3. 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
4. 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”
5. 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
6. 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)
7. 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.
8. Role of Fractionation
• “ Shoulder” on the
graph
• Late reacting tissues
have a more curvy graph
than the acute reacting
ones
9. 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
10. Role of Radiosensitizers
• Hypoxic cells : Radioresistant
• Use of HYPERBARIC OXYGEN
• Other Modalities : Recombinant Erythropoeitin
• Nicotinamide
• Halogenated Pyrimidines
• Nitroimidazoles
• Depletion of natural radioprotector : ‘ Glutathione’
11. 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)
12. 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.
13. 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
14. 5 R’s of radiation biology
• Repair of cellular damage
• Reoxygenation of the tumor
• Redistribution within the
cell cycle
• Repopulation of cells
• Radiosensitivity Inherent
15. 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.
16. CURE & COMPLICATIONS
• Central part of both curves-steep
Small ↑ in dose » ↑ cure/complications
Small ↓ in dose » ↓ cure
17. 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
18. 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
19. 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
20. 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
21. COMBINATION CT & RT
• CT may be administered as follows :-
Neo adjuvant
Concurrent
Adjuvant
• Aim
Downsize tumor
Reduce incidence of distant metastasis
22. 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)
23. 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.
25. 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
26. ORTHOVOLTAGE RT
• Most Basic form of RT
• Obsolete
• Disadvantages
Poor penetration
Skin tolerance – Limiting factor
Unable to treat lesion at sig. depth
Increased incidence of Osteoradionecrosis
• Radiobiological Efficiency was Higher
1 Gy 1.15 Gy
Same biological effect
27. 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.
28. Megavoltage GAMMA Rays
• Radioactive isotopes
• Origin : Beam from RADIUM BOMB
• Artificially Radioactive isotopes: Cs; Co
• Cobalt Unit
Advtgs Disadvtgs
Cheaper Penumbra
Less Maintainance
• Preferred for Economic and Logistic reasons
29. 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
30. 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
31. 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
32. 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
34. Unsealed Radionucleide sources
Radioactive isotopes used in the form of drugsRadioactive isotopes used in the form of drugs
(iv / im)(iv / im)
eg. Radioactive iodine in Follicular Ca Thyroideg. Radioactive iodine in Follicular Ca Thyroid
35. Various Radiation Methods
• (3D)-Conformal Radio Therapy(3DRT / 3DCRT)
• Intensity Modulation Radio Therapy (IMRT)
• Stereotactic Radiotherapy
37. (3D) Conformal
• Multi beam conforming
• Rectangular Window collimation &
Multi Leaf Collimation (MLC)C)
• Single Intensity per beam
38. 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
39. IMRT
• A specialized
3D conformal radiation
treatment plan where
thousands of tiny
beams from several
beam angles are used
to target a tumor.
40. 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.
41. 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
42. 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
43. 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).
44. 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”
45. 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)
46. 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
49. 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/radi
osurgery/radiosurgery_intro.html
50. 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
51. Gamma Knife
-Targeting Precision of within 2mm
-Multiple targets can be easily treated in one session
http://www.elekta.com/ContentUS.nsf
52. LINAC-Based Systems
-Less accurate
-In use in more hospitals
-Less efficient (longer
treatment times)
http://www.radionics.com/resources/patient/xknife_description.shtml
53. CyberKnife
-Can treat most regions of body
-w/ Stereotactic frame, can approach accuracy of LINAC or GammaKnife
-Real-time frameless stereotaxy can be used
54. 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
55. 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
56. 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 Session
Verification / Check films :: Simulator
films
On line portal verification eqpt.
57. UNITS OF RADIATION MEASUREMENT
Radiation dose is prescribed using SI units of absorbed
dose Gy (gray)
1 cGy = 0.01 Gy
Rad = cGy
Dose to tumor should describe
Physical dose
No. of fractions
Fraction size
Inter fraction interval
Overall time
Volume treated
Radiation quality
Beam energy
58. 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
59. Complications of RT
• Acute Tissue Reactions / Immediate
• Late Tissue Reactions / Delayed
60. 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)
61. 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
64. Xerostomia
• Acute / Chronic
• Changes in Saliva : Dose > 45Gy
Reduced buffering capacity
Diminshed salivary flow rate
Less antimicrobial defenses
• Alteration Oral flora : Cariogenic
• Impact on quality of life
• Pathology
• Histology
• Treatment : Prevention - Reversible <30 Gy
Symptomatic / Specific
65. Late Complications
• Develop within months to years. > 90 days
• Permanent / Irreversible
• Severe
• Cells with low turnover (fibroblasts, neurons)
• Incidence : 5 – 15%
• Most common – xerostomia
66. 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))
67. 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)
68. 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
