Principles of radiation oncology

1. Principles of Radiation Principles of Radiation
OncologyOncology

2. IntroductionIntroduction
•Increasing use for head and neck cancerIncreasing use for head and neck cancer
•Combined or as single modalityCombined or as single modality
•Outline basic principles, radiobiologyOutline basic principles, radiobiology
•General treatment approachGeneral treatment approach
•Common complicationsCommon complications

3. Radiation PhysicsRadiation Physics
•Basis – ionizing particles interact with cellular Basis – ionizing particles interact with cellular
moleculesmolecules
•Relies on transfer of energy created by Relies on transfer of energy created by
secondary charged particles (usually electrons)secondary charged particles (usually electrons)
•Break chemical bondsBreak chemical bonds
•External beam vs. BrachytherapyExternal beam vs. Brachytherapy
•Radiant energy is discrete yet randomRadiant energy is discrete yet random

4. External Beam IrradiationExternal Beam Irradiation
•Dual-energy linear accelerators generate:Dual-energy linear accelerators generate:
–Low energy megavoltage x-rays (4-6 MeV)Low energy megavoltage x-rays (4-6 MeV)
–High energy x-rays (15-20 MeV)High energy x-rays (15-20 MeV)
–Photon energyPhoton energy
•Particle Radiation (electrons, protons, neutrons)Particle Radiation (electrons, protons, neutrons)
•Photon therapy advantagesPhoton therapy advantages
–Skin sparing, penetration, beam uniformitySkin sparing, penetration, beam uniformity
•Head and Neck sites – 4-6 MeV x-ray or Co60 Head and Neck sites – 4-6 MeV x-ray or Co60
gamma ray radiationgamma ray radiation

5. External Beam IrradiationExternal Beam Irradiation

6. BrachytherapyBrachytherapy
•Radioactive source in direct contact with tumorRadioactive source in direct contact with tumor
–Interstitial implants, intracavitary implants or surface Interstitial implants, intracavitary implants or surface
moldsmolds
•Greater deliverable doseGreater deliverable dose
•Continuous low dose rateContinuous low dose rate
•Advantage for hypoxic or slow proliferatorsAdvantage for hypoxic or slow proliferators
•Shorter treatment timesShorter treatment times

7. BrachytherapyBrachytherapy
•LimitationsLimitations
–Tumor must be accessibleTumor must be accessible
–Well-demarcatedWell-demarcated
–Cannot be only modality for tumors with high risk Cannot be only modality for tumors with high risk
of regional lymph node metastasisof regional lymph node metastasis

8. BrachytherapyBrachytherapy

9. RadiobiologyRadiobiology
•Ionizing radiation ejects an electron from a Ionizing radiation ejects an electron from a
target moleculetarget molecule
•Distributed randomly within cellDistributed randomly within cell
•Double-strand DNA breaks – lethalDouble-strand DNA breaks – lethal
•Cell death: no longer able to undergo unlimited Cell death: no longer able to undergo unlimited
cell divisioncell division
•Direct vs. Indirect injury (free radicals – ODirect vs. Indirect injury (free radicals – O
22))
•Inadequate cellular repair mechanisms impliedInadequate cellular repair mechanisms implied

10. RadiobiologyRadiobiology

11. RadiobiologyRadiobiology
•Random cell deathRandom cell death
–Deposition of energy & injury is random eventDeposition of energy & injury is random event
–Same proportion of cells is damaged per doseSame proportion of cells is damaged per dose
–100 to 10 cell reduction = 10100 to 10 cell reduction = 10
66
to 10 to 10
5 5
cell reductioncell reduction
– Larger tumors require more radiationLarger tumors require more radiation
–1010
55
cells = nonpalpable cells = nonpalpable
–Applies to normal tissue alsoApplies to normal tissue also
•Therapeutic advantage – 4 R’s of radiobiologyTherapeutic advantage – 4 R’s of radiobiology

12. 4 R’s of radiation biology4 R’s of radiation biology
•RRepair of cellular damageepair of cellular damage
•RReoxygenation of the eoxygenation of the
tumortumor
•RRedistribution within the edistribution within the
cell cyclecell cycle
•RRepopulation of cellsepopulation of cells

13. Repair of sublethal injuryRepair of sublethal injury
•Sublethal injury – cells exposed to sparse Sublethal injury – cells exposed to sparse
ionization fields, can be repairedionization fields, can be repaired
•Killing requires greater total dose when given in Killing requires greater total dose when given in
several fractionsseveral fractions
•Most tissue repair in 3 hours, up to 24 hoursMost tissue repair in 3 hours, up to 24 hours
•Allows repair of injured normal tissue, potential Allows repair of injured normal tissue, potential
therapeutic advantage over tumor cellstherapeutic advantage over tumor cells
•Radioresistance – melanoma?Radioresistance – melanoma?

14. ReoxygenationReoxygenation
•Oxygen stabilizes free radicalsOxygen stabilizes free radicals
•Hypoxic cells require more radiation to killHypoxic cells require more radiation to kill
•Hypoxic tumor areasHypoxic tumor areas
–Temporary vessel constriction from massTemporary vessel constriction from mass
–Outgrow blood supply, capillary collapseOutgrow blood supply, capillary collapse
•Tumor shrinkage decreases hypoxic areasTumor shrinkage decreases hypoxic areas
•Reinforces fractionated dosingReinforces fractionated dosing
•Hypoxic cell radiosensitizers, selective chemoHypoxic cell radiosensitizers, selective chemo

15. ReoxygenationReoxygenation

16. RedistributionRedistribution
•Cell cycle position sensitive cellsCell cycle position sensitive cells
•S phase – radioresistantS phase – radioresistant
•GG
22 phase delay = increased radioresistance phase delay = increased radioresistance
•RAD9 gene mutation – radiosensitive yeastRAD9 gene mutation – radiosensitive yeast
•H-ras and c-myc oncogenes - GH-ras and c-myc oncogenes - G
2 2 delaydelay
•Fractionated XRT redistributes cellsFractionated XRT redistributes cells
•Rapid cycling cells more sensitive (mucosa, skin)Rapid cycling cells more sensitive (mucosa, skin)
•Slow cyclers (connective tissue, brain) sparedSlow cyclers (connective tissue, brain) spared

17. RedistributionRedistribution

18. RepopulationRepopulation
•Increased regeneration of surviving fractionIncreased regeneration of surviving fraction
•Rapidly proliferating tumors regenerate fasterRapidly proliferating tumors regenerate faster
•Determines length and timing of therapy courseDetermines length and timing of therapy course
•Regeneration (tumor) vs. Recuperation (normal)Regeneration (tumor) vs. Recuperation (normal)
•Reason for accelerated treatment schedulesReason for accelerated treatment schedules
•Reason against:Reason against:
–Treatment delayTreatment delay
–Protracted XRT, split course XRT (designed delay)Protracted XRT, split course XRT (designed delay)

19. RepopulationRepopulation

20. Dose-Response RelationsDose-Response Relations
•Control probability variablesControl probability variables
–Tumor sizeTumor size
–XRT doseXRT dose
•Favorable response curvesFavorable response curves
–Small, well-vascularized tumorsSmall, well-vascularized tumors
–Homogeneous tumorsHomogeneous tumors
•Unfavorable response curvesUnfavorable response curves
–Large, bulky tumors (hypoxia)Large, bulky tumors (hypoxia)
–Heterogeneous, variable cell numbersHeterogeneous, variable cell numbers
•Normal tissue injury risk increases with XRT Normal tissue injury risk increases with XRT
dose (size of tumor)dose (size of tumor)

21. Dose-Response RelationsDose-Response Relations

22. FractionationFractionation

23. Fractionation SchedulesFractionation Schedules
•ConventionalConventional
–1.8 to 2.0 Gy given 5 times/week1.8 to 2.0 Gy given 5 times/week
–Total of 6 to 8 weeksTotal of 6 to 8 weeks
–Effort to minimize late complications Effort to minimize late complications
•Accelerated fractionationAccelerated fractionation
–1.8 to 2.0 Gy given bid/tid1.8 to 2.0 Gy given bid/tid
–Similar total dose (less treatment time)Similar total dose (less treatment time)
–Minimize tumor repopulation (increase local control)Minimize tumor repopulation (increase local control)
–Tolerable acute complications (increased)Tolerable acute complications (increased)

24. Fractionation SchedulesFractionation Schedules
•HyperfractionationHyperfractionation
–1.0 to 1.2 Gy bid/tid, 5 times/week1.0 to 1.2 Gy bid/tid, 5 times/week
–Similar total treatment time (increased total dose)Similar total treatment time (increased total dose)
–Increases total dose Increases total dose
–Potentially increases local controlPotentially increases local control
–Same rates of late complicationsSame rates of late complications
–Increased acute reactionsIncreased acute reactions

25. Treatment PrinciplesTreatment Principles
•Size and location of primarySize and location of primary
•Presence/absence and extent/incidence of Presence/absence and extent/incidence of
regional or distant metastasisregional or distant metastasis
•General condition of patientGeneral condition of patient
•Early stage cancersEarly stage cancers
–Surgery alone = XRT aloneSurgery alone = XRT alone
–Treatment choice depends on functional deficitsTreatment choice depends on functional deficits
•Late stage – usually combination of treatmentsLate stage – usually combination of treatments

26. Treatment PrinciplesTreatment Principles
•Surgical salvage of primary radiation failures is Surgical salvage of primary radiation failures is
better than radiation salvage of surgical failurebetter than radiation salvage of surgical failure
•Explains rationale behind organ preservation Explains rationale behind organ preservation
strategiesstrategies
•XRT tumor cell killing is exponential functionXRT tumor cell killing is exponential function
–Dose required for tumor control is proportional to Dose required for tumor control is proportional to
the logarithm of the number of viable cells in the the logarithm of the number of viable cells in the
tumortumor

27. Shrinking field techniqueShrinking field technique
•Initial dose = 45 to 50 Gy (4.5 to 5.0 weeks)Initial dose = 45 to 50 Gy (4.5 to 5.0 weeks)
–Given through large portalsGiven through large portals
–Covers areas of possible regional metastasis and Covers areas of possible regional metastasis and
primaryprimary
•Second dose = 15 to 25 Gy (1.5 to 2.5 weeks)Second dose = 15 to 25 Gy (1.5 to 2.5 weeks)
–Boost field (gross tumor and small margin)Boost field (gross tumor and small margin)
–Total dose of 60 to 75 Gy in 6 to 7.5 weeksTotal dose of 60 to 75 Gy in 6 to 7.5 weeks
•Boost dose = 10 to 15 Gy Boost dose = 10 to 15 Gy
–Massive tumorsMassive tumors
–Second field reduction at 60 to 65 GySecond field reduction at 60 to 65 Gy
–Total of 7 to 8 weeksTotal of 7 to 8 weeks

28. Shrinking field techniqueShrinking field technique

29. Combined ModalitiesCombined Modalities
•Surgery and XRT complement each otherSurgery and XRT complement each other
•Surgery – removes gross tumor (bulky tumors Surgery – removes gross tumor (bulky tumors
are more difficult to control with XRT)are more difficult to control with XRT)
•XRT – effective for microscopic disease, better XRT – effective for microscopic disease, better
with exophytic tumors than ulcerative ones with exophytic tumors than ulcerative ones
(Surgical failures may leave subclinical disease)(Surgical failures may leave subclinical disease)
•Combining treatments counteracts limitationsCombining treatments counteracts limitations
•Pre or Post-operative XRTPre or Post-operative XRT

30. Preoperative XRTPreoperative XRT
•AdvantagesAdvantages
–Unresectable lesions may become resectableUnresectable lesions may become resectable
–Extent of surgical resection diminishedExtent of surgical resection diminished
–Smaller treatment portalsSmaller treatment portals
–Microscopic disease more radiosensitive (blood supply)Microscopic disease more radiosensitive (blood supply)
–Decreased risk of distant metastasis from surgical Decreased risk of distant metastasis from surgical
manipulation?manipulation?
•DisadvantagesDisadvantages
–Decreased wound healingDecreased wound healing
–Decreased safe dose (45 Gy in 4.5 weeks eradicates Decreased safe dose (45 Gy in 4.5 weeks eradicates
subclinical disease in 85% to 90% of patients)subclinical disease in 85% to 90% of patients)

31. Postoperative XRTPostoperative XRT
•AdvantagesAdvantages
–Better surgical stagingBetter surgical staging
–Greater dose can be given safely (60 to 65 Gy in 6 to Greater dose can be given safely (60 to 65 Gy in 6 to
7 weeks)7 weeks)
–Total dose can be based on residual tumor burdenTotal dose can be based on residual tumor burden
–Surgical resection is easierSurgical resection is easier
–Tissue heals betterTissue heals better
•DisadvantagesDisadvantages
–Distant metastasis by manipulation?Distant metastasis by manipulation?
–Delay in postoperative treatment if healing problems Delay in postoperative treatment if healing problems
(poorer results if delayed more than 6 weeks)(poorer results if delayed more than 6 weeks)

32. ComplicationsComplications
•Acute Tissue ReactionsAcute Tissue Reactions
•Late Tissue ReactionsLate Tissue Reactions

33. Acute ToxicityAcute Toxicity
•Time onset depends on cell cycling timeTime onset depends on cell cycling time
•Mucosal reactions – 2Mucosal reactions – 2
ndnd
week of XRT week of XRT
•Skin reactions – 5Skin reactions – 5
thth
week week
•Generally subside several weeks after completion Generally subside several weeks after completion
of treatmentof treatment
•RTOG – acute toxicity <90 days from start of RTOG – acute toxicity <90 days from start of
treatment (epithelial surfaces generally heal within treatment (epithelial surfaces generally heal within
20 to 40 days from stoppage of treatment)20 to 40 days from stoppage of treatment)

34. Acute ToxicityAcute Toxicity
•Mucositis – intensity-limiting side effect for Mucositis – intensity-limiting side effect for
aggressive schedulesaggressive schedules
•Accelerated fractionation – increase acute Accelerated fractionation – increase acute
toxicitiestoxicities
•Conventional fractionation conservatively Conventional fractionation conservatively
emphasized maximum tolerated dose is limited by emphasized maximum tolerated dose is limited by
late not acute tissue injurylate not acute tissue injury

35. Acute ToxicityAcute Toxicity

36. Late ToxicityLate Toxicity
•Injury tends to be permanentInjury tends to be permanent
•Cells with low turnover (fibroblasts, neurons)Cells with low turnover (fibroblasts, neurons)
•Develop within months to yearsDevelop within months to years
•Xerostomia, dental caries, fibrosis, soft-tissue Xerostomia, dental caries, fibrosis, soft-tissue
necrosis, nerve tissue damagenecrosis, nerve tissue damage
•Most common - xerostomiaMost common - xerostomia

37. Late ToxicityLate Toxicity

38. Late ToxicityLate Toxicity
•XerostomiaXerostomia
–Injury to serous acinar cellsInjury to serous acinar cells
–May have partial recoveryMay have partial recovery
–Results in dental caries (in or outside of fields)Results in dental caries (in or outside of fields)
•Soft tissue necrosisSoft tissue necrosis
–Mucosal ulceration, damage to vascular connective Mucosal ulceration, damage to vascular connective
tissuetissue
–Can result in osteo-/chondroradionecrosisCan result in osteo-/chondroradionecrosis

39. Late ToxicityLate Toxicity

40. Late ToxicityLate Toxicity
•FibrosisFibrosis
–Serious problem, total dose limiting factorSerious problem, total dose limiting factor
–Woody skin texture – most severeWoody skin texture – most severe
–Large daily fractions increase riskLarge daily fractions increase risk
•Ocular – cataracts, optic neuropathy, retinopathyOcular – cataracts, optic neuropathy, retinopathy
•Otologic – serous otitis media (nasopharynx, Otologic – serous otitis media (nasopharynx,
SNHL (ear treatments)SNHL (ear treatments)

41. Late ToxicityLate Toxicity

42. Late ToxicityLate Toxicity
•Central Nervous SystemCentral Nervous System
–Devastating to patientsDevastating to patients
–Myelopathy (30 Gy in 25 fractions)Myelopathy (30 Gy in 25 fractions)
•Electric shock from cervical spine flexion (Lhermitte sign)Electric shock from cervical spine flexion (Lhermitte sign)
–Transverse myelitis (50 to 60 Gy)Transverse myelitis (50 to 60 Gy)
–Somnolence syndrome (months after therapy)Somnolence syndrome (months after therapy)
•Lethargy, nausea, headache, CN palsies, ataxiaLethargy, nausea, headache, CN palsies, ataxia
•Self-limiting, transientSelf-limiting, transient
–Brain necrosis (65 to 70 Gy) – permanent Brain necrosis (65 to 70 Gy) – permanent

43. ConclusionsConclusions
•XRT key role in treatment of H&N cancerXRT key role in treatment of H&N cancer
•Fundamentals of radiation physics and Fundamentals of radiation physics and
radiobiology explain rationale behind treatment radiobiology explain rationale behind treatment
schedules and complicationsschedules and complications
•Basic knowledge important with regard to Basic knowledge important with regard to
patient counselingpatient counseling