This document provides an overview of chemotherapy for head and neck cancer. It discusses the cell cycle effects of chemotherapy drugs and classifications including cytotoxic, targeted, and hormonal agents. Specific drugs are explained including mechanisms of action, indications, and side effects. The document also reviews landmark clinical trials establishing concurrent chemoradiotherapy as the standard of care for locally advanced head and neck cancer. Targeted agents like cetuximab are now being used for recurrent/metastatic disease.

1. Chemotherapy in Head
and Neck Cancer

2. Content
1. Introduction
2. Cell cycle/ tumor biology and chemotherapy
3. Pharmacology of Chemotherapy drugs
4. Chemotherapy treatment modalities
5. Agents used in Head and neck cancer
6. Landmark trials in HNC treatment
7. Summary
8. Reference

3. Introduction
The term chemotherapy was coined by Paul Ehlrich
It is defined as the use of chemical compounds in treatment of neoplastic
diseases so as to destroy offending cancer cells without damaging the host
Expansion of the role of chemotherapy in HNSCC
Various trials shown that CTRT, brings improvements in locoregional control,
organ preservation, and overall survival.
Development of novel targeted therapies

4. Doxorubicin
5 fluorouracil
Vinblastine
Cisplatin
Lomustine
5FU
Methotrexate
Doxorubicin
Lomustine
5FU
Vincristine
Vinblastine
Bleomycin
Cisplatin
Carmustine
Doxorubcin

6. Classification of CT drugs
Cytotoxic drugs
Targeted agents
Hormonal agents
1. Alkylating agents
2. Platinum based compound
3. Antimetabolites
4. Microtubule damaging agents
5. Topoisomerase 1 and 2 inhibitors
6. Antibiotic
7. Miscellaneous
1. Tyrosine protein kinase inhibitor
2. EGF receptor inhibitors
3. Angiogenesis inhibitors
4. Proteasome inhibitors
5. Unnamed monoclonal antibody
Hormonal drugs
1. Glucocorticoids
2. Estrogens
3. Aromatase inhibitor
4. Antiandrogen
5. 5 Alpha reductase
6. GnRH antagonist
7. Progestin

8. Alkylating Agents
Electrophilic alkyl group or a substituted alkyl group can covalently bind to
cellular nucleophilic sites.
Discovered during the World war I- Mustard gas had vesicant property
Mechlorethamine – first alkylating agent used in human cancer treatment
Most alkylating agents cause dose related bone marrow toxicity and intestinal
mucosa injury.

9. Alkylating agents
Class Examples
ALKYL SULPHONATES BUSULFAN, BENDAMUSTINE
ETHYLENEIMINES/METHYLMELAMINES THIOTEPA, ALTRETAMINE
NITROGEN MUSTARD MECHLORETHAMINE,
MELPHALAN,CHLORAMBUCIL,
CYCLOPHOSPHAMIDE, IFOSFAMIDE
NITROSOUREA CARMUSTINE, STREPTOZOTOCIN
TRIAZENES DACARBAZINE

10. Platinum based compounds
Discovered during 1961 by Dr. Barnett Rosenberg accidently from his work on
effect of electromagnetic radiation on bacteria
Cis-diamminedichloroplatinum (II) (cisplatin)
cis-diamminecyclobutanedicarboxylato platinum (II) (carboplatin)
1,2-diaminocyclohexaneoxalato platinum (II) (oxaliplatin)
nedaplatin (Japan), lobaplatin (China)

11. Antimetabolites
Reduced folates play a central role in one-carbon metabolism, as they are essential for
the biosynthesis of purines, thymidylate, and protein
Antimetabolites block either the synthesis or mimic action of certain DNA substrates
Aminopterin was the first antimetabolite -1940
Targets multiple enzymes involved in folate metabolism
◦ Thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide
ribonucleotide (GAR) formyltransferase, and aminoimidazole carboxamide (AICAR)
formyltransferase

12. Antimetabolites
CLASS EXAMPLE
ANTIFOLATES METHOTREXATE, PEMETREXED,
PRALATREXATE
FLUROPYRAMIDINES 5-FU
CAPECITABINE
TAS-102
DEOXYCYTIDINE ANALOGS CYTARABINE, GEMCITABINE,
PURINE ANALOGS 6-MP
6-TG, FLUDARABINE, CLADRIBINE,
CLOFARABINE

14. Microtubule damaging agents
CLASS EXAMPLE
VINKA ALKALOIDS VINCRISTINE, VINBLASTINE, VINORELBINE
TAXANES PACLITAXEL, DOCETAXEL, ESTRAMUSTINE

15. MECHANISM OF ACTION

16. Topoisomerase inhibitors
CLASS EXAMPLES
IA NONE
IIB TOPOTECAN, IRINOTECAN
IIA ANTHRACYCLINE- DOXORUBICINE,DAUNORUBICIN

17. MECHANISM OF ACTION

18. Antibiotics
1. ACTINOMYCIN D
2. DAUNORUBICIN
3. EPIRUBICIN
4. BLEOMYCIN
5. MITOMYCIN C

19. Miscellaneous
1. HYDROXYUREA
2. L ASPARAGINASE
3. ARSENIC TRIOXIDE

20. Targeted therapy
Class Examples
TYROSINE PROTEIN KINASE INHIBITOR IMATINIB, NILOTINIB
EGF RECEPTOR INHIBITORS GEFTINIB, ERLOTINIB, CETUXIMAB
ANGIOGENESIS INHIBITOR BEVACIZUMAB, SUNITINIB
PROTEOSOME INHIBITOR BORETEZOMIB
UNAMMED MONOCLONAL ANTIBODY TRANTUZUMAB, RITUXIMAB

21. Hormonal agents
DRUGS CLASS EXAMPLES
GLUCOCORTICOIDS PREDNISOLONE
ESTROGENS FOSFESTROL, ETHINYLESTRADIOL
SELECTIVE ESTROGEN RECEPTOR MODIFIER TAMOXIFEN, TOREMIFENE
SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR FULVESTRANT
AROMATASE INHIBITOR LETROZOLE, ANESTROZOLE, EXEMESTANE
ANTIANDROGEN FLUTAMIDE
5 ALPHA REDUCATASE INHIBITOR FINASTERIDE, DUTASTERIDE
GNRH ANALOGUE NAFARELIN, LEUPROLIN
PROGESTIN HYDROXYPROGESTERONE

22. CHEMOTHERAPY TREATMENT MODALITY
1. Adjuvant chemotherapy
2. Induction chemotherapy
3. Concurrent chemotherapy
4. Palliative chemotherapy
Curative intent

23. Induction Chemotherapy
Could shrink primary Tumor volume
Better blood flow to the tumor
Reduce the hypoxic areas within the tumor and make them more radiosensitive
Sx and RT treat loco regional disease- Induction CT could address distant
metastasis
Veteran affair and MACH NC

24. INDUCTION CHEMOTHERAPY
Regimen commonly used
Cisplatin 100mg/m2 with 5FU 1gm/m2 per day for 4-5 days via infusion bottle 3 cycles
Often followed by concurrent chemoradiotherapy (rarely surgery)
TAX 323, 324- Docetaxel or paclitaxel

25. Concurrent Chemotherapy
Used for the cytotoxic effect and the radiosensitizing effect
Reported to have less treatment break ( comparatively lesser toxicity)
Most common regimen used is Cisplatin 100mg/m2 at day 1,22,43 of RT
With or without 5FU 1g on day1-4

26. Rationale for concurrent CTRT
Local antitumor activity of RT is enhanced by the simultaneous CT as radio
sensitizer
Ct may eradicate possible micro metastasis outside RT field
Active against different tumor cell population
Decreased tumor cell repopulation following RT fractionation
Increase tumor cell recruitment from G0 to RT sensitive phase
Improved drug delivery with shrinkage of tumor
Less chances of RT/CT resistance

27. Response in Chemotherapy treatment
Complete response- Indicative of total tumor regression
Partial response- indicative of 50% or greater reduction in the product of the
two largest perpendicular diameters of all measurable lesion
No response- indicative of no change in the size of the tumour, or less than 50%
reduction of all measurable lesion
Major response- implies complete or partial response.
Minor response- implies less than 50% reduction in the dimensional product

28. CHARACTERESTICS RECIST 1.1 PERCIST 1.0
Measurability of a lesions at
baseline
Lesions- longest diameter >10mm
Lymph nodes; short axis>15mm
SUL peak of baseline lesions
atleast 1.5 fold greater than liver
SUV mean +2 SD. If liver is
abnormal, primary tumour should
have the uptake >2x SUL mean of
blood pool
Objective response CR: disappearance of all target
lesion
PR: Reduction of atleast 30% in
the sum of diameter of target
lesions
PD: Increase of atleast 20% in the
sum of diameters of target lesions
or appearance of new lesions
SD: not CR/PR/PD
CMR- complete resolution of
18FDG within all lesions to level
of less than or equal to that of
mean liver activity and
indistuinguishable from the
background.
PMR- reducation of atleast 30% in
SL peak and an absolute drop of
0.8 SL
PMD- Increase of atleast 30% in
SUL peak and an absolute
increase of 0.8 SUL peak units
(or)75% increase in TLG with no
increase in SUL

29. Common Agents used in HNC
Cisplatin
5 FU
Cetuximab
Geftinib
Bevacizumab
Nivolumab

30. Platinum bases compound
Cisplatin- Di amminedichloroplatinum- Heavy metal platinum- 2 chloride and 2
ammonia molecules in cis position
Described by Michele Peyrone in 1844. Its anticancer property was identified by
Barnett Rosenberg.
USFDA approved for anticancer treatment in 1978

31. Mechanism of action
DNA Adduct Formation- N7 position of guanine and adenine to form a variety of
monofunctional and bifunctional adducts
Ribosome Biogenesis Stress- oxaliplatin’s major cytotoxic impact

32. Cisplatin
DNA Adducts-
Intra and inter
DNA
Platinum DNA damage binding
protein
DNA damage
signalling and halt of
cell cycle
DNA repair

33. Use of cisplatin in head and neck
Used in various HPE- sarcoma, carcinoma, lymphoma
Used as a induction agent, concurrent agent, palliative agent
Dose- 100mg/m2 IV on day 1,22,43 of the RT or 40-50mg/m2 IV weekly for 6-7
weeks

34. Side effects and contraindication
Side effects-
◦ Nephrotoxicity
◦ Neurotoxicity
◦ Pancytopaenia
◦ Ototoxicity
◦ Peripheral neuropathy

35. Side effects and contraindication
Contraindication
◦ Acute leukemia
◦ Severe infection
◦ Hypomagnesaemia, hypocalcaemia, hyponatraemia
◦ Renal failure, stroke
◦ Pregnancy, lactating mother

36. 5 Fluorouracil (5 FU)
Antimetabolite
Discovered by Heidelberger, Chaudary and Weston in 1950
Mechanism of action – Primarily inhibits thymidylate synthase
5FU will cause the death of rapidly proliferating cancer cells by scarcity of
thymidine for DNA synthesis

37. Deoxyuridine
monophosphate
Deoxy thymidine
monophosphate
TS

38. Indication of 5 FU
Essential component in HNSCC CT ( induction, concurrent, palliative)
Can also be used topically for BCC and actinic keratosis
Dose- with cisplatin 1000mg/m2/day IV infusion on day 1-4 and 22-25

39. Side effects and contraindication
Side effects
◦ Myelosupressioon
◦ Maculopapular eruptions
◦ Cardiotoxicity
◦ Mucositis
◦ Mood disorder

40. Side effects and contraindications
Contraindication
◦ Patient with bone marrow suppression
◦ Pregnancy
◦ Breast feeding

41. Cetuximab
Chimeric monoclonal antibody for EGFR
May 2000 ImClone reported positive results from stage 1 clinical trials
2006 US FDA approval use in HNSCC as monotherapy and combination
MOA- 10 times more affinity to EGFR. Hence blocks the EGFR and growth stimuli
and results in cell death

43. Indication in head and neck cancer
Initial treatment as monotheraoy with RT
Combination with cisplatin in metastatic disease
Dose- 400mg/m2 IV infused over 2 hrs maximum 10mg.m2/min (loading)
250mg/m2 maintainence over 60 min once a week

44. Side effects
Acneiform rashes
Fatigability
Hypomagnesaemia
Fever chills and nausea
Anorexia, abdominal cramps
Sever toxicities- fatal bullous mucocutaneous disease, anaphylactic disease
Some suggest that the
patients who develop rashes
are also those who have
better tumour response and
survival benefit

45. Geftinib
Signal transduction inhibitor
Mainly used in metastatic HNC
MOA- Geftinib selectively inhibits the tyrosine kinase domain and interrupts
signal transduction to the nucleus
Dose- 250mg once a day (max 500mg)
Side effects- skin reactions, diarrhea, anorexia, nausea
◦ Interstitial lung disease, corneal erosion, GI perforation

46. Nivolumab
Newer monoclonal antibody- Human programmed death receptor-1
(PD-1)
FDA approved for melanoma
MOA- bind to PD-1 receptors and blocks interaction with PDL1 and
PDL2. hence prevents inhibition of immune response
In head and neck- Classical non hodgkins lymphoma, melanoma,
recurrent/ metastatic disease
Side effects- Lymphocytopaenia, hyponatraemia, breath shortness,
cough, Loss of appetite, musculoskeletal pain

47. Clinical trials
1. Head and neck contracts programme trial
2. Vetteran affair trial
3. EORTC trial
4. TAX 323, TAX 324 trial
5. Intergroup trial
6. RTOG trial
7. Bonner trial
Induction CT
Concurrent CT
Targeted therapy

48. Head and neck contracts programme

49. Veterans affairs trail

50. European organization for research and
treatment of cancer EORTC

51. Tax 323 and tax 324

52. Intergroup trial

53. RTOG-91-11 trial

54. Bachaud et al CTRT trial

55. RTOG 95 01

56. EORTC 22931

57. Bonner trial

58. Chemoprevention
Use of natural or synthetic chemical for the reversal, suppression or prevention
of conversion premalignant lesion to invasive forms.
Chemopreventive agents used-
1. Retinoids and vitamin A
2. Vitamin E
3. Selenium, cyclo oxygenase2 inhibitors
4. Tyrosine kinase inhibitors
5. ONYX 015, Protease inhibitors

59. Summary
Concurrent chemoradiotherapy is at present the standard of care for treatment
of locally advanced head and neck cancer with a confirmed absolute survival
benefit of 6.5% at 5 years.
Single agent cisplatin, which in the past has been shown to be as effective as
multiple drug regimes, is now being challenged by the introduction of the use of
taxanes.
Targeted biological agents, such as cetuximab, have a role to play in both
advanced head and neck cancer and recurrent or metastatic disease but those
roles are still being established.

60. Reference
Scott brown 8th edition
Jatin shah head and neck surgery and oncology
DeVita Cancer principle and practice of oncology