:intercalate between DNA strands and interfere with its template function.

Dose:30 mg B.D. I.V / I.M. twice weekly (Total dose of 300-400 mg)

Side effects:Vomiting, stomatitis, diarrheaDesquamation of skin, alopeciaBone marrow depression

TOPICAL CHEMOTHERAPY

• Actinic keratotic lesions• Multiple superficial basal cell carcinomas

• 5% FU cream applied topically B.D. untill areas exhibit a significant inflamatory reaction and ulceration (Usually 3-4 weeks)

INTRALESIONAL CHEMOTHERAPY• Kaposis sarcoma• Keratoacanthoma• Vincristin/Vinblastin/Interferon (Single Injection

or if required reinjection at 3-6 week intervals)

Chemotherapy in oral cancerDEFINITIVE:

Cytotoxic drugs are rarely of curative value for oral squamous cell carcinomas.• CURE/ REMISSION

– Ewing’s sarcoma– Rhabdomyosarcoma– Lymphoma

• Hodgkin’s (CHOP)• Nonhodgkin’s» Burkitt’s lymphoma» Leukaemia, ,» Multiple myeloma

CHEMOTHERAPY COMBINED WITH RADICAL LOCAL TREATMENT

(Chemotherapy may be combined with radical local treatment in one of three ways)

• Adjuvant / Maintenance chemotherapy

• Neo-adjuvant / induction chemotherapy

• Concomitant / simultaneous chemotherapy.

SEQUENTIAL CHEMOTHERAPY/RADIATION

NEOADJUVANT APPROACH

CHEMOTHERAPYSURGERYRADIATION THERAPY

ADJUVANT APPROACH

SURGERYRADIATION THERAPY CHEMOTHERAPY

CONCOMITANT CHEMOTHERAPY /RADIATION

CHEMOTHERAPYRADIATION THERAPY

Induction (Neo-adjuvant) chemotherapy

• Chemotherapy given before local therapy (Surgery &/or radiation)

• Rationale & objective:– Greater drug concentration in the tumor because

of intact vascular supply– Reduction of tumor size (Reduce the extent of

surgery/ make nonresectable tumor resectable)– Eradicate micrometastasis– Can be given in higher dose and is better tolerated

prior to definitive locoregional therapy

Disadvantages:• Delay in potential curative surgery or radiation therapy• Patient may refuse potentially curative follow up

radiotherapy/surgery because of tumor response to initial chemotherapy

• Costs of treatment

• Induction chemotherapy (cisplatin & 5-FU) for stage III & stage IV ca of larynx followed by definitive radiotherapy has shown to preserve organ function.

• Induction chemotherapy for head & neck Ca limited to clinical trials and has very limited supportive studies

Drugs used :- Cis-platin, Methotrexate, Fluorouracil

Adjuvant (Maintenance) chemotherapy

At this time, adjuvant chemotherapy has been shown to have very limited role management of carcinomas of head and neck.

Surgery & / or radiation

Micrometstatic disease outside the surgical field or portals of radiation

ADJUVANT CHEMOTHERAPY

Concomitant chemotherapy.

• THE USE OF CHEMOTHERAPY CONCURRENTLY WITH RADIOTHERAPY

• THE POTETIAL ADVANTAGES OF THIS APPROACH ARE CHEMO MAY POTENTIATE THE EFFECT OF RADIOTHERAPY

• Chemotherapy can sensitize tumors to radiotherapy by inhibiting tumor repopulation

• preferentially killing hypoxic cells, inhibiting the repair of sublethal radiation damage

• Sterilizing micrometastatic disease outside of the radiation fields and decreasing the tumor mass, which leads to improved blood supply and reoxygenation.

• radiotherapy, in turn, may sensitize tumors to chemotherapy by inhibiting the repair of drug-induced damage and by decreasing the size of the tumor mass,

• leading to improved blood supply and enhanced drug delivery.

• Most common approach of concomitant chemotherapy is Radiotherapy with low dose chemotherapy as a radiosensitizing agent

• Statistically significant improved survival using concomitant chemotherapy in head and neck cancers

• Administered in 3 different ways.– Chemotherapy + radiotherapy administered at full or nearly full

dosage (split course radiotherapy).– single agent chemo with continuous course of radiation – alternating chemo with radiotherapy

• Drugs used:-– Cisplatin (100 mg/m2 every 3 weeks for 3 doses )– Carboplatin (45 mg/m2 for 5 days during weeks 1,3,5 & 7)

• Arlene A et al. Concurrent chemotherapy and radiotherapy • For organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-8.

In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control. Cisplatin, drug of choice.

ADVANTAGES DISADVANTAGES

NEOADJUVANT ~High response rate~Less Toxicity~Provide prognostic information

~Delay loco-regional treatment~Expensive~Less patient compliance

ADJUVANT No delay ~Often poorly tolerated after loco-regional treatment~Limited data available regarding action of chemo on primary site.

CONCURRENT Higher response rate Enhanced toxicity

Treatment of Selected Head and Neck tumors

Tumor Radiotherapy Chemotherapy Surgery

Squamous cell carcinoma + + +

Basal cell carcinoma + +

Kaposi s sarcoma + + +

Melanoma + + +

Leiomyoma & Leiomyosarcoma +

Phabdomyoma & Rhabdomyosarcoma + + +

Mucoepidermoid carcinoma + +

Polymorphous low-grade adenocarcinoma + +

Adenoid Cystic carcinoma + +

Clear cell carcinoma +

Hodgkins Lymphoma + +

Non-Hodgkins Lymphoma +

Multiple Myeloma +

Solitary Plasmocytoma of Bone + +

Tumor Radiotherapy Chemotherapy Surgery

Leukemia +

Osteosarcoma + + +

Chondrosarcoma +

Ewings Sarcoma + + +

Burkitts Lymphoma +

Granular Cell tumor +

Schwannoma +

Neurofibroma +

Treatment of selected tumors. Modified from Ang KK. Advances in the Treatment of Head and Neck Cancer. In: James D. Cox KKA, editor. Radiation Oncology, Treatment, Technique Rationale. 9th ed. Philadelphia, PA: Mosby, Elsevier; 2010. p. 161-353

Induction chemotherapy for locally advanced disease (oral cavity, pharyngeal and laryngeal cancers) : Stage III,IV

Chemotherapy with radiation therapy for locally advanced disease

(oral cavity, pharyngeal and laryngeal cancers) : Stage III,IV

chemotherapy for metastatic / recurrent disease : Stage IV

Palliative chemotherapy

• Palliation should be defined as maintenance of quality of survival as close to normal as possible, rather than simply as relief of pain

• Chemo considered as standard treatment• Regimem 1: - Cisplatin 80 mg/m2 - 5 FU 425 mg/m2

• Regimem 2: - Cisplatin 75 mg/m2

- Docetexal 75 mg/m2

- 5 FU 750 mg/m2

• Regimen 3:-MTX 40mg/m2 weekly

methotrexate is the standard drug due to low toxicity

and cost

General toxicity of cytotoxic drugs

• Have profound effect on rapidly multiplying cells (because the most important target of action is nucleic acid)

Bone marrowReticuloendothelial systemEpithelial lining (GIT, skin)Gonads & Foetus

Bone marrow depression

• Most serious & common toxicity• Limits the dose that can be employed• Causes:

Granulocytopenia , agranulocytosis (infection)

Aplastic anemiaThrombocytopenia (bleeding tendencies)

Chemotherapy

Bone marrow depression

Anemia

Hypoxia

Release of growth signals by cancer cells

1. Cancer cell proliferation

2. Neoangiogenesis

Since cancer cells thrive in a hypoxic environment

The cancer patient's hematocrit and hemoglobin should be maintained in the upper one-third of normal range prior to the initiation of chemotherapy.

Lymphoreticular tissue: Inhibition of lymphocyte function + lymphocytopenia

Inhibition of cell mediated and humoral immunity

Damage to epithelial surface

Increased susceptibility to infectionViral (herpes zoster, CMV)Fungal ( candida, pneumocystis carni)

GITDamage to GIT mucosa & turnover rate

High Moderate MildCisplatinActinomycin

VinblastinDoxyrubicin

BleomycinFluorourailMethotrexate

Stomatitis HemorrhageNausea and vomiting Bleomycin Actinomycin Florouracil Methotrexate

skin

Damage to epithelium

Dermatitis

Damage to cells in hair follicle

Alopecia

Gonads and Foetus

• Inhibition of gonadal cellsMale ( oligozoospermia)Female (inhibition of ovulation,

amenorrhoea)

• Damage to foetusTeratogenesisAbortionFetal death

Side effects of chemotherapy

Nausea, vomitingHair lossSuppression of blood count- risk of infectionAnemiaBleedingRenal dysfunctionNeuropathy Impact on fertility

Oral complications of chemotherapy:-

• Ulceration and mucositis• Xerostomia• Generalised oral pain• Necrotizing Ulcerative Gingivitis• Haemorrhage.

Chemoprevention of Cancer

• Chemoprevention is the administration of agents to block or reverse carcinogenesis

Chemoprevention Agents– Retinoids- they exert regulatory control over

cellular differentiation– beta-carotene– Vitamin E– Zinc

CONCLUSION

References

• Shafers Text Book of Oral Pathology. 7th Edition by R Rajendran, B Sivapathasundaram.

• Head and Neck Surgery and Oncology –Jatin Shah

• Textbook of Maxillofacial surgery vol 1 –Peter Ward booth

• The chemotherapy source book – Michael C . Perry

Thank you…