Late Radiation Tissue Injury Late Radiation Tissue Injury Late Effects on Normal Tissue “LENT” Continuing Medical Education Baptist Medical Center November

Late Radiation Tissue InjuryLate Radiation Tissue InjuryLate Effects on Normal Tissue “LENT”Late Effects on Normal Tissue “LENT”

Continuing Medical EducationContinuing Medical EducationBaptist Medical CenterBaptist Medical Center

November 18, 2009November 18, 2009

Financial Relationships

• “As it pertains to CME, I have no relevant financial relationships with any commercial interest to disclose.”

Late Radiation Tissue InjuryLate Radiation Tissue Injury……outlineoutline

• Injurious effects and incidence of therapeutic radiation on non-target tissues

• Basis for hyperbaric oxygen therapy and its historical perspective

• Evolution of HBO’s clinical evidence of efficacy

• ‘‘Acute’ effects are usually benign, and mostly Acute’ effects are usually benign, and mostly controlled by alteration in therapy schedulecontrolled by alteration in therapy schedule

• ‘‘Chronic’ effects appear dose-dependent; Chronic’ effects appear dose-dependent; resulting fibrosis leads to complex wounds, loss resulting fibrosis leads to complex wounds, loss of organ or structure, and possible deathof organ or structure, and possible death

Late Radiation Tissue InjuryLate Radiation Tissue Injury……overviewoverview

Acute vs. Chronic Injury

Hong JJ, et al. 2001

Late Radiation Tissue InjuryLate Radiation Tissue Injury……incidenceincidence

• Published incidence: 4% - 22%

• Up to 36% with combination XRT & chemo

• More severe forms are life-threatening

• Mortality reported as 2% - 8%

Despite advancement in techniques complications remain relatively common

Late Radiation Tissue InjuryLate Radiation Tissue Injury……evolution of soft tissue LENTevolution of soft tissue LENT

Unpredictable Natural History

• Some minor symptoms resolve spontaneously - others with only conservative care

• Remitting-relapsing symptoms characteristic of LENT

• Seemingly minor symptoms often prove refractory

Late Radiation Tissue InjuryLate Radiation Tissue Injury……evolution of soft tissue LENTevolution of soft tissue LENT

Unpredictable Natural History

• Disease progression may occur despite more aggressive care

• New forms of injury may evolve, requiring advanced care with some cases leading to loss of organ/structure

Total Radiation Dose No. Cases

< 5,000 cGy 5

5 - 6,000 cGy 24

6 -7,000 cGy 33

> 7,000 cGy 42~ 89.4% trauma-induced~ 10.6% spontaneous

Curi MM, et al. 1997 J. Oral Maxillo Surg

Late Radiation Tissue InjuryLate Radiation Tissue Injury……incidence of ORN per radiation doseincidence of ORN per radiation dose

~ retrospective review of 104 cases

Consequential LENTConsequential LENT: :

Injury as a consequence of acute damage to the Injury as a consequence of acute damage to the same organ or structure same organ or structure

Generic LENT:

Damage that appears independent of any earlier acute radiation-induced injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……etiologyetiology

LENT often refractory to a wide range of treatment optionsLENT often refractory to a wide range of treatment options

Late Radiation Tissue InjuryLate Radiation Tissue Injury……chronic effectschronic effects

Typically begins 3-6 months after radiation

• Epithelial apparatus destroyed

• Obliteration of the lumen size of arterioles

• Progressive fibrosis and decreased vascularity

• Decreased blood flow, low tissue pO2

• Fibrosis, necrosis, ulceration, fistula formation

• “Chronic radiation wound”

11

HORTIS VIII (PROFILAXIS)

Late Radiation Tissue InjuryLate Radiation Tissue Injury……bone injurybone injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……bone and soft injurybone and soft injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……bone and soft tissue injurybone and soft tissue injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……soft tissue injurysoft tissue injury



Late Radiation Tissue InjuryLate Radiation Tissue Injury……dental cariesdental caries

Late Radiation Tissue InjuryLate Radiation Tissue Injury……bladder injurybladder injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……uterine cervical injuryuterine cervical injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……rectal injuryrectal injury

Late Radiation Tissue InjuryLate Radiation Tissue Injury……hyperbaric oxygenhyperbaric oxygen

Evolution of Hyperbaric Oxygen (HBO) Therapy for LENT

• High failure rates with conventional treatments led to the use of HBO therapy

• First reported in bone and soft tissue in the early 1970’s

• Several small retrospective case series

• Prompted further study of LENT pathophysiology and HBO’s mechanistic basis

Late Radiation Tissue InjuryLate Radiation Tissue Injury……pathophysiology of LENTpathophysiology of LENT

• Controlled prospective clinical study

• Infection of bone ruled out

• Radiation induced avascular necrosis

• “Triple H” tissue– Hypovascular

– Hypocellular

– Hypoxic Marx RE, 1983 J Oral Max. Surg.

A shallow oxygen gradient has been created by the nature of XRT delivery.

Late Radiation Tissue InjuryLate Radiation Tissue Injury……pathophysiologypathophysiology

Radiation damaged tissue is a unique wound, not capable of revascularization or recovery.

= 10 - 20 mmHg

5 5 10 15 20 35 40 55


Shallow oxygen gradient at 1 ATA

Knighton DR, et al. Surgery; 1981

Hyperbaric OxygenHyperbaric Oxygen……mechanisms of actionmechanisms of action

Angiogenesis

• Large oxygen gradient required for initiation Large oxygen gradient required for initiation of angiogenesisof angiogenesis

• Hypoxic tissue gradient mandatory for wound healing

• When this gradient is destroyed capillary growth ceases

• Higher inspired oxygen concentrations increase rate and density of capillary growth

• Minimum level of oxygen required as a substrate Minimum level of oxygen required as a substrate for:for:

– Fibroblast proliferationFibroblast proliferation

– Collagen formationCollagen formation

– Collagen maturationCollagen maturation

• Stem Cell mobilization with resultant Stem Cell mobilization with resultant vasculogenesisvasculogenesis

HYPERBARIC MEDICINEHYPERBARIC MEDICINE……mechanistic basis and resulting indicationsmechanistic basis and resulting indications

Neovascularization

Mehm WJ, et al. J. Hyperbaric Med; 1988


Fibroblast Proliferation

• Oxygen–dependent effects are first evident during fibroplasia

• Good cell growth at 38 mmHg, essentially a normal state of tissue oxygenation

• Most rapid growth observed at 80 mmHg, double the normal tissue oxygen levels

• At higher levels (160-1722 mm) oxygen appears toxic to cells

Gibson JJ, et al. Surgical Forum; 1997


Angiogenesis

• Angiogenesis is proportional to ambient pO2

• Hypoxia within the wound stimulates VEGF release

• Endothelial 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 .89

Normobaric O2 vs. Hyperbaric O2 p < 0 .01

Normobaric Air vs. Hyperbaric O2 p < 0 .01 Marx RE, et al. Am J Surgery; 1990

Late Radiation Tissue InjuryLate Radiation Tissue Injury……neovascularizationneovascularization

1.0 ATA Air 1.0 ATA Oxygen 2.5 ATA Oxygen


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 Density

Marx RE, Hyper Med 1993


Dose-Dependent Angiogenesis

Hyperbaric OxygenHyperbaric Oxygen……Physiology of Gas ExchangePhysiology of Gas Exchange

Profound hyperoxia is achieved under hyperbaric conditions

• Hyperbaric oxygen exposure results in Hyperbaric oxygen exposure results in significant increases in:significant increases in:

– Arterial partial pressure of oxygen (PaOArterial partial pressure of oxygen (PaO22))

– Oxygen content of the arterial and venous Oxygen content of the arterial and venous blood (CaOblood (CaO22 and CvO and CvO22))

– Tissue oxygen delivery (DOTissue oxygen delivery (DO22))

HYPERBARIC MEDICINEHYPERBARIC MEDICINE……mechanistic basismechanistic basis

• Increased diffusion of oxygenIncreased diffusion of oxygen

• Greater tissue gradientsGreater tissue gradients

• Maintenance of oxygen delivery Maintenance of oxygen delivery despite low or abnormal hemoglobindespite low or abnormal hemoglobin

Hyperoxygenation

HyperoxygenationHyperoxygenationO

xyge

n P

arti

al P

ress

ure

(mm

Hg)

Time (hr)

500

Com

pres

sion

400

300

200

100

1 2 3 4 5

PO2 Subq tissue

Dec

omp

ress

ion

PO2 Muscle

The The Multiplace Multiplace ChamberChamber

The Multiplace ChamberThe Multiplace Chamber

HoodHoodMaskMask

Built in Breathing System (BIBS)Built in Breathing System (BIBS)

= 10 - 20 mmHg

5 5 10 15 20 35 40 55


Shallow oxygen gradient at 1 ATA

50 50 90 120 350

= 230 mmHg


Steep oxygen gradient at 2.4 ATA

= 10 mmHg

5 15 25 40 55 55


Rapid Rise Phase

30 40 55 55 55


Plateau Phase

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 40 1yr 2yr 3yr

%TcPO

2Tissue Vascular DensityTissue Vascular Density

% T

cPO

2

100

90

80

70

60

50

40

30

20

10

0

Normal (LSICS)

Irradiated Tissue

Lag Phase

Rapid Rise PhasePlateau Phase

Lin S, et al. Biochem Biophys Res Comm; 2002


Angiogenesis

• HBO observed to induce angiogenesis• VEGF critical to new vessel formation• VEGF activity only initiates formation of immature

vessels• VEGF must work in concert with angiopoietins for

maturation to functional vessels • In this model, HBO selectively enhanced Ang2 gene

expression through an eNOS pathway


Angiogenesis

• Hyperbaric oxygen therapy acts by means of a signal transduction pathway

• Stimulation of growth factors and/or their receptor sites through nitric oxide dependent processes


Epithelialization

• Changes in oxygen tension significantly influence revascularization and epithelialization in a variety of animals

• Rate of epithelialization is also correlated with oxygen’s availability

Pai MR Hunt TK, Surg. Gyne.Obstet: 1972

Silver IA, Epiderm.Wound Heal. 1972

30 treatments

Late Radiation Tissue InjuryLate Radiation Tissue Injury……ORN treatmentORN treatment

• Thirty initial treatments

• Decreased amount of exposed bone

• Softening of exposed bone

• Resorption or spontaneous sequestration

• 10 additional tx’s to achieve full mucosal cover, if necessary.

The Marx Protocol

Stage I responder: Small area of exposed bone

30 treatments


• Following initial 30 treatments, local surgical debridement

• 10 additional treatments if wound is progressing without complications

• If wound dehisces, leaving exposed bone, pt. is advanced to Stage III.

The Marx Protocol

Stage II responder: Stage I non-responder

30 treatments


• Thirty initial HBO treatments, local surgical debridement

• Transoral partial jaw resection, with fixation

• Primary closure of fistulae

• Ten post-operative HBO treatments

The Marx Protocol

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

30 treatments


• Following an 8-10 week period from resection:– Patient undergoes bony reconstruction

– Ten additional HBO treatments

– Jaw fixation maintained for 8 weeks

The Marx Protocol

Stage III R: Bony reconstruction

Non-HBO 116 44,000 152,000 10

HBO- no surg. 81 38,000 79,000 18

Marx Protocol 492 48,000 48,000 100

Marx Protocol 112 41,000 41,000 100

Late Radiation Tissue InjuryLate Radiation Tissue Injury……cost analysis – 2001 US Dollarscost analysis – 2001 US Dollars

Treatment No. Pts. Avg 1 yr. Total Resolution Cost Cost Rate (%)

"Osteoradionecrosis is best managed with HBO therapy oxygen alone, or in conjunction with surgery"

National Cancer Institute, 1990

Late Radiation Tissue InjuryLate Radiation Tissue Injury……osteoradionecrosisosteoradionecrosis

...in high-risk patients, pre-extraction hyperbaric oxygen therapy should be considered

Late Radiation Tissue InjuryLate Radiation Tissue Injury

……prophylactic protocolprophylactic protocol

• Basis for 20 pre-op. procedures– Angiogenesis plateau

• Basis for 10 post operative treatments– Reduced wound dehiscence by promoting collagen

production along incisional lines and fixture surfaces

– Assistance in graft survival and early revascularization by intermittent reversal of inherent hypoxia in surgical wounds

– Attenuation of ischemia/reperfusion injury


……HORTIS TrialHORTIS Trial

• Multicenter, international study

• Randomized, prospective, double blind, placebo controlled, cross-over trial.

• Eight arms:– Bladder

– Colon

– Laryngeal

– Mandible

– Rectum

– Skin/soft tissue

– Uterine/Vaginal/Pelvic

– Prophylaxis


……HORTIS treatment courseHORTIS treatment course

• Study entry:– Baseline SOMA-LENT; – Clinical Assessment; – Quality of Life Assessment (QoL)

• 30 treatments; repeat assessments

• 10 additional treatments; individual responses

• Un-blinding; crossover option for shams/controls

• Entry into long term follow-up


……HORTIS primary outcomesHORTIS primary outcomes

• Primary Outcome Measures– SOMA LENT score

– Clinical assessment

• Secondary Outcome Measure– Bowel-specific quality of life

58

59

60

61

62

63

64

Mean SOMA LENT ScoresMean SOMA LENT Scores

Initial

10

8

6

4

2

HBO Only

Sham / HBO

12

SO

MA

LE

NT

Sco

re

Rando

m

X-over

3 m

onth

6 m

onth

1 year

2 year

3 year

4 year

5 year

Late Radiation Tissue InjuryLate Radiation Tissue Injury……HORTIS TrialHORTIS TrialStudy Outcome

• Clinical Outcome:

– Group A (HBO): 16/29 (53.3%) healed/significantly improved

– Group B (Sham): 6/27 (22.2%) significantly improved

• SOMA LENT score change:

– Group A (HBO): Average improvement 4.60

– Group B (Sham): Average improvement 0.05

p = 0.0015 NNT = 3 Absolute Risk Reduction = 32%

68 pts. assessed at completion of active treatment phase

Initial

80

70

60

50

40

HBO Only

Sham / HBO

90

Rando

m

X-over

3 month

6 m

onth

1 year

2 year

3 year

4 year

5 year

Radiation ProctitisRadiation Proctitis……Mean Bowel Function Quality of LifeMean Bowel Function Quality of Life

Initial

80

70

60

50

40

HBO Only

Sham / HBO

90

Rando

m

X-over

3 month

6 m

onth

1 year

2 year

3 year

4 year

5 year

Radiation ProctitisRadiation Proctitis……Means of Mixed Model for Bowel BotherMeans of Mixed Model for Bowel Bother

Late Radiation Tissue InjuryLate Radiation Tissue Injury……HORTIS TrialHORTIS Trial

Hyperbaric Treatment Failure and Cancer

• Local recurrence vs. residual tumor as a healing risk factor – 45% of those who failed to respond per SOMA

LENT scale were diagnosed with cancer.

– 3 pts. suffered recurrence/residual tumor during treatment

– 11 pts. during follow-up: 10 at one year, 1 at year five years

Late Radiation Tissue InjuryLate Radiation Tissue Injury……HORTIS TrialHORTIS Trial

Hyperbaric Treatment Failure and Cancer

• SOMA LENT scores in those who initially failed to respond or improved followed by relapse increased by an average of 9 (4-17) at f/u when cancer was diagnosed

Late Radiation Tissue InjuryLate Radiation Tissue Injury……conclusionsconclusions

• Provision of HBO therapy resulted in a significantly improved healing response vs. controls

• Enduring response with continued improvement over extended follow-up period

• Bowl-specific quality of life was enhanced

• Excellent hyperbaric oxygen safety profile

Level 1 evidence of efficacy now exists for HBO treatment of soft tissue radiation injury

Documents

Late Radiation Tissue Injury Late Radiation Tissue Injury Late Effects on Normal Tissue “LENT” Continuing Medical Education Baptist Medical Center November