short and long term sequelae of radiation therapy to the ... · short and long term sequelae of...

Short and long term sequelae of radiation therapy to the oral cavity

Professor Alexander D Rapidis MD DDS PhD FACSProfessor Alexander D. Rapidis MD DDS PhD FACS

Chairman Dept. of Maxillofacial / Head and Neck Surgery

Greek Anticancer Institute Saint Savvas HospitalGreek Anticancer Institute, Saint Savvas Hospital

Athens Greece

Radiation TherapyRadiation TherapyGeneral Statements

Radiation alone or with other treatment d liti i d i i ifi t b fmodalities is used in a significant number of

patients with advanced stage oral cancer

A therapeutic dose of 5000-7000 cGy is externally delivered to the lesion

Increments of 200 cGy/day is delivered until the accumulated dose is achieved

Classification

Oral Complications f di thof radiotherapy

Acute Late

Mucositis Xerostomia

Skin Reactions Radiation caries

InfectionTrismus

Radiation induced

Infection

malignancies

Osteoradionecrosis

ChronicAcute

Acute

Mucositis

WHO Oral Mucositis ScaleWHO Oral Mucositis Scale

SevereOral Mucositis

Grade

43210Mucositis

to the extent Ulcers,

extensive Erythema,

ulcersSoreness

+/– erythemaNone

43210

that alimentation is not possible

erythema

Patients cannot swallow

Patients can swallow solid diet

No ulceration

cannot swallow solid diet

solid diet

Mucositis

Clinical Characteristics

Grade I White discoloration

Mucositis


Grade II Erythema

Mucositis


Grade III Pseudomembranous surface

Mucositis


Grade IV Ulcerations

Lessons Learned from Oral MucositisLessons Learned from Oral Mucositis

Mouth

» Extend to the entire GI tract Esophagus

Stomach

SmallIntestine

Colon

2004

Rectum

Anus

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Keefe D et al, Curr Opin Clin Nutr Metab Care. 2007

The Alimentary Canal

» The GI tract is all one tube from th t f d f

Mouth

mouth to anus—formed from primitive endoderm Esophagus

Pharyngeal gutPharyngeal gut

Stomach

SmallIntestine

Colon

Rectum

Anus

Midgut

2004

Hindgut

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The Alimentary Canal

» Toxicities resulting from h th di th RadiationRadiationchemotherapy or radiotherapy

don’t occur in isolation

RadiationRadiationTherapyTherapy

ChemotherapyChemotherapy» There are common mechanisms &

systemic effects

» The GI system can provide a whole new paradigm for

h & i iresearch & new intervention strategies

2004

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Mucositis

SymptomsSymptoms» Intense pain» Food and fluid intake decreases» Food and fluid intake decreases» Speech and swallowing difficult» May require ceasing therapyy q g py

Mucositis

Management» Mucosal coating agents» Mucosal coating agents

» Cleansing devices

» Chlorhexidine» Chlorhexidine

» Recombinant keratinocyte growth factor

» GMCSF (Combined Therapy)» GMCSF (Combined Therapy)

» Thalidomide?

Lo le el laser therap ?» Low-level laser therapy?

Radiation MucositisRadiation MucositisPain Management

Mild Pain

Non-opioids; +/- adjuvantsp ; j

Mild-Moderate Pain

Weak opioid; +/ non opioid / adjuvantsWeak opioid; +/- non-opioid / adjuvants

Moderate – Severe Pain

Strong opioid; +/- non-opioid / adjuvants

Rapid progress is being made in the understanding of this complex problemunderstanding of this complex problem» Mucositis is more than the mouth ulcer

Th h i i l b t i i l» The mechanism is complex but increasingly understood

» International collaboration is speeding things up

Acute

Ski tiSkin reactions

Late

X t iXerostomia

Xerostomia

Pathogenesis» Irreversible acinar cell damage

Clinical Characteristics» 50% decreased salivation after 1 week of radiation

» 75% decrease after 6 weeks5% dec ease a te 6 ee s

» 95% decrease years after

» Thick ropey saliva» Thick ropey saliva

» Candida albicans infection

» Dental caries» Dental caries

» Dysphagia / Odynophagia

Xerostomia

Symptoms» Difficulty in eating, speaking, & swallowing

» Taste disorders

» Denture-related pain / dysfunction

Pre-treatment StrategiesPre treatment StrategiesCurrent

IMRT / C f l b d iIMRT / Conformal beam design» Selective field designg

– Attempt oral mucosal sparing

Radioprotective agentsRadioprotective agents» Amifostine

» Antioxidants

Salivary stimulationSa a y st u at o» Pilocarpine; cevimeline; gustatory; other

agentsagents

Tumor

Dose

Tissue

Conventional Radiotherapy

Intensity Modulated Radiotherapy

XerostomiaXerostomiaDealing With It

Replacement

Lubricants

Gustatory stimulationGustatory stimulation

Drug intervention

Submandibular gland relocation

Daily living “tricks” or maneuversy g

Conclusion

IMRT for treatment of advanced oral cavity cancer should be considered during treatment planning

Potential benefits in terms of reduced xerostomia rates and osteoradionecrosis ratesrates and osteoradionecrosis rates

Late

Radiation caries

Radiation Caries

Pathogenesis» Shift to cariogenic microflora and xerostomic» Shift to cariogenic microflora and xerostomic

environment

Clinical CharacteristicsClinical Characteristics» Cervical, cusp, & incisal decay

Coronal fractures» Coronal fractures

Late

Trismus

TrismusTrismus

• more common with high posterior fields of radiationmore common with high posterior fields of radiation as muscles of mastication are in field (10%)•retention of coronoid process•made worse by concomitant chemotherapy

Trismus

Pathogenesis» Direct effects of radiation on muscles and/or

TMJ

Clinical Characteristics» Limited range of motion

ManagementManagement» Prevent with stretching exercises

» Prophylactic or therapeutic pentoxifylline» Prophylactic or therapeutic pentoxifylline,

α−tocopherol

Late

Radiation induced malignancies

Late complications following RT

No Event occurs above event threshold dose,

severity ↑ with dose

Event can occur at any dose level

P b bilit t it ↑ ith dProbability, not severity, ↑ with dose

increasing RT dose

Late complications following RT

Xerostomia

Soft tissue fibrosis

OsteoradionecrosisOsteoradionecrosis

Radiation associated tumors

increasing RT dose

InfectionsInfections

Erythematous candidiasis and angular cheilitis from mucositis

Infection Pseudomembranous candidiasis from ulcerative / pseudomembrane mucositis and / or HSV-1mucositis and / or HSV 1

1 of 3 to 1 of 2 H & N cancer patients receiving1 of 3 to 1 of 2 H & N cancer patients receiving RT or CRT will develop pseudomembranous candidiasiscandidiasisThe infection should respond to GI tract absorbed antifungal within 3 to 4 daysabsorbed antifungal within 3 to 4 days

Management of candidiasis

Identify and minimize / alleviate particular risk factorsfactorsSalivary gland function protectionMucosal protection from xerostomiaMucosal protection from xerostomiaAdministration of antifungals

Management of candidiasis

Topical antifungal agents» Polyene compounds» Polyene compounds

Systemic antifungal agents» Azole group compounds» Azole group compounds

Late

Osteoradionecrosis

Background

Devastating complication of radiation therapy that b diffi lt t t t th i i l tcan be more difficult to treat than original tumor

Clinical definition:Devitalized, irradiated bone that is exposed through overlying mucosa or skin persisting for > 6 months

•Osteoradionecrosis presents as a broad spectrum of disease severityy

•It is rare at radiation therapy doses of less 60 Gy

•It is more common when bracytherapy is used

•The mandible must be in the treatment volume area

•Dental extractions, surgery or trauma frequently proceed its onset

•Secondary infection may be present

Pathophysiology of osteoradionecrosis

Direct radiation effects on normal tissue may be lethal or sublethal

Lethal damage is caused by

lethal or sublethal

g yionization within the desoxyribonucleinic acid (DNA)

preventing cell replication and resulting in tissue death

Sublethal damage may cause cell mutation leading to further neoplasiafurther neoplasia

3 “H” Hypothesis & Osteoradionecrosis

Hypovascularity

HypoxiaHypoxia

HypocellularityTissue injury (usually)

Tissue breakdown / nonTissue breakdown / non--healing woundhealing wound

Tissue injury (usually)

gg

The incidence of osteoradionecrosis is reported to be between 5-25% of patients receiving radiotherapy in the head and neck area.

Mendenhall WM J Clin Oncol 2004

Reuther et al, Int J Oral Maxillofac Surg 2003

There are several classifications for mandibular osteoradionecrosis and they all stage the disease according to the severity of signs and

t i ith St G d Ssymptoms in either Stages, Grades or Scores

Jereczek-Fossa BA and Orecchia R, Cancer Treatment Reviews 2002

RTOG: Radiation Therapy Oncology Group

Extractions & OsteonecrosisExtractions & OsteonecrosisTraditional Concepts

Twice the risk of ORN is seen when selected t th t t d f ll i di ti thteeth are extracted following radiation therapy

Pre-radiation extractions associated with a 3.4% risk of ORN

Risk of ORN persists for years and reduced p yhealing capacity may be considered permanentp

The role of hyperbaric oxygen

The use of Hyperbaric Oxygen (HBO)

HBO treatment in ol es the deli er of 100% o gen at highHBO treatment involves the delivery of 100% oxygen at high pressure in special chambers. The pressure of the oxygen

inhaled by the patient is usually 2.4 times more than the atmospheric pressure and can be as high as 3 times more.

Advocates of HBO therapy support the view that HBO represents the only medical treatment for osteoradionecrosis. HBO can revert the d l d di ti h i ti b ti tdelayed radiation changes in tissues by generating steep oxygen gradients between the normal and the irradiated tissues causing

oxygen to diffuse into the affected areas.

HBO has been used as an adjunctive conservative measure

The use of Hyperbaric Oxygen (HBO)

HBO has been used as an adjunctive conservative measure along with antibiotics and irrigation since the 1960s.

Using Marx’s theory that osteoradionecrosis is a result ofUsing Marx s theory that osteoradionecrosis is a result of hypoxia, hypocellularity and hypovascularity, HBO seems likely

to increase oxygen supply in hypoxic tissues, stimulating fib bl t lif ti d i ifibroblast proliferation and angiogenesis.

The role of HBO in the treatment of

osteoradionecrosis.

The Marx protocol (1982)The Marx protocol (1982)

Gal TJ et al, Arch Otolaryngol Head Neck Surg 2003

Th f HBO i th t t t f t di i d it it id dThe use of HBO in the treatment of osteoradionecrosis despite its widespread use had been largely theoretical or anecdotal because of the paucity of

controlled trials and the lack of unified assessment of symptom improvement.

Epstein J et al, Oral Surg 1997

The role of HBO in the treatment of

osteoradionecrosisosteoradionecrosis.

The study by Annane et al (2004)Annane et al (2004)

The first randomized, placebo-controlledplacebo controlled, double-blind study

assessing the efficacy and safety of HBO forand safety of HBO for the treatment of overt

mandibular osteoradionecrosis

and included 68 patients.

Annane D et al, J Clin Oncol 2004

The trial was terminated prematurely because of the failure to demonstrate any beneficial effect of HBO over placebo (19% vs. 33% respectively). They also reported the progression of disease in recovery in the arm of

HBO patients and better recovery rates in the arm of the placebo treated patients.

Annane D et al, J Clin Oncol 2004a e e a , J C O co 00

The study by Annane resulted into strong criticism and disbelief by l th ti th t it i l t d thi l i i l bseveral authors quoting that it violated an ethical principle by

exposing the control group to the potentially serious risk of acute decompression illness; a risk not present in the treatment group.

Others stated that a major error in Annane’s study was the fact that the studied group of patients with an osteoradionecrosis was g p p

not well defined.

There were though supporters of the Annane study presentingThere were though supporters of the Annane study presenting evidence that the beneficial results of HBO treatment are

equivocal and the method is time consuming and expensive.

The debate is still going on.

Management of early and advanced osteoradionecrosis

Established ORN does not regress spontaneously It either stabilizes orEstablished ORN does not regress spontaneously. It either stabilizes or gradually worsens. One of the adverse factors implemented in the

development of ORN is the Radiation Induced Fibrosis (RIF) and necrosis. It has been shown that RIF greatly regressed after antioxidant treatment with as bee s o a g ea y eg essed a e a o da ea e

the combination of pentoxifylline, tocopherol and clodronate.

Delanian S et al Head Neck 2005

With this treatment applied to 18 patients with advanced ORN, pp p16 (89%) recovered after a median 6 months of treatment.

The results of this trial raise many questions primarily about the precise mechanisms of action of the drugs used, which will remain unanswered

until further randomized clinical trials will be conducted.

Delanian S et al Head Neck 2005

Selection of treatment in ORN

Stage I Superficial UlcerationSuperficial UlcerationExposed cortical bone Conservative management:

DebridementMeticulous oral hygieneMeticulous oral hygieneAntibiotics? HBO? HBO


Stage II Exposed medullary bone

Conservative management:+ soft tissue changes

HBO cannot revitalize dead bonebone

SequestrectomySequestrectomyin addition to other conservative measures


Stage III Sinus/Fistula

Surgical Intervention:Sinus/FistulaPathologic Fracture

Extensive soft tissue involvement

Extensive bony lossy

To include # and fistula

The only successful treatment of advanced y(Stage III) mandibular osteoradionecrosis is the surgical resection of diseased tissuesthe surgical resection of diseased tissues and their reconstruction with free tissue

transfertransfer.

The question whether HBO should be a precedent treatment or should be p

administered post-operatively or not at all is unansweredunanswered.

Reconstructive options in the treatment of severe (Stage III) mandibular osteoradionecrosis( g )

1. The radial forearm osteocutaneous flap

2. The fibula osteocutaneous flap

3. The use of additional flaps

Militsakh ON et al, Otolaryngol-Head and Neck Surg 2005

Shaha A et al, Head Neck 1997

Patients

47 patients between 1991 and 200647 patients between 1991 and 2006MSKCC=41; GACI=7

Age 34-81 (median 59) years

32 Males 15 Females32 Males 15 Females

Symptoms & SignsPain 75% Non-healing ulcer 66%gDraining Fistula/sinus 29%

Type of Reconstruction

OC-FRFFOther

19%Other6%

Fibula75%

n=16

Osteoradionecrosis of the mandible is a dreaded andOsteoradionecrosis of the mandible is a dreaded and devastating complication of radiation therapy for

malignant tumors of the head and neck area.malignant tumors of the head and neck area.

Various tumor, patient and treatment factors influence its development but the exact pathophysiology is still underdevelopment but the exact pathophysiology is still under

investigation.

It is especially important to prevent the development ofIt is especially important to prevent the development of osteoradionecrosis of the mandible by eliminating the so

far known risk factors.

When osteoradionecrosis reaches an advanced stage, the treatment of choice is resection of the necrosed

tissues and immediate reconstruction with free tissue transfer.

Other radiation sequelae

Carotid injury (stenosis)

Friedlander AH, Freymiller EG. J A, Dent Assoc 2003



» Mechanism: Generation of inflammatory cytokines / growth factors stimulate atherogenesis

» Increased stroke riskThe incidence of significant carotid stenosis following head and neck– The incidence of significant carotid stenosis following head and neck irradiation range from 30% to 50%. Patients with carotid stenosis are at increased risk for stroke.

» Factors such as hypertension, diabetes, smoking and obesity increase y g ythe risk.



Carotid stenosis is a major sequela of head and neck

irradiation that has not receivedirradiation that has not received the attention it deserves.

Evaluation:» Imaging» Imaging

– Ultrasonography, CT, MRA

Abayomi OK Oral Oncol 2004; 40:872-8.



Management:» Endarterectomy; stenting

» Anticoagulation

Abayomi OK Oral Oncol 2004; 40:872-8.

Summary

Radiotherapy is an important Rx modality in oral cancersM d RT l i d t t t t h i iModern RT planning and treatment techniques improve treatment outcomeAdvances in Rx may actually increase late complicationsAdvances in Rx may actually increase late complicationsSite specific approach allows organ-sparing with high conformality RT (e.g. parotid-sparing)y ( g g)Modest benefits associated with medical treatment of established complicationsA i R f i li i i i di dAggressive Rx of certain complications is indicatedImportance of prevention of late complications through identification correction and avoidance of risk factorsidentification, correction and avoidance of risk factors

Second World Congress of the gInternational Academy of Oral Oncology

(IAOO)( )

July 8 – 11, 2009

Sheraton Centre Toronto

Invitation to Toronto!

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