Principles of Principles of Radiation OncologyRadiation Oncology

Michael Underbrink, MDMichael Underbrink, MD

Anna Pou, MDAnna Pou, MD

IntroductionIntroduction

• Increasing use for head and neck Increasing use for head and neck cancercancer

• Combined or as single modalityCombined or as single modality• Outline basic principles, Outline basic principles,

radiobiologyradiobiology• General treatment approachGeneral treatment approach• Common complicationsCommon complications

Radiation PhysicsRadiation Physics

• Basis – ionizing particles interact with Basis – ionizing particles interact with cellular moleculescellular molecules

• Relies on transfer of energy created Relies on transfer of energy created by secondary charged particles by secondary charged particles (usually electrons)(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

External Beam External Beam IrradiationIrradiation

• 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, Particle Radiation (electrons, protons, neutrons)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 Head and Neck sites – 4-6 MeV x-ray or Co60 gamma ray radiationCo60 gamma ray radiation

External Beam External Beam IrradiationIrradiation

BrachytherapyBrachytherapy

• Radioactive source in direct contact Radioactive source in direct contact with tumorwith tumor– Interstitial implants, intracavitary Interstitial implants, intracavitary

implants or surface moldsimplants or surface molds

• Greater deliverable doseGreater deliverable dose• Continuous low dose rateContinuous low dose rate• Advantage for hypoxic or slow Advantage for hypoxic or slow

proliferatorsproliferators• Shorter treatment timesShorter treatment times

BrachytherapyBrachytherapy

• LimitationsLimitations– Tumor must be accessibleTumor must be accessible– Well-demarcatedWell-demarcated– Cannot be only modality for tumors Cannot be only modality for tumors

with high risk of regional lymph node with high risk of regional lymph node metastasismetastasis

BrachytherapyBrachytherapy

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 Cell death: no longer able to undergo

unlimited cell divisionunlimited cell division

• Direct vs. Indirect injury (free radicals – ODirect vs. Indirect injury (free radicals – O22))

• Inadequate cellular repair mechanisms Inadequate cellular repair mechanisms impliedimplied

RadiobiologyRadiobiology

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 = 1066 to 10 to 105 5 cell cell

reductionreduction– Larger tumors require more radiationLarger tumors require more radiation– 101055 cells = nonpalpable cells = nonpalpable– Applies to normal tissue alsoApplies to normal tissue also

• Therapeutic advantage – 4 R’s of Therapeutic advantage – 4 R’s of radiobiologyradiobiology

4 R’s of radiation biology4 R’s of radiation biology

• RRepair of cellular epair of cellular damagedamage

• RReoxygenation of eoxygenation of the tumorthe tumor

• RRedistribution edistribution within the cell within the cell cyclecycle

• RRepopulation of epopulation of cellscells

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 Killing requires greater total dose when given in several fractionsgiven in several fractions

• Most tissue repair in 3 hours, up to 24 Most tissue repair in 3 hours, up to 24 hourshours

• Allows repair of injured normal tissue, Allows repair of injured normal tissue, potential therapeutic advantage over tumor potential therapeutic advantage over tumor cellscells

• Radioresistance – melanoma?Radioresistance – melanoma?

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 Hypoxic cell radiosensitizers, selective

chemochemo

ReoxygenationReoxygenation

RedistributionRedistribution

• Cell cycle position sensitive cellsCell cycle position sensitive cells• S phase – radioresistantS phase – radioresistant• GG22 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 - G2 2 delaydelay• Fractionated XRT redistributes cellsFractionated XRT redistributes cells• Rapid cycling cells more sensitive (mucosa, Rapid cycling cells more sensitive (mucosa,

skin)skin)• Slow cyclers (connective tissue, brain) Slow cyclers (connective tissue, brain)

sparedspared

RedistributionRedistribution

RepopulationRepopulation

• Increased regeneration of surviving fractionIncreased regeneration of surviving fraction• Rapidly proliferating tumors regenerate Rapidly proliferating tumors regenerate

fasterfaster• Determines length and timing of therapy Determines length and timing of therapy

coursecourse• Regeneration (tumor) vs. Recuperation Regeneration (tumor) vs. Recuperation

(normal)(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)

RepopulationRepopulation

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 Normal tissue injury risk increases with XRT dose (size of tumor)with XRT dose (size of tumor)

Dose-Response RelationsDose-Response Relations

FractionationFractionation

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 Minimize tumor repopulation (increase

local control)local control)– Tolerable acute complications (increased)Tolerable acute complications (increased)

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 Similar total treatment time (increased

total dose)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

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 Treatment choice depends on functional

deficitsdeficits

• Late stage – usually combination of Late stage – usually combination of treatmentstreatments

Treatment PrinciplesTreatment Principles

• Surgical salvage of primary radiation Surgical salvage of primary radiation failures is better than radiation salvage failures is better than radiation salvage of surgical failureof surgical failure

• Explains rationale behind organ Explains rationale behind organ preservation strategiespreservation strategies

• XRT tumor cell killing is exponential XRT tumor cell killing is exponential functionfunction– Dose required for tumor control is Dose required for tumor control is

proportional to the logarithm of the number proportional to the logarithm of the number of viable cells in the tumorof viable cells in the tumor

Shrinking field techniqueShrinking field technique• Initial dose = 45 to 50 Gy (4.5 to 5.0 Initial dose = 45 to 50 Gy (4.5 to 5.0

weeks)weeks)– Given through large portalsGiven through large portals– Covers areas of possible regional metastasis Covers areas of possible regional metastasis

and primaryand primary• Second dose = 15 to 25 Gy (1.5 to 2.5 Second dose = 15 to 25 Gy (1.5 to 2.5

weeks)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

Shrinking field techniqueShrinking field technique

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, XRT – effective for microscopic disease,

better with exophytic tumors than ulcerative better with exophytic tumors than ulcerative ones (Surgical failures may leave subclinical ones (Surgical failures may leave subclinical disease)disease)

• Combining treatments counteracts limitationsCombining treatments counteracts limitations• Pre or Post-operative XRTPre or Post-operative XRT

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 Microscopic disease more radiosensitive

(blood supply)(blood supply)– Decreased risk of distant metastasis from Decreased risk of distant metastasis from

surgical manipulation?surgical manipulation?• DisadvantagesDisadvantages

– Decreased wound healingDecreased wound healing– Decreased safe dose (45 Gy in 4.5 weeks Decreased safe dose (45 Gy in 4.5 weeks

eradicates subclinical disease in 85% to 90% eradicates subclinical disease in 85% to 90% of patients)of patients)

Postoperative XRTPostoperative XRT• AdvantagesAdvantages

– Better surgical stagingBetter surgical staging– Greater dose can be given safely (60 to 65 Greater dose can be given safely (60 to 65

Gy in 6 to 7 weeks)Gy in 6 to 7 weeks)– Total dose can be based on residual tumor Total dose can be based on residual tumor

burdenburden– 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 Delay in postoperative treatment if healing

problems (poorer results if delayed more problems (poorer results if delayed more than 6 weeks)than 6 weeks)

ComplicationsComplications

• Acute Tissue ReactionsAcute Tissue Reactions• Late Tissue ReactionsLate Tissue Reactions

Acute ToxicityAcute Toxicity

• Time onset depends on cell cycling timeTime onset depends on cell cycling time• Mucosal reactions – 2Mucosal reactions – 2ndnd week of XRT week of XRT• Skin reactions – 5Skin reactions – 5thth week week• Generally subside several weeks after Generally subside several weeks after

completion of treatmentcompletion of treatment• RTOG – acute toxicity <90 days from RTOG – acute toxicity <90 days from

start of treatment (epithelial surfaces start of treatment (epithelial surfaces generally heal within 20 to 40 days from generally heal within 20 to 40 days from stoppage of treatment)stoppage of treatment)

Acute ToxicityAcute Toxicity

• Mucositis – intensity-limiting side Mucositis – intensity-limiting side effect for aggressive scheduleseffect for aggressive schedules

• Accelerated fractionation – increase Accelerated fractionation – increase acute toxicitiesacute toxicities

• Conventional fractionation Conventional fractionation conservatively emphasized maximum conservatively emphasized maximum tolerated dose is limited by late not tolerated dose is limited by late not acute tissue injuryacute tissue injury

Acute ToxicityAcute Toxicity

Late ToxicityLate Toxicity

• Injury tends to be permanentInjury tends to be permanent• Cells with low turnover (fibroblasts, Cells with low turnover (fibroblasts,

neurons)neurons)• Develop within months to yearsDevelop within months to years• Xerostomia, dental caries, fibrosis, Xerostomia, dental caries, fibrosis,

soft-tissue necrosis, nerve tissue soft-tissue necrosis, nerve tissue damagedamage

• Most common - xerostomiaMost common - xerostomia

Late ToxicityLate Toxicity

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 Results in dental caries (in or outside of

fields)fields)

• Soft tissue necrosisSoft tissue necrosis– Mucosal ulceration, damage to vascular Mucosal ulceration, damage to vascular

connective tissueconnective tissue– Can result in osteo-/chondroradionecrosisCan result in osteo-/chondroradionecrosis

Late ToxicityLate Toxicity

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, Ocular – cataracts, optic neuropathy, retinopathyretinopathy

• Otologic – serous otitis media Otologic – serous otitis media (nasopharynx, SNHL (ear treatments)(nasopharynx, SNHL (ear treatments)

Late ToxicityLate Toxicity

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 Electric shock from cervical spine flexion (Lhermitte sign)(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

ConclusionsConclusions

• XRT key role in treatment of H&N XRT key role in treatment of H&N cancercancer

• Fundamentals of radiation physics Fundamentals of radiation physics and radiobiology explain rationale and radiobiology explain rationale behind treatment schedules and behind treatment schedules and complicationscomplications

• Basic knowledge important with Basic knowledge important with regard to patient counselingregard to patient counseling