2. 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
3. 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
4. • 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
8. MODE OF ACTION
Chemotherapy targets rapidly dividing cells
and the two most susceptible stages are the
M-phase and S-phase of the cell cycle.
The cell cycle
13. 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
14. 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
15. TOXICITIES OF ALKYLATING AGENT
– ALOPECIA
– HEMORRHAGIC CYSTITIS- ONE OF ITS
DEGRADATION PRODUCT ACROLEIN, (MESNA)
– SIADH
– PULMONARY FIBROSIS
– SECONDARY LEUKEMIAS
– CNS DEPRESSION
16. 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
17. Methotrexate
Folic 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
18. • 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 :
IM
orally
Regional intra-arterial infusion
(into the superficial temporal or superior thyroid artery)
20. 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
21. 5-Fluorouracil :
Pyrimidine antagonist
• Mechanism of action:
disrupts Pyrimidine synthesis
Capecitabine is an oral pro-drug
• Route of administration:
Intravenously
orally
continuous IV infusion
22. • 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.
24. 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, diarrhea
Desquamation of skin, alopecia
Bone marrow depression
25. 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)
26. INTRALESIONAL CHEMOTHERAPY
• Kaposis sarcoma
• Keratoacanthoma
• Vincristin/Vinblastin/Interferon (Single
Injection or if required reinjection at 3-6 week
intervals)
27. Chemotherapy in oral cancer
DEFINITIVE:
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
28. 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.
30. 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
31. 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
32.
33. 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
34. 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.
35. • 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.
36. • 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)
37. • 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.
38. 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
44. 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
45. General toxicity of cytotoxic drugs
• Have profound effect on rapidly multiplying cells
(because the most important target of action is nucleic acid)
Bone marrow
Reticuloendothelial system
Epithelial lining (GIT, skin)
Gonads & Foetus
46.
47. Bone marrow depression
• Most serious & common toxicity
• Limits the dose that can be employed
• Causes:
Granulocytopenia , agranulocytosis
(infection)
Aplastic anemia
Thrombocytopenia (bleeding tendencies)
49. 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.
50. Lymphoreticular tissue:
Inhibition of lymphocyte function
+
lymphocytopenia
Inhibition of cell mediated
and humoral immunity
Damage to epithelial
surface
Increased susceptibility to infection
Viral (herpes zoster, CMV)
Fungal ( candida, pneumocystis carni)
53. Gonads and Foetus
• Inhibition of gonadal cells
Male ( oligozoospermia)
Female (inhibition of ovulation,
amenorrhoea)
• Damage to foetus
Teratogenesis
Abortion
Fetal death
54. Side effects of chemotherapy
Nausea, vomiting
Hair loss
Suppression of blood count- risk of infection
Anemia
Bleeding
Renal dysfunction
Neuropathy
Impact on fertility
56. 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
59. 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
