2. Topics of discussion
• Historical perspective
• Tumour and its biology
• Chemotherapy and classification of chemotherapeutic
agents
• Choice of chemotherapy in head and neck cancer
• Strategies of chemotherapy
• Challenges in chemotherapy
3. CHEMOTHERAPY: HISTORICAL PERSPECTIVE
• German chemist Paul Ehrlich (1900) – coined the term
“chemotherapy”
• Originally chemotherapy referred to treatment of disease with drugs or
chemicals.
• But by mid 1950’s the term was only used primarily in reference to
drugs which were used to treat cancer.
• 1943-During World War II, soldiers were exposed to nitrogen mustard
gas and shows marked depletion in marrow and lymphoid cells.
• Based on this, Alfred and Louis used nitrogen mustard to induce
remission of lymphoma in mice.
4. • 1948-Sidney Farber showed that aminopterin, a folic acid analogue
can induce remission in acute lymphoblastic leukemia.
• 1950-Actinomycin D was developed which have significant antitumour
activity.
• 1951-Hitchings and Elion isolated 6-thioquanine and 6-
mercaptopurine that inhibited purine metabolism, are used in various
cancer and as immunosuppressant.
• 1970-golden age of medical oncology, development of effective
combination chemotherapy regimens. New classes of drugs developed
(anthracyclines, platinum compounds). Cures achieved in some forms
of cancer ( breast, stomach, small cell lung cancer )
5. What is cancer?
• Uncontrolled growth of cells coupled with malignant behaviour:
invasion and metastasis.
• It arises through a complex interaction between genetic and
environmental factors causing -
Genetic mutations in oncogenes and tumour suppressor genes.
6. Principles of tumour biology
• Cellular kinetics : Cell cycle
Tumour growth
• Cell signalling
• Metastatic spread
• Mechanism of cell death
• Fractional cell kill hypothesis and drug dosing
7. Cell cycle
• G0 - normal non-dividing cells are present here.
When actively recruited into the cell cycle – cells pass through 4 phases :
• G1 - cell increases in size & prepares to copy DNA
• S (synthesis) - allows doubling of the chromosomal material & synthesis
of DNA occures
• G2 - further growth occurs before cell division
• M (mitosis) - chromosomes separate and the cell divides.
At the end of a cycle the daughter cells can either continue through the cycle,
leave and enter the resting phase or becomes terminally differentiated.
8.
9. Tumour growth
The kinetics of any population of tumour cells is regulated by the
following :
• Doubling time - the cell cycle time, which varies considerably between
tissue types.
• Growth fraction - the percentage of cells passing through the cell cycle
at a given point in time, which is greatest in the early stages influenced
by the rate of cell death and the availability of blood supply.
• Cell loss - result from unsuccessful division, death, desquamation,
metastasis and migration.
10. Tumour growth cont…
• Tumours characteristically follow a sigmoid shaped growth curve, in
which tumour doubling size varies with tumour size.
• Tumours grow most rapidly at small volumes.
• Chemotherapy is therefore more likely to be successful in eradicating a
small tumour.
11. Cell signalling
Cell respond to their environment via external signals ( growth factors )
GF interact with cell surface receptors that activate an internal signalling
cascade
Ultimately acts at the DNA level through transcription factors that bind to
the promotor regions of relevant genes
Stimulate the cell cycle and influence cell division, migration and
programmed cell death (apoptosis)
12. Metastatic spread
• A tumour is considered malignant when it has the capacity to spread
beyond its original site and invade surrounding tissue.
• Normally cells are anchored to the extracellular matrix by cell adhesion
molecules, including the integrins.
• Abnormalities of the factors maintaining tissue integrity will allow local
invasion and ultimately metastases of the tumour cells.
13. Mechanism of cell death
• There are two main types of cell death :
apoptosis and necrosis
• Necrotic cell death : caused by gross cell injury, and results in the death
of groups of cells within a tissue.
• Apoptosis : regulated form of cell death that may be induced or is
preprogrammed into the cell (e.g. during development) and is
characterized by specific DNA changes and no accompanying
inflammatory response.
It can be triggered if mistakes in DNA replication are identified.
14. Mechanism of cell death cont…
• Loss of this protective mechanism ( i.e apoptosis ) would
allow mutant cells to continue to divide and grow
thereby conserving mutations in subsequent cell divisions.
15. FRACTIONAL CELL KILL HYPOTHESIS
AND DRUG DOSING
• Theoretically the administration of successive doses of chemotherapy will
result in a fixed reduction in the number of cancer cells with each cycle.
• A gap between cycles is necessary to allow normal tissue to recover.
• Unfortunately these first order dynamics are not observed in clinical practice.
• Factors such as variation in tumour sensitivity and effective drug delivery
with each course result in an unpredictable cell response
16. Invasion growth & metastasis of malignant tumour
Acquired DNA damaging agent
Chemical / Radiation / Viruses
Normal cells
DNA damage Inherited mutations in gene
affecting : DNA repair / cell growth / apoptosis
Failure of DNA repair
Mutation in the genome of somatic cells
Activation of growth Inactivation of tumour Alterations in genes that regulate
promoting oncogenes suppresor genes apoptosis
Unregulated cell proliferation Decrease apoptosis
Clonal expansion
17. Angiogenesis / escape from immunity Additional mutation
Tumour progression
Malignant neoplasm
Invasion and metastasis
18. What is chemotherapy ?
Defined as –
Use of chemical compounds in treatment of neoplastic diseases so as to
destroy offending cancer cells without damaging the host.
19. Aims of chemotherapy
• To exploit the resulting differences in biological and proliferative
characteristics between normal and cancer cells.
• To induce mutations in cancer cells that are not sufficient to cause cell
death but that can be recognized by the cell, to trigger apoptosis.
• Most cytotoxic drugs preferentially affect dividing cells in tumours.
20. Goals of chemotherapy
To cure
To control - Prolong remission
Decrease rate of relapse
Palliation - Relive symptoms
Improve quality of life
21. CLASSIFICATION OF
CHEMOTHERAPEUTIC AGENTS
• Depending on the effect on the cell cycle :
Phase-specific
Non-phase-specific
• According to mechanisms of action :
Alkylating agents
Heavy metals
Antimetabolites
Cytotoxic antibiotics
Spindle poisons
Topoisomerase inhibitors
Hormones & hormone antagonist
22. Phase-specific chemotherapy
• Kills proliferating cells only during a specific part or parts of the cell
cycle.
Examples :
• S-specific : methotrexate, 5-FU, 6-mercaptopurine, hydroxyurea.
• G2-specific : bleomycin
• M-specific : vincristine, vinblastine
• G1-specific : L-asparaginase
23. Phase Non-specific chemotherapy
• They do not act on a specific phase and are independent of cell
cycle phases, meaning that they act predominantly on cells that
are actively dividing.
• They have a dose-related plateau in their cell killing ability
because only a subset of proliferating cells remains fully sensitive
to drug-induced cytotoxicity at any one time.
• The way to increase cell kill is therefore to increase the
duration of exposure rather than increasing the drug dose.
• Some drugs have an equal effect on tumour and normal cells
whether they are in the proliferating or resting phase (e.g.
alkylating agents, platinum derivatives). They have a linear dose-
response curve; that is, the greater the dose of the drug, the
greater the fractional cell kill.
24. ALKYLATING AGENTS
• These include, Nitrogen mustards (Melphalan, Chlorambucil,
Mechlorethamine, uracil mustard) and Oxazaphosphorines
(Cyclophosphamide and Ifosfamide) and Alkyl sulfonates ( Busulfan,
Ethylenimines )
• These highly reactive compounds produce their effects by covalently linking
an alkyl group (R-CH2) to a chemical species in nucleic acids or
proteins. The site at which the cross-links are formed and the number of cross-
links formed is drug-specific.
25. ALKYLATING AGENTS Cont…
• Most alkylating agents are bipolar (i.e. they contain two groups
capable of reacting with DNA).
• They can form bridges between a single strand or two
separate strands of DNA, interfering with the action of the
enzymes involved in DNA replication.
• The cell then either dies, or is physically unable to divide or
triggers apoptosis.
• The damage is most serious during the S phase as the cell has
less time to remove the damaged fragments.
26. HEAVY METALS
• These include, platinum agents (carboplatin, cisplatin and
oxaliplatin )
• Cisplatin is an organic heavy metal complex. Chloride ions are lost
from the molecule after it diffuses into a cell allowing the compound to
cross-link with the DNA strands, mostly to guanine groups.
• This causes intra- and inter-strand DNA cross-links, resulting in
inhibition of DNA, RNA and protein synthesis.
27. HEAVY METALS Cont…
• Carboplatin has the same platinum moiety as cisplatin but is bonded
to an organic carboxylate group.
• Oxaliplatin contains a platinum atom complexed with oxalate and
a bulky diaminocyclohexane (DACH) group. It forms reactive
platinum complexes that are believed to inhibit DNA synthesis by
forming inter-strand and intra-strand cross-linking of DNA molecule
28. ANTIMETABOLITES
• Antimetabolites are compounds that bear a structural similarity to
naturally occurring substances such as vitamins, nucleosides or amino
acids.
• They compete with the natural substrate for the active site on an
essential enzyme or receptor. Some are incorporated directly into DNA
or RNA.
• Most are phase specific, acting during the S phase of the cell cycle.
Their efficacy is usually greater over a prolonged period of time, so they
are usually given continuously.
• There are three main classes: folic acid antagonists, pyrimidine
analogues and purine analogues.
29. Antimetabolite : folic acid antagonists
• Methotrexate competitively inhibits dihydrofolate
reductase, which is responsible for the formation of tetrahydrofolate
from dihydrofolate.
• This is essential for the generation of a variety of coenzymes that are
involved in the synthesis of purines, thymidylate, methionine and
glycine.
• It also causes inhibition of the production of thymidine
monophosphate, which is essential for DNA and RNA synthesis.
31. Antimetabolites : pyrimidine analogues
• These drugs work by either :
Inhibiting the synthesis of nucleic acids (e.g. Fluorouracil ), /
Inhibiting enzymes involved in DNA synthesis (e.g. cytarabine,
which inhibits DNA polymerase) or /
By becoming incorporated into DNA (e.g. gemcitabine),
interfering with DNA synthesis and resulting in cell death.
32. Antimetabolites : Purine analogues
• These are analogues of the natural purine bases and nucleotides.
• 6 mercaptopurine (6MP) and thioguanine are derivatives of adenine
and guanine respectively.
• A sulphur group replaces the keto group on carbon-6 in these
compounds. In many cases, the drugs require initial activation. They are
then able to inhibit nucleotide biosynthesis by direct incorporation into
DNA.
33. CYTOTOXIC ANTIBIOTICS
• Most antitumour antibiotics have been produced from bacterial and
fungal cultures (often Streptomyces species). They affect the function
and synthesis of nucleic acids in different ways.
• Anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin)
intercalate with DNA and affect the topoisomerase II enzyme. This
DNA gyrase splits the DNA helix and reconnects it to overcome the
torsional forces that would interfere with replication. The anthracyclines
stabilize the DNA topoisomerase II complex and thus prevent
reconnection of the strands.
34. CYTOTOXIC ANTIBIOTICS Cont…
• Actinomycin D intercalates between guanine and cytosine base pairs.
This interferes with the transcription of DNA at high doses. At low doses
DNA-directed RNA synthesis is blocked.
• Bleomycin consists of a mixture of glycopeptides that cause DNA
fragmentation.
• Mitomycin C inhibits DNA synthesis by cross-linking DNA, acting like
an alkylating agent.
35. SPINDLE POISONS
• Vinca alkaloids
The two prominent agents are vincristine and vinblastine, which act
as mitotic spindle poisons. They bind to tubulin, the building block of the
microtubules, which inhibits further assembly of the spindle during
metaphase, thus inhibiting mitosis. Other examples include vindesine and
vinorelbine.
• Taxoids
Paclitaxel (Taxol) and docetaxel (Taxotere) promote assembly of
microtubules and inhibits their disassembly. Direct activation of apoptotic
pathways has also been suggested to be critical to the cytotoxicity of this
drug.
36. TOPOISOMERASE INHIBITORS
• Topoisomerases are responsible for altering the 3D structure of DNA by
a cleaving/unwinding/rejoining reaction.
• They are involved in DNA replication, chromatid segregation and
transcription.
• It has previously been considered that the efficacy of topoisomerase
inhibitors in the treatment of cancer was based solely on their ability to
inhibit DNA replication.
• The drugs are phase-specific and prevent cells from entering mitosis
from G2.
37. TOPOISOMERASE INHIBITORS Cont…
• Topoisomerase I inhibitors (e.g. irinotecan and topetcan).
These bind to the enzyme-DNA complex, stabilizing it and preventing
DNA replication.
• Topoisomerase II inhibitors (e.g. etoposide). These stabilize the
complex between topoisomerase II and DNA that causes strand breaks
and ultimately inhibits DNA replication.
39. CHEMOTHERAPY IN HEAD AND
NECK CANCERS
• Chemotherapy is regularly employed in the management of head and
neck cancer.
• It has not changed the cure rates of locally advanced head and neck
cancer.
• It has, however, allowed improved organ preservation when combined
with radiotherapy and has led to a reduction in rates of distant
metastases.
40. Choice of chemotherapy
Choice of drugs depends on :
• Tumour type
• General performance status of patient
• Renal and hepatic function
• Bone marrow reserve
• Concurrent medical problem
• Patient willingness
• Patients physical and emotional tolerance for side effects
41. Choice of chemotherapy in head and neck
cancers
• The single agents active in head and neck cancer, with response rates
between 15% and 40%, include methotrexate, cisplatin, carboplatin,
fluorouracil, ifosfamide, bleomycin, paclitaxel, and docetaxel.
• Cisplatin is one of the most active drugs against squamous head and
neck cancer.
• Taxoids and gemcitabine are gaining favour and are being incorporated
into many current drug trials.
44. Cisplatin
• Inorganic metal compound
• Binds to DNA and causes inter and intra-strand cross linking
Dose :
• 80-12 mg/m2 every 3 to 4 weeks with mannitol diuresis
Mode of administration :
• IV
Toxicity :
• Renal dysfunction, ototoxicity, nausea & vomiting, neutropenia, thrombocytopenia, acute haemolytic anaemia, hypomagnesemia,
peripheral neuropathy
Advantages :
• Rapid response / Response rate 30 % / Duration of response 4 months
Disadvantage :
• High toxicity & requires hospitalization
45. Taxanes ( Paclitaxel / Docetaxel )
• Act on G2 phase
• Bind to beta subunit of tubulin & inhibits microtubule depolymerization cell cycle arrest
Dose :
• Paclitaxel – 135-250 mg/m2 over 3 to 24 hours every 3 weeks
• Docetaxel – 60-100 mg/m2 bolus every 3 weeks
Toxicity :
• Neutropenia and infection
• Response rate : 30-40%
46. Cyclophosphamide
• Acts by cross linking of DNA strands
Dose :
• 50-1500 mg/m2 3 to 4 weekly IV
Toxicity :
• Bone marrow suppression
• Nausea, vomiting
• Alopecia, ridging of nails
• Azoospermia, cessation of menses
• Acute haemorrahagic cystitis
• Bladder cancer
47. 5-Fluorouracil
• Competes with enzyme thymidylate synthetase by displacing uracil
• Inhibits formation of thymidine decrease DNA synthesis
Dose :
• 1gm/m2/day as continuous infusion for 5 days and repeated 3 to 4 weekly
Toxicity :
• Myelosuppression
• Nausea, vomiting, diarrhoea
• Alopecia, hyperpigmentation, maculopapular rash
• Response rate 15%
48. Vinca alkaloids ( Vincristine / Vinblastine )
• Disrupt microtubular spindle formation cause mitotic arrest
Dose :
• Vincristine ( oncovin ) – 1-1.5 mg/m2 once or twice a month IV
• Vinblastine ( velban ) – 5 mg/m2 weekly IV
Toxicity :
• Vincristine – neurotoxicity, hoarseness, constipation, alopecia
• Vinblastine – myelosuppression, myalgia, alopecia
49. Bleomycin
• Antineoplastic antibiotis
• Binds to DNA and generates O2 free radicals which cause DNA strands to breakup
Dose :
• 10-20 units/m2 once or twice a week IM/IV
Toxicity :
• Fever with chills
• Alopecia
• Erythema
• Stomatitis
• Pulmonary toxicity ( pulmonary fibrosis, restrictive lung disease )
• Anaphylactic reaction
51. Single agent therapy
• One third of patient response to single agents, out of which less than 5% have complete response.
• Duration of response – 2-4 months
• Median survival time – approx. 6 months
Following are the single agent that may be used in treatment of squamous cell carcinoma of
head and neck cancers :
• Methotrexate
• Cisplatin
• Carboplatin
• 5-FU
• Vinca alkaloids
52. COMBINATION CHEMOTHERAPY
• Combinations of cytotoxic agents are widely used for many cancers and
may be more effective than single agents.
Possible explanations for this include:
- Exposure to agents with different mechanisms of action
and non overlapping toxicities
- Reduction in the development of drug resistance
- The ability to use combinations of drugs that may be
synergistic.
• Combination chemotherapy in head and neck cancers usually includes
cisplatin and 5-FU ( most common drug regimen )
53. Adjuvant chemotherapy
• This is the administration of chemotherapy after curative surgery or
radiotherapy, in patients considered to be at high risk of relapse.
• The intention is to eradicate micro metastatic disease.
• Randomized trials assessing the use of adjuvant chemotherapy for the
patients with head and neck squamous carcinoma do not suggest a
significant survival benefit.
54. Neoadjuvant chemotherapy
(induction chemotherapy)
• Neoadjuvant, or induction chemotherapy, is the use of chemotherapy
prior to definitive surgery or radiotherapy in patients with locally
advanced disease.
• The intention is to reduce the tumour bulk before definitive treatment
and hence improve local and distant control of the disease.
• This will also achieve greater organ preservation and overall survival.
55. Concurrent chemoradiation (CRT)
• This involves the synchronous use of chemotherapy and radiotherapy.
• In the context of head and neck cancer, this is often used after definitive
surgery.
• The rationale is that chemotherapy can sensitize tumours to
radiotherapy by inhibiting tumour repopulation, preferentially
killing hypoxic cells, inhibiting the repair of sublethal radiation damage,
sterilizing micrometastatic disease outside of the radiation fields and
decreasing the tumour mass, which leads to improved blood supply and
reoxygenation.
56. Concurrent chemoradiation (CRT) Cont…
• Fractionated radiotherapy, in turn, may sensitize tumours to
chemotherapy by inhibiting the repair of drug-induced damage and by
decreasing the size of the tumour mass, leading to improved blood
supply and enhanced drug delivery.
• Patients with high-risk features (positive lymph nodes, positive margins,
extracapsular spread (ECS), perineural/vascular invasion) have been
shown to demonstrate an improved 5-year survival by 13%.
57. Major contributions of chemotherapy in Head & Neck cancers
• Chemotherapy is efficacious for the treatment of recurrent head and neck squamous cancers when
given in combination with other modalities.
• Chemoradiotherapy is the treatment of choice for nasopharyngeal carcinoma.
• Chemotherapy has a major role in the treatment of intermediate grade non-hodgkins lymphoma
• Induction therapy has shown positive result in organ preservation in case of carcinoma laryng.
• Role of chemotherapy in soft tissue sarcomas is only for recurrences except rhabdomyosarcomas.
• Thyroid cancer is ablated with radioiodine if the primary tumour is inoperable or when there is
residual or recurrent post operative thyroid cancer or metastatic nodes.
58. FUTURE TREND OF CHEMOTHERAPY
• Despite the introduction of new cytotoxic drugs, the management of
advanced head and neck cancer remains challenging.
• Over the last years interest has focused on the role of novel agents with
more targeted mechanisms of action or agents that are able to
manipulate the immune system to provide tumour control
(immunotherapy).
59. Targeted therapy
• Targeted therapy aims to specifically act on a well-defined target or biologic
pathway that, when inactivated, causes regression or destruction of the
malignant process.
The therapies mainly targeted against the following properties of cancer
cells :
• Growth factor independence
• Ability to recruit a dedicated blood supply
• Avoidance of apoptosis
• Reactivation of telomerase
• Insensitivity to antigrowth signals
60. Monoclonal antibodies
Monoclonal antibodies can be derived from a variety of sources:
• Murine – mouse antibodies
• Chimeric – part mouse/part human antibodies
• Humanized – engineered to be mostly human
• Human – fully human antibodies.
61. Monoclonal antibodies cont…
There are several proposed mechanisms of action of monoclonal
antibodies as anticancer agents. These include:
• Induction of apoptosis
• Blocking of the receptors needed for cell proliferation/function
• Antibody dependent cellular cytotoxicity (ADCC)
• Complement-mediated cellular cytotoxicity (fixation of complement
leading to cytotoxicity).
62. Monoclonal antibodies against EGFR
• Monoclonal antibody developed against EGFR is the chimeric IgG
antibody cetuximab.
• It can effectively block the effect of epidermal growth factor and
transforming growth factor α.
• It also causes internalization of EGFR and targets the cytotoxic immune
effector cells towards EGFR expressing tumour cells.
63. Monoclonal antibodies against VEGFR
• Bevacizumab (Avastin) is a humanized murine monoclonal antibody
targeting VEGF.
• It is the first anti-angiogenic drug to have induced a survival advantage
in cancer therapy.
• The use of bevacizumab in head and neck cancer is supported by
information derived in preclinical trials.
64. IMMUNOTHERAPY
• Immune checkpoint inhibitors are a new class of systemic agents being
increasingly used in oncology.
• They function by interrupting the immunosuppressive pathways, called
inhibitory checkpoints, which are normally used by tumour cells to prevent
detection and elimination by the host immune system.
• Molecular targets of immune checkpoint inhibitors are found on T cells and
include cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed
cell death protein 1 (PD-1) receptor.
• There is interest in the role of immune checkpoint inhibitors particularly in
tumours with high levels of endogenous PD-L1 expression, which include
some head and neck squamous cell carcinomas.
66. Resistance to chemotherapeutic agents
• Lack of response to drug induced tumour growth inhibition
• Primary resistance : no response from very first exposure
• Acquired resistance : during continuation of therapy
Due to – adaption of tumour cells / mutation in one or more
gene.
67. Mechanism of resistance
• Increase drug efflux via p-glycoprotein transporter
• Overexpression of multidrug resistance protein 1
• Decrease inward transport
• Insufficient activation of the drug
• Increase in inactivation
• Increase concentration of target enzyme
• Rapid repair of drug induced lesions
• Altered activity of target proteins
68. Overcoming resistance
• Using different classes of drugs with different mechanism of action
• With narrowest cycle intervals, necessary for bone marrow recovery