H & N cancer has been potentially curable for decades with surgery or RT or by combination of these Both of these are only successful in early stage of disease In more advanced disease the results have been disappointing .Approximately 50%-60% of patients manifest loco-regional recurrence within two years. 20%-30% develop distant metastasis if they survive long enough.

1. ADVANCED NONSURGICAL
THERAPY
FOR
HEAD AND NECK CANCERS
Presenter-Dr.Ninan
Moderator-Prof.Dr.A.Thangavelu
HOD Dept Of OMFS

2. I ntroduction

3. H & N cancer has been potentially curable forH & N cancer has been potentially curable for
decades withdecades with surgery or RTsurgery or RT or by combination of theseor by combination of these
Both of these are only successful in early stage of
disease
In more advanced disease the results have beendisease the results have been
disappointingdisappointing
 ApproximatelyApproximately 50%-60%50%-60% of patients manifest loco-of patients manifest loco-
regional recurrence within two yearsregional recurrence within two years
 20%-30%20%-30% develop distant metastasis if they survivedevelop distant metastasis if they survive
long enoughlong enough

4.  RRecent innovations- intensify treatment withecent innovations- intensify treatment with
improved survival as the predominant goalimproved survival as the predominant goal
Non Surgical Treatment Used areNon Surgical Treatment Used are::
1.Induction Chemotherapy1.Induction Chemotherapy
2.Concurrent Chemo-Radiotherapy2.Concurrent Chemo-Radiotherapy
3.Altered Fractionation Radiotherapy3.Altered Fractionation Radiotherapy
4.Targeted Molecular Therapy4.Targeted Molecular Therapy
5.IMRT And IGRT5.IMRT And IGRT
6.Photodynamic Therapy6.Photodynamic Therapy

5. 1.Induction Chemotherapy
 The use of chemotherapy as a primary treatmentThe use of chemotherapy as a primary treatment
for Pts presenting with advanced CA for which nofor Pts presenting with advanced CA for which no
alternative treatment existsalternative treatment exists
These doses may be high, with the goal of attemptingThese doses may be high, with the goal of attempting
to quickly attack the cancerto quickly attack the cancer cells
 Very high doses of drugs are often used in inductionVery high doses of drugs are often used in induction
chemotherapy, with the goal of avoiding repeat cycleschemotherapy, with the goal of avoiding repeat cycles
in the future by eliminating the cancer with the first fewin the future by eliminating the cancer with the first few
roundsrounds

6.  standard induction chemotherapy regimen-standard induction chemotherapy regimen-
** It consists of a platinum agent and 5-fluorouracil (5-It consists of a platinum agent and 5-fluorouracil (5-
FU), a regimen known as PFFU), a regimen known as PF
** More recently, the addition of a taxane such asMore recently, the addition of a taxane such as
docetaxel to the PF (a triple combinationdocetaxel to the PF (a triple combination
known as TPF) is emerging as a more effectiveknown as TPF) is emerging as a more effective
regimenregimen
2.Concurrent Chemo-radiotherapy2.Concurrent Chemo-radiotherapy
 Chemotherapy and radiation therapy are givenChemotherapy and radiation therapy are given
simultaneously rather than sequentiallysimultaneously rather than sequentially

7. This approach is aimed at killing radiation-resistantThis approach is aimed at killing radiation-resistant
cancer cells with chemotherapycancer cells with chemotherapy
 CChemotherapy can enhance cell killing by radiationhemotherapy can enhance cell killing by radiation
therapytherapy
Toxicity (especially mucositis 70–80%) is increasedToxicity (especially mucositis 70–80%) is increased
with concomitant chemo radiotherapywith concomitant chemo radiotherapy
 AAn improvement in 5-year survival of 8% withn improvement in 5-year survival of 8% with
concomitant chemotherapy and radiation therapyconcomitant chemotherapy and radiation therapy

8.  CCR produces significant improvement overCCR produces significant improvement over
postoperative radiation therapypostoperative radiation therapy
 EEven large volume T4 laryngeal SCC...treated withven large volume T4 laryngeal SCC...treated with
chemoradiotherapy have excellent rates of localchemoradiotherapy have excellent rates of local
controlcontrol
 Monoclonal antibody to the EGFR (cetuximab)Monoclonal antibody to the EGFR (cetuximab)
increases survival rates when administered duringincreases survival rates when administered during
radiotherapyradiotherapy
 EGFR blockade results in radiationEGFR blockade results in radiation sensitization andsensitization and
has milder side effects than traditional chemotherapyhas milder side effects than traditional chemotherapy
agentsagents

9. TK Intracellular
Domain
Transmembrane
Domain
Extracellular
Domain
EGFR (Epithelial GrowthFactorR eceptor)Structure

10. TK
EGFR FunctioninNormal Cell
TKATP ATP
Cell Proliferation Antiapoptosis
Angiogenesis
Gene Transcription
Cell Cycle Progression
+

11. TKTK
EGFR signal transduction in tumour cells
Survival
(anti-apoptosis)
PI3-K
STAT3
AKTPTEN
MEK
Gene transcription
MAPK
Proliferation/
maturation
Chemotherapy /
radiotherapy
resistance
Angiogenesis
Metastasis
pY
pY
RAS RAF
SOS
GRB2pY
G1
SM
G2

12. TK
Gene transcription
Cell Cycle Progression
Cell Proliferation Metastasis
Anti Apoptosis
Cancer
ATP
EG
FR
variant

13. Normal Cell
Cancerous Cell
Up Regulation
Mutation
Consequence of proliferation
of EGFR receptors

14. RationaleforEGFRInhibitorsinHead&Neckcancer:
EGFR expressed in > 90% of head & neck cancers.
EGFR over expression associated with decreased
survival
Increased EGFR expression is an early event in
carcinogenesis & even present in premalignant lesions
Inhibition of EGFR – TK slows the growth of
xenograft tumour models of head & neck

15. DrugsAvailable
 Gefitinib
 Erlotinib
Highly selective, potent & reversible
EGFR Tyrosine Kinase Inhibitor
 Cetuximab – Monoclonal Anti EGFR antibody
 H 447
 MDX 210
Bispecific Anti EGFR antibody
linked to Anti CD 64

16. SideEffects
 Skin rash
 Diarrhoea ( EGFR – TKI s )
 Fever ( EGFR – mAb )
 Interstitial lung disease – 1% (only for Gefitinib)
Discontinuationratesduetoadverseeffectsareverylowunlike
chemotherapy.

17. AdvantagesofEGFR I nhibitors
 Orally effective
 Better quality of life.
 Can be used as monotherapy.
 No need for premedication or dose monitoring.
 No hematological toxicity.
 Potential for long term treatment.
 Reduced resistance to radiation or hormone
therapy

18. CurrentStatus
Gefitinib
 FDA Approved on May ,2003 for Lung cancer-NSCFDA Approved on May ,2003 for Lung cancer-NSC
(Accelerated Approval Programme)(Accelerated Approval Programme)
Erlotinib
 FDA Approved on Nov, 2004 for Lung cancer –
Non Small Cell (AAP)
Cetuximab
 FDA Approved on Feb, 2004 for advancedFDA Approved on Feb, 2004 for advanced
colorectal cancercolorectal cancer

19. 3.Altered Fractionation Radiotherapy3.Altered Fractionation Radiotherapy
 Standard dose fractionation for treatment of radicalStandard dose fractionation for treatment of radical
H &N cancers generally comprises a seven-weekH &N cancers generally comprises a seven-week
course of daily 2Gy fractions five times a weekcourse of daily 2Gy fractions five times a week
(Mon-Fri)(Mon-Fri)
Aims AFR:Aims AFR:
1. Shortening the overall treatment time to reduce the1. Shortening the overall treatment time to reduce the
effect of tumour repopulation (accelerated RT)effect of tumour repopulation (accelerated RT)

20. 2. De2. Delivering two to three fractions a day with cumulativelivering two to three fractions a day with cumulative
similar or augmented total doses delivered over thesimilar or augmented total doses delivered over the
same overall time (hyperfractionated RT)same overall time (hyperfractionated RT)
 An IPD meta-analysis of fifteen trials, which includedAn IPD meta-analysis of fifteen trials, which included
6515 patients by the Meta-Analysis of Radiotherapy in6515 patients by the Meta-Analysis of Radiotherapy in
Carcinomas of the Head and Neck (MARCH)Carcinomas of the Head and Neck (MARCH)
Collaborative group, compared altered fractionation andCollaborative group, compared altered fractionation and
conventional (five daily fractions per week) radiotherapyconventional (five daily fractions per week) radiotherapy

21. This confirmed an absolute survival benefit of 3.4% atThis confirmed an absolute survival benefit of 3.4% at
five years and with most benefit seen in youngerfive years and with most benefit seen in younger
patients under 50year oldpatients under 50year old
TTreatment benefit decreases with increasing agereatment benefit decreases with increasing age
4.Targeted Molecular Therapy4.Targeted Molecular Therapy
 In this aIn this a molecular targeted agent with radiotherapymolecular targeted agent with radiotherapy
is combined as the sole treatment strategyis combined as the sole treatment strategy
 The addition of cetuximab, an EGFR antagonist, to RTThe addition of cetuximab, an EGFR antagonist, to RT
improved the three-year overall survival rateimproved the three-year overall survival rate

22. New Trials : Molecular TargetedNew Trials : Molecular Targeted
Therapy, EGF InhibitorsTherapy, EGF Inhibitors
Bonner, et al, NEJM, 2005Bonner, et al, NEJM, 2005
Radiation only Cetuximab+RT p-value
Patients randomized 213 211
Median survival
- Two-year survival
- Three-year survival
28 mo
55%
44%
54 mo
62%
57%
0.02 (log-rank test)
Grade 3/4 mucositis 52% 55% 0.50 (Fisher's exact)
Grade 3/4 infusion
reaction
- 3% 0.01 (Fisher's exact)
Grade 3/4 skin reaction 18% 34%
0.0003 (Fisher's
exact)

23. OutcomeswithTargetedTherapy
 Quality of life
 Response to treatment
 Safety
 Overall Survival

24. 5.IMRT And IGRT5.IMRT And IGRT
 Intensity modulated radiotherapy (IMRT) has theIntensity modulated radiotherapy (IMRT) has the
ability to‘dose sculpt’ and protect organs at riskability to‘dose sculpt’ and protect organs at risk
It allows intensification of radiotherapy treatmentIt allows intensification of radiotherapy treatment
regimes by selective dose accumulation through ‘doseregimes by selective dose accumulation through ‘dose
painting’ when compared to standard conformal fieldspainting’ when compared to standard conformal fields

25. Image guided radiation therapy (IGRT) accounts formage guided radiation therapy (IGRT) accounts for
changes in target shape, size, and position throughoutchanges in target shape, size, and position throughout
the course of treatmentthe course of treatment
This usually involves on-line image guidance andThis usually involves on-line image guidance and
additional re-optimisation of IMRT plansadditional re-optimisation of IMRT plans

26. 6.Photodynamic Therapy6.Photodynamic Therapy (PDT)(PDT)
 PDT can be defined as the use of light to inducePDT can be defined as the use of light to induce
reactions in the body which help treat diseases inreactions in the body which help treat diseases in
patientspatients
 PDT is the combination of light and light sensitivePDT is the combination of light and light sensitive
agents (such as porphyrins) in an oxygen-richagents (such as porphyrins) in an oxygen-rich
environmentenvironment

27. Porphyrins are a component of hemoglobin, which inPorphyrins are a component of hemoglobin, which in
turn is a component of red blood cellsturn is a component of red blood cells
Hemoglobin is what carries oxygen in the bloodHemoglobin is what carries oxygen in the blood
When porphyrins are not used as a component ofWhen porphyrins are not used as a component of
hemoglobin, they can absorb energy from photonshemoglobin, they can absorb energy from photons
(particles of light) and transfer this energy to(particles of light) and transfer this energy to
surrounding oxygen moleculessurrounding oxygen molecules

28. Toxic oxygen species such as singlet oxygen andToxic oxygen species such as singlet oxygen and
free radicals are thus formedfree radicals are thus formed
These chemicals are very reactive and can damageThese chemicals are very reactive and can damage
proteins, lipids, nucleic acids and other cellularproteins, lipids, nucleic acids and other cellular
componentscomponents
how PDT workshow PDT works
A chemical which is not harmful to the body in itsA chemical which is not harmful to the body in its
original state is administered to the patientoriginal state is administered to the patient

29. Light exposure (often from a laser) of the abnormalLight exposure (often from a laser) of the abnormal
tissue containing the chemical activates it, causing it totissue containing the chemical activates it, causing it to
change into a poison that destroys the irradiated tissuechange into a poison that destroys the irradiated tissue
 Most desirable chemicals are those that concentrateMost desirable chemicals are those that concentrate
in tumors (and certain other kinds of proliferatingin tumors (and certain other kinds of proliferating
tissue) rather than the surrounding healthy tissue,tissue) rather than the surrounding healthy tissue,
which remains unaffectedwhich remains unaffected
Everything happens fast (trillionths of a second)Everything happens fast (trillionths of a second)
Special laser equipment is required to “see”Special laser equipment is required to “see”
molecules react so fastmolecules react so fast

31. R eference

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