Late Radiation Tissue Injury Late Radiation Tissue Injury Late Effects on Normal Tissue “LENTâ€‌ Continuing Medical Education Baptist Medical Center November

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  • Late Radiation Tissue InjuryLate Effects on Normal Tissue LENTContinuing Medical EducationBaptist Medical CenterNovember 18, 2009

  • Financial RelationshipsAs it pertains to CME, I have no relevant financial relationships with any commercial interest to disclose.

  • Late Radiation Tissue InjuryoutlineInjurious effects and incidence of therapeutic radiation on non-target tissuesBasis for hyperbaric oxygen therapy and its historical perspectiveEvolution of HBOs clinical evidence of efficacy

  • Acute effects are usually benign, and mostly controlled by alteration in therapy scheduleChronic effects appear dose-dependent; resulting fibrosis leads to complex wounds, loss of organ or structure, and possible death Late Radiation Tissue InjuryoverviewAcute vs. Chronic Injury

  • Hong JJ, et al. 2001 Late Radiation Tissue InjuryincidencePublished incidence: 4% - 22%Up to 36% with combination XRT & chemo More severe forms are life-threateningMortality reported as 2% - 8%

    Despite advancement in techniques complications remain relatively common

  • Late Radiation Tissue Injuryevolution of soft tissue LENTUnpredictable Natural HistorySome minor symptoms resolve spontaneously - others with only conservative careRemitting-relapsing symptoms characteristic of LENTSeemingly minor symptoms often prove refractory

  • Late Radiation Tissue Injuryevolution of soft tissue LENTUnpredictable Natural HistoryDisease progression may occur despite more aggressive careNew forms of injury may evolve, requiring advanced care with some cases leading to loss of organ/structure

  • Total Radiation DoseNo. Cases < 5,000 cGy 55 - 6,000 cGy246 -7,000 cGy33 > 7,000 cGy42~ 89.4% trauma-induced~ 10.6% spontaneousCuri MM, et al. 1997 J. Oral Maxillo Surg Late Radiation Tissue Injuryincidence of ORN per radiation dose~ retrospective review of 104 cases

  • Consequential LENT: Injury as a consequence of acute damage to the same organ or structure Generic LENT: Damage that appears independent of any earlier acute radiation-induced injury Late Radiation Tissue InjuryetiologyLENT often refractory to a wide range of treatment options

  • Late Radiation Tissue Injurychronic effectsTypically begins 3-6 months after radiationEpithelial apparatus destroyedObliteration of the lumen size of arteriolesProgressive fibrosis and decreased vascularityDecreased blood flow, low tissue pO2Fibrosis, necrosis, ulceration, fistula formation Chronic radiation wound

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  • Late Radiation Tissue Injurybone injury


  • Late Radiation Tissue Injurybone and soft injury

  • Late Radiation Tissue Injurybone and soft tissue injury

  • Late Radiation Tissue Injurysoft tissue injury

  • Late Radiation Tissue Injurysoft tissue injury

  • Late Radiation Tissue Injurysoft tissue injury

  • Late Radiation Tissue Injurydental caries

  • Late Radiation Tissue Injurybladder injury

  • Late Radiation Tissue Injuryuterine cervical injury

  • Late Radiation Tissue Injuryrectal injury

  • Late Radiation Tissue Injuryhyperbaric oxygenEvolution of Hyperbaric Oxygen (HBO) Therapy for LENT

  • Late Radiation Tissue Injurypathophysiology of LENTControlled prospective clinical studyInfection of bone ruled outRadiation induced avascular necrosisTriple H tissueHypovascularHypocellularHypoxic

    Marx RE, 1983 J Oral Max. Surg.

  • A shallow oxygen gradient has been created by the nature of XRT delivery. Late Radiation Tissue InjurypathophysiologyRadiation damaged tissue is a unique wound, not capable of revascularization or recovery.

  • = 10 - 20 mmHg5 5 10 15 20 35 40 55 Late Radiation Tissue InjurypathophysiologyShallow oxygen gradient at 1 ATA

  • Knighton DR, et al. Surgery; 1981 Hyperbaric Oxygenmechanisms of actionAngiogenesisLarge oxygen gradient required for initiation of angiogenesisHypoxic tissue gradient mandatory for wound healingWhen this gradient is destroyed capillary growth ceasesHigher inspired oxygen concentrations increase rate and density of capillary growth

  • Minimum level of oxygen required as a substrate for:Fibroblast proliferationCollagen formationCollagen maturationStem Cell mobilization with resultant vasculogenesisHYPERBARIC MEDICINEmechanistic basis and resulting indicationsNeovascularization

  • Mehm WJ, et al. J. Hyperbaric Med; 1988 Hyperbaric Oxygenmechanisms of actionFibroblast ProliferationOxygendependent effects are first evident during fibroplasiaGood cell growth at 38 mmHg, essentially a normal state of tissue oxygenationMost rapid growth observed at 80 mmHg, double the normal tissue oxygen levelsAt higher levels (160-1722 mm) oxygen appears toxic to cells

  • Gibson JJ, et al. Surgical Forum; 1997 Hyperbaric Oxygenmechanisms of actionAngiogenesisAngiogenesis is proportional to ambient pO2Hypoxia within the wound stimulates VEGF releaseEndothelial cell response to VEGF requires normoxia and increases with hyperoxia

  • NormobaricAir(N=7)NormobaricOxygen(N=14)HyperbaricOxygen(N=14) Maximum VDE 18 19 99 Minimum VDE 6 6 78 Mean VDE 13 13 93 Normobaric Air vs. Normobaric O2 p < 0 .89Normobaric O2 vs. Hyperbaric O2 p < 0 .01Normobaric Air vs. Hyperbaric O2 p < 0 .01 Marx RE, et al. Am J Surgery; 1990 Late Radiation Tissue Injuryneovascularization

  • 1.0 ATA Air 1.0 ATA Oxygen 2.5 ATA Oxygen Late Radiation Tissue Injuryneovascularization

  • 1.00 0.09 1.50 0.12 1.75 0.25 2.00 0.43 2.50 0.74 3.00 0.91 Oxygen (ATA) Tissue DensityMarx RE, Hyper Med 1993 Late Radiation Tissue InjuryneovascularizationDose-Dependent Angiogenesis

  • Hyperbaric Oxygen Physiology of Gas ExchangeProfound hyperoxia is achieved under hyperbaric conditionsHyperbaric oxygen exposure results in significant increases in:Arterial partial pressure of oxygen (PaO2)Oxygen content of the arterial and venous blood (CaO2 and CvO2)Tissue oxygen delivery (DO2)

  • HYPERBARIC MEDICINEmechanistic basisIncreased diffusion of oxygenGreater tissue gradientsMaintenance of oxygen delivery despite low or abnormal hemoglobinHyperoxygenation

  • HyperoxygenationOxygen Partial Pressure (mmHg)Time (hr)500Compression40030020010012345PO2 Subq tissueDecompressionPO2 Muscle

  • The Multiplace Chamber

  • The Multiplace ChamberHoodMaskBuilt in Breathing System (BIBS)

  • = 10 - 20 mmHg5 5 10 15 20 35 40 55 Late Radiation Tissue InjurypathophysiologyShallow oxygen gradient at 1 ATA

  • 50 50 90 120 350= 230 mmHg Late Radiation Tissue InjurypathophysiologySteep oxygen gradient at 2.4 ATA

  • = 10 mmHg5 15 25 40 55 55 Late Radiation Tissue InjurypathophysiologyRapid Rise Phase

  • 30 40 55 55 55 Late Radiation Tissue InjurypathophysiologyPlateau Phase

  • 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 40 1yr 2yr 3yr %TcPO2Tissue Vascular Density% TcPO2 1009080706050403020100Normal (LSICS)Irradiated TissueLag PhaseRapid Rise PhasePlateau Phase

  • Lin S, et al. Biochem Biophys Res Comm; 2002 Hyperbaric Oxygenmechanisms of actionAngiogenesisHBO observed to induce angiogenesisVEGF critical to new vessel formationVEGF activity only initiates formation of immature vesselsVEGF must work in concert with angiopoietins for maturation to functional vessels In this model, HBO selectively enhanced Ang2 gene expression through an eNOS pathway

  • Hyperbaric Oxygenmechanisms of actionAngiogenesisHyperbaric oxygen therapy acts by means of a signal transduction pathwayStimulation of growth factors and/or their receptor sites through nitric oxide dependent processes

  • Hyperbaric Oxygenmechanisms of actionEpithelializationChanges in oxygen tension significantly influence revascularization and epithelialization in a variety of animalsRate of epithelialization is also correlated with oxygens availability

    Pai MR Hunt TK, Surg. Gyne.Obstet: 1972Silver IA, Epiderm.Wound Heal. 1972

  • 30 treatments Late Radiation Tissue InjuryORN treatmentThirty initial treatmentsDecreased amount of exposed boneSoftening of exposed boneResorption or spontaneous sequestration10 additional txs to achieve full mucosal cover, if necessary.

    The Marx ProtocolStage I responder: Small area of exposed bone

  • 30 treatments Late Radiation Tissue InjuryORN treatmentFollowing initial 30 treatments, local surgical debridement10 additional treatments if wound is progressing without complicationsIf wound dehisces, leaving exposed bone, pt. is advanced to Stage III.

    The Marx ProtocolStage II responder: Stage I non-responder

  • 30 treatments Late Radiation Tissue InjuryORN treatmentThirty initial HBO treatments, local surgical debridementTransoral partial jaw resection, with fixationPrimary closure of fistulaeTen post-operative HBO treatments

    The Marx ProtocolStage III responder: Stage II non-responder, or pts. with fistulae, pathological fracture or x-ray evidence of bone resorption

  • 30 treatments Late Radiation Tissue InjuryORN treatmentFollowing an 8-10 week period from resection:Patient undergoes bony reconstructionTen additional HBO treatmentsJaw fixation maintained for 8 weeks

    The Marx ProtocolStage III R: Bony reconstruction

  • Late Radiation Tissue Injurycost analysis 2001 US DollarsTreatment No. Pts. Av