Radiotherapy in Head & Neck Malignancies

RADIOTHERAPY

• Introduction

• History

• Role as treatment modality

• Principal advantage

Mechanism of Action

• Direct damage• Indirect damage

3 pathways triggered by DNA Damage

Cell cycle arrest DNA repair Apoptosis

Sub lethal Damage Potentially Lethal damage

lethal damage

Characteristics of RT • Cells killed in mitosis

• Malignant cells divide more frequently

• Malignant cells repair less efficiently

Malignant cells have lower repair capacity & shorter cell cycle than normal ones

So the chances of a dose of radiation killing a malignant cells are greater than those of killing a normal cell

“ Quantitative Difference in Response to radiation”

RADIOBIOLOGY• Inherent Radiosensitivity State of maturity of cell Its functional Role

• Cell cycle; M, G1, S, G2 ; more sensitive in M & Late G2

• If large dose is given, tumour cells in S phase are resistant & a second dose would not be effective

• However if time is allowed, these cells re-assort themselves in to more sensitive phases of the cell cycle & a second dose would be effective

Fractionation of Radiotherapy

• “ Fraction” and its significance• Radical therapy Conventional – 60 Gy in 30 fractions of 2 Gy each over 42

days

Experimental

- Hypofractionation – Smaller no. of fractions each > 2 Gy - Hyperfractionation – Large no. of fractions each < 2 Gy - Accelerated fractionation – Shortened overall time - Split course – gap to allow acute reaction to settle(2 wk)

Fractionation of Radiotherapy

• Theory of Hyper fractionation.• Inter fraction Interval

Minimum safe inter fraction interval is 6 hrs

• CHART – 12 days. 3 fractions/day. 7 days a week

• Prolongation of course of therapy decreases likelihood of cure. 0.5% FOR EVERY SINGLE DAY.

Role of Fractionation

• “ Shoulder” on the graph

• Late reacting tissues have a more curvy graph than the acute reacting ones

Role of Hypoxia & RT

• Oxygen stabilizes free radicals• Hypoxic cells require more radiation to kill• Hypoxic tumor areas– Temporary vessel constriction from mass– Outgrow blood supply, capillary collapse

• Tumor shrinkage decreases hypoxic areas• Reinforces fractionated dosing• Hypoxic cell radiosensitizers, selective chemo

Role of Radiosensitizers

• Hypoxic cells : Radioresistant

• Use of HYPERBARIC OXYGEN• Other Modalities : Recombinant Erythropoeitin• Nicotinamide• Halogenated Pyrimidines• Nitroimidazoles• Depletion of natural radioprotector : ‘ Glutathione’

Role of Bioreductive Drugs

• Not true Radiosensitizers but they are reduced intracellularly to form Cytotoxic agents

• Used as adjuncts in RT• eg. Tirapazamine (SR 4233)

Mitomycin C

Aliphatic amine N oxides (AQ4N)

Role of Hyperthermia

• Tumors are more radiosensitive if ambient temp is raised. Anoxic cells are sensitive to radiation when heated

• Combining modalities with RT to increase tumor cell kill.

Rationale for Combining Modalities

• Enhanced tumor efficacy• Non over- lapping toxicities• Spatial co- operation

• Reasons for failure contributing to RT

• Response to RT : 5 R’S

5 R’s of radiation biology

• Repair of cellular damage• Reoxygenation of the tumor• Redistribution within the

cell cycle• Repopulation of cells• Radiosensitivity Inherent

CURE & COMPLICATIONS

• High radiation dose to the target organ + minimal dose to the surrounding normal tissue

But it is complicated by following

• SCC is less radiosensitive ; requires high dose

• Juxtaposition of critically radiosensitive organs

» therapeutic ratio is Low

• Aim of modification of technique.

CURE & COMPLICATIONS

• Central part of both curves-steep

Small ↑ in dose » ↑ cure/complications

Small ↓ in dose » ↓ cure

COMBINED MODALITY OF TREATMENT

RT alone as principle treatment

RT as definitive treatment and as adjunct to surgery

RT planned in conjunction with surgery (Pre/ Post op)

Salvage RT for recurrence after surgery

Pathology guided post op RT

COMBINED MODALITY TREATMENT

• Alone or with surgery/chemotherapy or both• Pre-op RT• Post-op RT

Pre-op : Advantages Pre-op : Disadvantage

• Shrinks the tumour distorts anatomy,

vitality » delays healing• ↓ tumour dissemination

POST-OP RT

Advantage

• Proper pathological staging is possible

» better guide to the extent of radiation required

• Only microscopic, well vascularised tumour will be left behind- relatively easy to cure with RT

Disadvantage

• ↓ blood supply » hypoxic cells will not respond to RT

ADJUVANT RADIOTHERAPY

• Elective post operative irradiation following complete surgical excision + prophylactic irradiation of a clinically negative node

• Irradiation of known residual disease following incomplete surgery is not considered to be adjuvant

• Entails giving a high-dose fractionated course, similar to that in radical treatment

COMBINATION CT & RT

• CT may be administered as follows :-

Neo adjuvant

Concurrent

Adjuvant• Aim

Downsize tumor

Reduce incidence of distant metastasis

RADIOTHERAPY & CHEMOTHERAPY

• Before RT : (induction chemotherapy)

Reduces the bulk, while its vascularity is maintained or has been enhanced ( ↓ in the size of the tumour)

• Along with RT :

CT acts as a radio sensitizers; improve the effect of RT

Methotrexate & bleomycin are radio sensitizers

• After RT :

Less likely to penetrate the tissue (poor blood supply)

COMBINATION CT AND RT

• Cisplatin + 5 FU

• Incidence of Locoregional recurrence was

• Survival advantage : Concurrent combination - 8%

• Absolute Benefit for CT overall is 4.4% at 5 yrs.

Types of Radiation Treatment

• External Beam Radiotherapy / Teletherapy

• Brachytherapy : Interstitial / Intracavitatory

• Unsealed Radionucleide therapy

TYPES OF RADIATION TREATMENT

• External beam RT (Teletherapy)A beam of radiation either photons/ particles is directed to the target area through the skin

Photons (High energy electromagnetic radiation)X Rays

- Superficial (100 KV)- Orthovoltage (300 KV)

- Megavoltage/supervoltage (4-20 MV)Gamma Rays – 2 MV

Particles (Ionizing radiation) – Electrons, Neutrons, Protons

ORTHOVOLTAGE RT

• Most Basic form of RT • Obsolete• Disadvantages

Poor penetrationSkin tolerance – Limiting factorUnable to treat lesion at sig. depthIncreased incidence of Osteoradionecrosis

• Radiobiological Efficiency was Higher1 Gy 1.15 Gy

Same biological effect

MEGAVOLTAGE RT• Linear accelerators produce X Rays from a point source

and have a sharp fall off at the edges of the field

• Advantages of Megavoltage: -

- Greater penetration- Skin sparing- Homogenous dose distribution- Diminished bone absorption- Better precision

• Forward scatter of energy : The higher the energy of the accelerator, the more the skin sparing

• Max dose at a depth of 1cm & a gradual fall of dose.

Megavoltage GAMMA Rays

• Radioactive isotopes• Origin : Beam from RADIUM BOMB• Artificially Radioactive isotopes: Cs; Co• Cobalt UnitAdvtgs DisadvtgsCheaper PenumbraLess Maintainance

• Preferred for Economic and Logistic reasons

Electron Beam

• Photon beam is absorbed exponentially but electron energy is absorbed at a finite depth dependant on energy of the electron

• Give relatively uniform dose up to a certain depth of penetration & then the dose falls off very rapidly

• Can be used to boost the dose to a nodal mass overlying the spinal cord following initial photon treatment to a cord tolerance dose

• Absorption is not dependant on density of the tissue

• Advantages

• Specific Indications

PARTICLE BEAM IRRADIATIONPARTICLE BEAM IRRADIATION

Neutron Beam

• Beam of heavy uncharged particles produced by high energy machine

• High energy transfer with Low Oxygen enhancement ratio (X rays – 3; Neutron beam – 1.5)

• Although the initial clinical response was good, there was enhanced late damaging effect on normal tissues

• Clinical trials have failed to demonstrate the benefits

Proton Beam• Very limited application and not widely available

• Bragg Peak : Area of deposition of max. energy at a depth in tissues

• Small defined area of very much heightened effect which can be arranged to coincide with the tumour, thereby leaving a very much lower dose at the entry & exit point of the beam

• Low oxygen enhancement ratio

• Radioresistant lesions : Chondrosarcoma of skull base

Chordomas of clivus

Ocular melanoma

BRACHYTHERAPY

• Short distance RT• Sealed sources of radioactive isotopes in close contact with the

tumour

Advantages:- Enables high radiation dose to be given to a very limited volume with rapid fall off of isodoses at a distance- Addl radiation does not have same depth/dose distribution as ext beam therapy and does not add to skin toxicity

Disadvantage - Depth of penetration is poor. Only small vol. is raised to target dose.- Used when tumor size is as small as possible after completion of Ext beam RT

BRACHYTHERAPY

• Intracavitary RT

• Interstitial RT Radioactive isotope Implants Removable/ permanent Radium/ Caesium/ Irridium Radon / Gold Implant : Directly inserted

After loading technique

Unsealed Radionucleide sources

Radioactive isotopes used in the form of drugs Radioactive isotopes used in the form of drugs (iv / im)(iv / im)

eg. Radioactive iodine in Follicular Ca Thyroideg. Radioactive iodine in Follicular Ca Thyroid

Various Radiation Methods

• (3D)-Conformal Radio Therapy(3DRT / 3DCRT)• Intensity Modulation Radio Therapy (IMRT)• Stereotactic Radiotherapy

Conventional• 2D Beam orientation • Single beam intensity

(3D) Conformal• Multi beam conforming• Rectangular Window collimation &

Multi Leaf Collimation (MLC)C) • Single Intensity per beam

Intensity-Modulated Radiotherapy (IMRT)

• High precision RT

• Instead of beams of uniform intensity, each beam is modified in a sophisticated manner

• Higher and more effective radiation can be given to the tumor with minimal side effects

• Apart from 3D CT, PET & MRI might be required for planning IMRT

• 15-30 min session 5 times/wk for 6 – 10 wks

IMRT

• A specialized 3D conformal radiation treatment plan where thousands of tiny beams from several beam angles are used to target a tumor.

IMRT

• The radiation intensity of these beams is modulated, or controlled, with a system of movable leaves called a multi-leaf collimator (MLC).

• The leaves conform to the shape of the tumor and block out unwanted radiation.

• With sophisticated dose calculation methods each leaf

can move independently to create tiny beamlets of radiation that specifically target a tumor.

IMRT

• Less radiation to normal tissues translates into fewer complications for patients.

• IMRT is ideal for tumors situated near critical structures such as the spinal cord, heart and eyes

IMRT

• Means of delivery of IMRT is as follows

Dynamic IMRT

Stepwise System IMRT

Step and shoot IMRT

• Extensive pgme of IMRT was designed for Nasopharyngeal CA

Stereotactic RT

• A technique that delivers high radiation doses to tumour target in a hypo-fractionated schedule.

• Use multiple narrow radiation beams.

• Target small, well-defined areas with precision.

• Use immobilization devices or techniques that monitor any movement during treatment.

• Give high doses of radiation safely and accurately over a few treatments (usually one to five total treatments).

Stereotactic Radiosurgery

• Method to non-invasively & specifically treat benign/malignant tumors and tissue abnormalities– Uses methods of stereotactic 3-D localization of

surgical site– Uses radiosurgical techniques to perform the

“surgery”

3-D Stereotactic Localization

• Goal: To target the tissue of interest with as much accuracy as possible

• Use imaging and 3-D mapping techniques to target tissue of interest– 4 general medical imaging modalities used:• X-Ray• PET • CT/MRI• Digital Subtracted Angiography

• Use the patient as a reference for the localization– 2 general methods:• Frame stereotactic localization (old school)• Frameless stereotactic localization (new school)

Frame Techniques

With tomographic imaging modalities (CT and MRI), use the N-frame as a basis for 3-D visualization:

CT

N-Frame

MRI

Gibson D, et al. Stereotactic Localization in Medical Imaging: A Technical and Methodological Review. Journal of Radiosurgery, Vol 2, No. 3, 1999

Frameless Stereotaxy

Implanted Gold Markers

Amorphous silicon detectors (CyberKnife)

Display of treatment planning:

http://virtualtrials.com/jhrs.cfm

Radiosurgery

• Focused radiation beams delivered to a specific tissue volume

• Multiple beams or multiple passes (fractionated treatment) that intersect– Keeps radiation exposure to surrounding tissue at benign

levels– Treats targeted tissue (the point of intersection) with a

higher dose of radiation

http://neurosurgery.medsch.ucla.edu/programs/radiosurgery/radiosurgery_intro.html

Different Machines in Use

• Gamma Knife– Gamma radiation from Cobalt-60 Source– Use multiple beams to treat tissue volume

• LINAC-based systems (X-Knife)– High-energy X-ray from Linear Accelerator device– Use fractionation

• CyberKnife– Also a LINAC system, but LINAC is on a robotic arm– Use fractionation– Can be used for parts of body other than the head

Gamma Knife

-Targeting Precision of within 2mm

-Multiple targets can be easily treated in one session

http://www.elekta.com/ContentUS.nsf

LINAC-Based Systems

-Less accurate

-In use in more hospitals

-Less efficient (longer treatment times)

http://www.radionics.com/resources/patient/xknife_description.shtml

CyberKnife

-Can treat most regions of body

-w/ Stereotactic frame, can approach accuracy of LINAC or GammaKnife

-Real-time frameless stereotaxy can be used

TREATMENT PLANNING & QUALITY CONTROL OF RT

Initial assessment

Selecting treatment volume

Preparation of a shell

Preparation of the Mask

Impression filled with liq. Plaster

Thermoplastic vacuum forming machines

Treatment Planning

Simulation

Beam shaping – Modern linear accelerators are equipped with multileaf collimators which allow automatic beam shaping.

Wedges and Compensators – Aim of treatment is high & uniform dose to target vol & min dose to surrounding. Two or more beams if fired from angles intersect at the tumor which receives max dose. Metal wedges are used to attenuate dose differentially across at its width

ISODOSE PLANS

• Map/ plan of radiation dose distribution within patient

• Plan shows outline of the patient, position of tumor and any vulnerable structures

• Position of radiation field is indicated and contour lines are drawn joining points which receive same dose (Isodose lines)

• This is checked to ensure that tumor is contained within high dose volume

Treatment Verification First Treatment SessionVerification / Check films :: Simulator filmsOn line portal verification eqpt.

UNITS OF RADIATION MEASUREMENT

Radiation dose is prescribed using SI units of absorbed dose Gy (gray)1 cGy = 0.01 GyRad = cGy

Dose to tumor should describe Physical doseNo. of fractionsFraction size Inter fraction intervalOverall timeVolume treated Radiation quality Beam energy

CARE OF PATIENT DURING RT

• Nutrition

• Care of teeth

• Care of skin

• Care of oral cavity - Oral hygiene. Antifungal mouth washes. Pilocarpine in small doses may stimulate parotid to overcome post RT dryness of mouth

Complications of RT

• Acute Tissue Reactions / Immediate

• Late Tissue Reactions / Delayed

Immediate Complications

• Occurance• Settle spontaneously• Severe & Dose limiting• Mucosal reactions – 2nd week of XRT• Skin reactions – 5th week• Acute toxicity <90 days from start of treatment

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

Early Complications

• Radiation sickness (loss of appetite & nausea)

• Mucositis & dryness of mucus membrane

• Skin reactions (erythema, dry / moist desquamation)

• Laryngeal oedema

• Candida infections

• Haematopoietic suppression

COMPLICATIONS OF RADIOTHERAPYCOMPLICATIONS OF RADIOTHERAPY

Cutaneous Manifestations

• Erythema : 2-3wks.• Dry desquamation• Moist desquamation / Blistering• Hyperpigmentation• Alopecia : Temporary / Permanent

Mucositis

• Onset• Incidence• Stages :

Inflammatory

Epithelial

Bacterial

Healing• Treatment

Xerostomia

• Acute / Chronic• Changes in Saliva : Dose > 45Gy

Reduced buffering capacityDiminshed salivary flow rateLess antimicrobial defenses

• Alteration Oral flora : Cariogenic• Impact on quality of life• Pathology• Histology• Treatment : Prevention - Reversible <30 Gy

Symptomatic / Specific

Late Complications

• Develop within months to years. > 90 days• Permanent / Irreversible• Severe• Cells with low turnover (fibroblasts, neurons)• Incidence : 5 – 15%• Most common – xerostomia

Late Complications

• Permanent xerostomia

• Skin (subcutaneous fibrosis)

• Osteo radio necrosis

• Trismus (fibrosis of TMJ & muscles)

• Transverse myelitis

• Ocular / Otologic

• Hypothyroidism / Hypopituitarism

• Malignancy (thyroid, osteosarcoma of orbit))

Late Toxicity

• Fibrosis– Serious problem, total dose limiting factor– Woody skin texture – most severe– Large daily fractions increase risk

• Ocular – cataracts, optic neuropathy, retinopathy

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

Late Toxicity

• Central Nervous System– Devastating to patients– Myelopathy (30 Gy )• Electric shock from cervical spine flexion (Lhermitte

sign)

– Transverse myelitis (50 to 60 Gy)– Somnolence syndrome (months after therapy)• Lethargy, nausea, headache, CN palsies, ataxia• Self-limiting, transient

– Brain necrosis (65 to 70 Gy) – permanent

Osteoradionecrosis

• Defn• Common site• Types Spontaneous

Traumatic• Pathogenesis• Histology• Risk Factors• Treatment