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ADVANCED NONSURGICAL THERAPY FOR HEAD AND NECK CANCERS
The document discusses advanced nonsurgical therapies for head and neck cancers, highlighting the limitations of traditional treatments like surgery and radiation therapy, particularly in advanced stages. It outlines various innovative non-surgical treatments including induction chemotherapy, concurrent chemoradiotherapy, altered fractionation radiotherapy, targeted molecular therapy, IMRT, IGR, and photodynamic therapy, emphasizing improvements in survival and quality of life. Significant advancements in targeted therapies, particularly those involving EGFR inhibitors, have also been noted for their enhanced efficacy and reduced side effects compared to conventional chemotherapy.
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ADVANCED NONSURGICAL THERAPY FOR HEAD AND NECK CANCERS
- 1. ADVANCED NONSURGICAL THERAPY FOR HEAD ANDNECK CANCERS Presenter-Dr.Ninan Moderator-Prof.Dr.A.Thangavelu HOD Dept Of OMFS
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- 3. H & Ncancer 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 Theuse 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 inductionchemotherapy 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 isaimed 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 producessignificant 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 (EpithelialGrowthFactorR eceptor)Structure
- 10. TK EGFR FunctioninNormal Cell TKATPATP Cell Proliferation Antiapoptosis Angiogenesis Gene Transcription Cell Cycle Progression +
- 11. TKTK EGFR signal transductionin 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 CycleProgression Cell Proliferation Metastasis Anti Apoptosis Cancer ATP EG FR variant
- 13. Normal Cell Cancerous Cell UpRegulation 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 Highlyselective, 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 Approvedon 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.AlteredFractionation 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. Deliveringtwo 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 anabsolute 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 oflife Response to treatment Safety Overall Survival
- 24. 5.IMRT And IGRT5.IMRTAnd 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 radiationtherapy (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 acomponent 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 speciessuch 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 (oftenfrom 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.
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