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Radiobiology

This document discusses principles of radiobiology including types of radiation, how radiation causes biological effects, and factors that affect radiobiological outcomes. It covers topics like linear energy transfer, relative biological effectiveness, oxygen enhancement ratio, and how tissue factors like the cell cycle, chromatin structure, and regeneration influence radiation responses in normal and tumor tissues. The key aims are to understand how radiation damages cells and tissues at the molecular, cellular, and physiological levels and how these principles apply clinically in areas like radiation therapy fractionation schedules and the risks of reirradiation.

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Reirradiation ; Background state of art and prespective part I : Principles Of Radiobiology By Ereny S. Poles Ass.lecutrer of clinical oncology, Assuit university
• *Objectives: 1- Types of radiation. 2- effect of radiation . 3- physical factors affecting radiobiology. 4- Tissue factor affecting radiobiology.
10-9 10-8 10-7 10-6 10-5 10-4 10-3 10-2 10-1 1 10 102 103 104  rays X-rays U.V. v i s i b l e Infra Red Radio Waves Microwaves Short Waves T.V. Radio Radar IONIZING RADIATION NON-IONIZING RADIATION  (cms) E (eV) 1.24x107 1.24x102 1.24x10-13 ELECTROMAGNETIC RADIATIONS Photon E = h(energy = Planck’s const x frequency) = hc/ (c = speed of light,  = wave length)
Ionizing radiation has enough kinetic energy to detach at least one electron from an atom or molecule, creating ions Charged particles such as electrons, protons, heavy ions, alpha and beta particles are directly ionizing because they can interact directly with atomic electrons. In contrast, photons (x rays,  rays) and neutrons are chargeless and therefore more penetrating. They are indirectly ionizing.
What we want to penetrate???? What is our target ??????
What is the biological effect of radiation How it works *Biological effects of ionizing radiation are determined in large part by free radical *Since H2O is the major component in cells, the most common ionization event is radiolysis of water, producing reactive oxygen species (ROS) The most relevant water is within 2nm of the DNA and tightly bound *ROS produced include: H. - reducing; OH. - oxidizing; HO2 . - oxidizing (O2 + H.); H2O2 - oxidizing The net effect is oxidation of cellular constituents About 60% of DNA damage caused by x-rays is due to ROS About 75% of the indirect action of radiation is due to hydroxyl radicals (OH.)
p+ e- photon p+ photon INDIRECT ACTION DIRECT ACTION Direct and Indirect Action of Ionizing Radiation on DNA 4 nm 2 nm e- R. H2O OH .
Ionization produces ions, ion radicals, and free radicals concentrated along tracks and especially at Bragg peak of primary and secondary electrons. They are highly reactive and cause damage to biological matter Ion formation – H2O+ and e- Excitation and H and OH radical formation ION RADICAL LIFETIME FREE RADICAL LIFETIME BREAKAGE OF BONDS CHEMICAL REPAIR / MISREPAIR ENZYMIC REPAIR / MISREPAIR EARLY BIOLOGICAL EFFECTS LATE BIOLOGICAL EFFECTS 10-18 10-12 10-6 100 106 SECS Absorption of energy Physical effects Chemical lesions Chemical repair Enzyme repair/lesion Cellular effects Tissue effects Systemic effect Hrs-Days Mins-Hrs 10-16 10-14
10MvGamma rays 10MvProton , Neutron The Gray is the Physical Unit of Radiation • 1 GRAY, the unit of absorbed dose (1 joule / Kg), – Causes 1-2 x 105 ionization events / cell – 1% in DNA – A single cobalt 60 ray will deposit about 1mGy in a cell • Rad (Radiation Absorbed Dose) is the old unit = cGy
Factors affect the effect of radiation on tissue ?????? Radiation Tissue
Physical Factors Of Radiation Affect Radiobiological Effect: 1.Linear Energy transfer ( LET) 2.Relative Biological Effectivness (RBE) 3.Oxygen Enhancement Ratio (OER)
1- Linear Energy Transfer: LET is average energy (dE) imparted by excitation and Ionization events caused by a charged particle traveling a set distance (dl) - LET = dE/dl (keV/ m)
gamma rays deep therapy X-rays soft X-rays alpha-particle HIGH LET Radiation LOW LET Radiation Separation of ion clusters in relation to size of biological target LINEAR ENERGY TRANSFER LET is average energy (dE) imparted by excitation and Ionization events caused by a charged particle traveling a set distance (dl) - LET = dE/dl (keV/ m)
*What does mean?????? Irradiated colonies X- ray Neutron Alpha
2- Relative biological effectiveness: *Relative means comparison *Comparison between standard and variable *Here the standard is x-ray Dose of 250 kVp x-rays required to produce an effect Dose of test radiation required for the same effect
• A dose of 1 Gy will give 2x103 ionization events in 10-10 g (the size of a cell nucleus). This can be achieved by: – 1MeV electrons •700 electrons which give 6 ionization events per m. – 30 keV electrons •140 electrons which give 30 ionization events per m. – 4 MeV protons •14 protons which give 300 ionization events per m. • The biological effectiveness of these different radiations vary! -ray ’-ray excitation ionization  particle excitation and ionization
3-Oxygen Enhancement Ratio (OER) Why oxygen -Binds H radicals forming hydrogen peroxide H. + O2 HO2 . (+HO2 . ) H2O2 (+O2) -Binds electrons to give superoxide e- + O2 O2 - + (H2O) HO2 . + OH- -Binds organic radicals to form peroxides R. + O2 RO2 . (radical peroxide) RO2 . + R’ H ROOH + R’ (hydroperoxide) RO2 . + R’. ROOR’ (peroxide) Oxygen “fixes” the radical lesions in DNA in a form that can not be easily chemically repaired and therefore is a very powerful radiosensitizer.
Oxygen Enhancement Ratio (OER) Dose required to produce a specific biological effect in the absence of oxygen Dose required for the same effect in its presence = OER varies with level of effect but can be 2.5 - 3 fold 1) Culture Cells ( 3) Count cells in hemocytometer 4) irradiate under oxic or hypoxic conditions 0 Gy 2Gy 4Gy 6Gy 5) Plate cells and grow for about 12 days . . . . . . . . 6) Count colonies Dose (Gy) S.F. 0 2 4 6 8 10 1.0 0.1 0.01 oxic hypoxic 2) Suspend Cells trysinization)
-For low LET radiation the O.E.R. is 2.5-3.0 and in the higher range at higher doses - For neutrons, O.E.R is about 1.6 -The oxygen effect is greater for low LET than high LET radiation
Linear Energy Transfer (LET keV/m) RBE (for cell kill) 1000 100 10 1 0 2 4 6 8 RBE Diagnostic X-rays Fast Neutrons Alpha Particles overkill 0.1 Co-60 gamma rays 0 1 2 3 4 OER OER OER is the inverse of RBE because OER depends considerably on the indirect action of ionizing radiation RBE is maximal when the average distance between ionization events = distance between DNA strands = 2nm RBE and OER as a function of LET
Factors affect the effect of radiation on tissue ?????? Radiation Tissue
Tissue General principles Tumor Tissue Normal Tissue
General principles
Cytogenetic damage is normally assessed at first metaphase after irradiation. The type of cytogenetic damage depends upon where in the cell cycle the cell is when it is irradiated Chromosome aberrations G1 irradiation Both sister chromatids involved Chromatid aberrations S or G2 irradiation Usually only 1 chromatid involved
Repairable Sublethal Damage X- or -radiation is sparsely ionizing; most damage can be repaired 4 nm 2 nm
Single lethal hit Also known as  - type killing 4 nm 2 nm Unrepairable Multiply Damaged Site It is hypothesized that the lethal lesions are large double strand breaks with Multiply Damaged Sites (MDS) that can not be repaired. They are more likely to occur at the end of a track
At high dose, intertrack repairable Sublethal Damage may Accumulate forming unrepairable, lethal MDS Also known as  - type killing
Yield of radiation-induced chromosome damage Exchange-type “lethal” aberrations ≥ 2 hits required or 1 hit required P (2 hits) = D x D = D2 Y (yield) = k + D2 Y = k + D2 P( 1 hit) = D Y = D Y = D + D2 A plot of # “lethal” aberrations vs natural log S.F. showed that an average of 1 lethal lesion decreased survival by e. In other words, S.F. = e –(D + D2)
Repairable Sublethal Damage Sub-lethal (or accumulated) damage results from accumulation of events that individually are incapable of killing a cell but that together can be lethal 4 nm 2 nm Unrepairable Multiply Damaged Site
Cell Cycle and Radiosensitivity S.F. 20 16 12 8 4 0 0 .01 .1 1 Dose (Gy) LATE S EARLY S G1 PHASE G2/M PHASE Variations in sensitivity and in cell cycle arrest after irradiation could be important in radiation therapy, because fractionated irradiation can lead to sensitization by reassortment. The oxygen enhancement ratio (OER) does not vary much with the phase of the cell cycle. High LET responses are less affected by cell cycle phase than low LET radiation responses. G1 S G2 M Increasing radioresistance
Chromatin Structure and Radiation Responses Compact chromatin is more radiosensitive than non-compacted Mitotic cells are 2.8 times more sensitive to DNA breaks than interphase cells ,have a lower OER (eg 2.0 compared with 2.8) and do not have much of a “shoulder” on their survival curve Actively transcribing genes are less sensitive to damage Radiation Damage to DNA is not randomly distributed. It varies with cell cycle phase and level of gene expression
Tissue General principles Tumor Tissue Normal Tissue
Tissue Type SACUTE RESPONDING TISSUE LATE RESPONDING TISSUES (Responses seen during standard therapy) Gut Skin Bone Marrow Mucosa (Responses seen after end of therap Brain Spinal Cord Kidney Lung Bladder
Repair of sublethal damage spares late responding normal tissue preferentially Reassortment/Redistribution of cells in the cell cycle increases acute effects no influence on late effects increases damage to tumor Repopulation/Regeneration spares acute responding normal tissue preferentially no influence on late effects, danger of tumor repopulation Reoxygenation no influence on normal tissue responses increases tumor damage 4Rs OF RADIOBIOLOGY
Two another important definition regarding normal tissue response Latency Tolerance
Latency *Different tissues take different times to express damage (latency). This depends on their turnover time. Defined by the standard 6wks clinical treatment time
0 2 4 6 8 10 12 14 16 18 Dose (Gy) BONE MARROW Day 30 PERCENT LETHALITY GUT Day 7 LUNG Day 180 100% 0% There is no Relationship between Latency and Tolerance Different tissues have different tolerances to irradiation and fail at different times (latency) after irradiation Latency is determined by cell turnover kinetics in a tissue. It is NOT an indicator of radiosensitivity. After moderate doses, gut fails first, then bone marrow, then lung, but the hematopoietic system is the most radiosensitive
-Intrinsic cellular radiosensitivity and repair -Regeneration - Structural organization of tissues -Wound healing ability -Non-radiobiologically determined factors, for example medicolegal, psychological Tissue Tolerance Doses
In gut, symptoms appear rapidly (2 weeks). This is the time taken for epithelial cells to traverse the villus and be shed into the lumen. Tolerance is about 50 Gy in 2 Gy fx for the small intestine and slightly higher for the large intestine. Lag time before the onset of radiation-induced proliferation in jejunum may be less than 24 hours. In colon and stomach, slightly longer. Regeneration and repair
Segment of Mouse Gut Irradiated with Varying Doses 12.5Gy 14.0Gy 15.5Gy 17.0Gy a b c d XRT Day 13 Overt tissue response (e.g. ulceration) is dose-dependent with a threshold followed by a rapid increase in severity. a. Patchy breakdown of mucosa except in shielded mucosa at top of specimen. b. Ulcerated mucosa being resurfaced by near-confluent nodules regenerated from a large number of independently surviving jejunal clonogens. c. Severe ulceration but with about 60 discrete clonogenically-derived mucosal nodules. d. As for c. but only 4 regenerated nodules.
Probability of a normal tissue complication NTCP = 1/(1+(D/ED50)-k where k is sensitivity - typically about 7 for most normal tissues ED50 is typically 50-60 Gy Probability of complication free cure = [TCP][1-NTCP] small differences in total dose are amplified in late responding tissues, which are more subject to change with dose per fraction than are acute effect tissue
Probability of damage (%) 37 0 20 70 60 40 10 30 50 80 D10 ~ 7.5% per Gy 90 0 20 80 60 40 100 Small differences in dose can have major biological effects Dose (Gy) Curves for the probability of a normal tissue complication NTCP in the clinic are generally steep compared with TCP curves A 20% increase in dose could cause a large increase in the incidence of complications
Effect of Dose Fractionation on Clonogen Survival in Jejunum Repopulation Redistribution Repair Regeneration is a major factor contributing to increased tolerance of acute responding tissues during fractionation
Clinical Relevance of Regeneration Mucositis appears 2 to 3 weeks after the start of a standard RT course. Regeneration begins at about 10 to 12 days, before evident mucositis. This can increase the tolerance of the mucosa by about 1Gy/day, which is equivalent to clonogenic cell number doubling every 2 days.
Because of regeneration/repopulation in acute, but not late, normal tissue reactions during treatment: Protracting overall treatment time beyond the conventional 6 weeks may result in sparing (but tumors may also be spared) Decreasing overall treatment time to less than the conventional 6 weeks may result in more acute normal tissue reactions Treatment time has relatively little effect on responses in late effects tissues Regeneration/repopulation in late, normal tissue reactions after treatment, may allow recovery and make retreatment possible Clinical Relevance
If the initial dose is close to the ED50, the remembered dose is high but if it is 75% of the ED50, only 25% is ‘remembered’. Mason et al., Int J Radiat Biol Phys 26:643, 1993 Spinal Cord Regeneration may be important in recovery of late responding tissues and retreatment tolerance Recovery also depends on time van der Kogel and Fawcett 200 100 0 0 20 40 60 80 100 Time between treatments (days) 50% initial treatment as % of tolerance dose 70% 95% Retreat ment ED50 as a % of initial ED50
-The number of clonogens make up a FSU and their organization in series or in parallel in a tissue, can affect “tolerance” By definition, for an FSU to survive, at least one clonogen must survive FSUs can be discrete structures, such as a nephron in kidney or a liver lobule, or diffuse with no clear demarcation, eg skin 2-Functional Subunits
168 clonogens in 12 FSUs 168 clonogens in 4 FSUs Which is more radiation resistant and by how much? Examples: Epilation occurs at a lower dose than desquamation - because hair has fewer clonogenic cells per FSU Hair depigmentation occurs at a lower dose than skin depigmentation because follicles contain fewer melanocytes.
FSUs and Volume Effects FSUs can be arranged in parallel eg. lung, liver, kidney In tissues that are intrinsically radiosensitive and rely on a large functional reserve: A low dose to a large volume can be hazardous but A high dose to small volume can be innocuous This is because function is determined by the amount of tissue that is not irradiated I.e. the “reserve function determines the “volume” effect, which will be large. FSUs can also be arranged in series eg. spinal cord, nerves In tissues that are intrinsically radioresistant, and where cell migration may help tissue recovery: A low dose to a large volume may be innocuous but A high dose to a small volume may be hazardous i.e. a strong volume effect over a short distance This is a ‘true’ volume effect
Two types Tissues Hierarchical Tissues Rich in stem cells and highly proliferative progenito cells that differentiate into functional differentiated cells. They have a high turnover rate and a high rate of cell loss. They respond rapidly to irradiation and fail when the precursor pool fails to generate enough differentiated cells. Examples are Gut, Skin, Bone Marrow, Mucosa Flexible tissues have a slow turnover rate and respond slowly to irradiation. They fail when there is enough cell loss to induce regeneration, which triggers an avalanche of cell death, generally after a long lag period. Examples are Brain, Spinal Cord, Kidney, Lung, Bladder
Late Effects are Complex For example: Lung expresses damage in two major waves - pneumonitis and fibrosis. In mice, these vary with the strain and are genetically determined In brain, demyelination with white matter necrosis, edema, hemorrhagic necrosis, and atrophy are variably found.
Conclusions The time to a normal tissue complication depends on the tissue turnover time. It is relatively independent of dose for hierarchical, but not flexible, tissues The time to and extent of regeneration in normal tissues also determines how much dose can be tolerated Tissue tolerance depends not only on intrinsic radiosensitivity of clonogens, but also on organization into FSUs, and the number of clonogens per FSU Volume effects are complex, but a major volume effect may be due to differences in FSU organization Late effects are complex, but there is some reason to think they may, to an extent, be reversible. The balance of cytokines and growth factors determine both regeneration and normal tissue complications
Rirradiation to be continued ……………………
Reirradiation ; Background state of art and prespective part II : Reirradiation
• *Objectives: 1- Reirradiation of Head and neck. 2- Reirradiation of recurrent brain tumors. 3- Reirradiation of painful bone metastasis.
• Last decade witnessed major progress in management of pts with HNSCC due to – The addition of concomitant chemotherapy – Significant improvement in radiation techniques (IMRT) However, Vast majority of these occur in previously irradiated areas and thus poses a common challenge to H & N oncologists Reirradiation of Head and neck
Treatment options for Recurrent HNC Resectable / Unresectable Resectable Unresectable - Traditionally a std of care for resectable tumour - However only 20 % pts are candidates for curative resection - Results of salvage surgery are poor - Poor response rates - Limited palliation and - No long term survival - Nearly all pts die of disease progression within months - Historically been avoided owing to concerns regarding toxicity - Radiation tolerance of the normal tissue is significantly reduced compared with the first treatment - However, more recently published data demonstrated the feasibility and effectiveness of reirradiation Re irradiation Surgery Palliative Chemotherapy
• Most recurrences are local and in field. • Mostly in high dose regions. • Distant mets incidence increases if both primary and nodal failure occurs.
• Patients should be carefully selected: – Favourable sites such as larynx and nasopharynx; – Small tumour size (< 3cm); – A relatively longer period since previous irradiation (preferably ≥6 months); – No major late complications due to initial RT.
• PET CT based planning may be required as it may be difficult to distinguish fibrosis and recurrent tumor on CT/MRI. • RT dose fractionation not > 2 Gy/#. • Incidence of soft tissue necrosis- 0 to 40% • Pt. nutrition- should be excellent
• Re irradiation dose should be more than 58 Gy for better LRC, PFS and OS, in many studies (OS- 30% vs 6%) • Cumulative dose to target volume should be more than 100Gy (Either alone or combined with CT). • Cumulative RT dose not more than 130Gy @ 2Gy/#. • Radiation fields should be small. • Highly conformal techniques are usually required- IMRT, SRS, SRT, etc. • CTV should include only GTV and limited margins (1.5 to 2cm) or high risk areas – positive surgical margins or lymph nodes with extra nodal spread.
• Cumulative dose – subcutaneous tissue= 110Gy , spinal cord= 50Gy. • More than 90% of the initial dose can be given to subcutaneous tissues after 6 weeks of initial radiation. • 60% of the initial dose effect is repaired by the spinal cord if treatment courses are separated by 1–3 years. • Risk of myelitis < 6% if # size – 1.8 to 2.0 Gy.
• Better response and OS if overall cumulative field of RT <125 cm2. • More reactions expected if cumulative field of irradiation > 70 cm2. • 2 year loco regional control rate- – 52% with IMRT – 20% with conventional 2D RT.
Strictly involved field radiotherapy  No elective nodal irradiation  No elective Clinical Target volumes Target volume delineation
• Mucositis rates increase by 30% • Severe late reactions- 1 year • Severe late reaction rate- 9 to 41% (mean 25%) • Speech is preserved ,swallowing function is the concern. • Males more tolerant to side effects • Most severe reactions in age > 80 years
• Severe late toxicities (0 to 48%) – 6 mths to yrs. • Endocrine dysfunction, • Dysphagia, • Trismus, • Decreased hearing, • Osteonecrosis, and • Chondronecrosis. • Fatal complications (0 to 16%) • Carotid artery rupture, • Brain necrosis, • Aspiration due to cranial nerve paralysis, • Pharyngeal dysmotility, and • Narcotic overdose
2- Reirradiation of painful bone metastasis • Bone metastases are common manifestation in malignancy • It causes – Pain Spinal Cord Compression Hypercalcemia Fractures • Multidisciplinary Management is required
1) When should patients receive re-treatment with radiation to peripheral bone metastases? • Rates of re-treatment - 20% with single fraction as compared 8%with lengthier courses of treatment. • Normal tissue tolerance – limiting factor. • The presence of persistent pain in weight bearing or long bones would necessitate a re-assessment of pathologic fracture risk.
2) When should patients receive re-treatment with radiation to spine lesions causing recurrent pain? • Sites of recurrent pain in spine bones - palliated with EBRT re-treatment, but no conclusive data regarding dosing and fractionation. • If the re-irradiated volume contains the spinal cord, sum of the BEDs of earlier RT to estimate the risk of radiation myelopathy.
• Few retrospectives studies - good pain control with a limited risk of side effects following re-irradiation with single fractions between 4 Gy and 8 Gy. • Radiation myelopathy - 3% when : 1. Sum of two BEDs – 135.5 Gy (a/b = 2Gy for spine, according to LQ model) 2. Neither single course BED > 98 Gy. 3. Interval not less than 6 months
3) What promise does highly conformal radiotherapy hold for the primary treatment of painful bone metastasis? • Stereotactic body radiation therapy (SBRT). • Dosage and target delineation yet to be fully defined • Given under clinical trials and should not be the primary treatment of vertebral bone lesions causing spinal cord compression.
• Aims at identifying who may achieve more durable pain relief or overall failure-free survival with SBRT. • Late toxicities can occur such as : o Radiation myelopathy – in previously untreated patients o New or progressive vertebral compression fractures o Esophageal and bronchial problems
4) When should highly conformal radiotherapy be considered for re-treatment of spine lesions causing recurrent pain? • No definitive data to specify the proper patient selection criteria. • Re-treatment to spine lesions with SBRT may be feasible, effective, and safe. • Limited to the setting of clinical trial participation • No evidence of superiority of SBRT over conventional EBRT with respect to pain control. • May lead to unexpected side effect risks.
3-Reirradiation of recurrent brain tumors. *The current standard of care for glioblastoma multiforme (GBM) is radiotherapy with concurrent and adjuvant temozolomide. *This is associated with a5-year overall survival of 9.8% versus 1.9% with radiotherapy alone. *Because of the infiltrating nature of gliomas, they frequently recur and despite an increase in survival rates the majority of patients progress within 1–2 years. *With regards to anaplastic astrocytomas and low grade gliomas the time to local recurrence is longer, but the majority ultimately also recur.
*Salvage therapy is indicated in the majority of recurrent gliomas, and most patients receive chemotherapy or surgery at relapse *Re-irradiation for brain tumours is now attracting more interest as our understanding of the tolerance of the brain evolves. *Developments in radiation technology and imaging also mean that highly accurate targeting of biologically relevant tumour volumes is possible.
The Biology of Late Central Nervous System Toxicity: CNS toxicity following irradiation has been divided into three phases:- 1-early (days–weeksafter), 2-early delayed (1–6 months after and includes somnolence syndrome and Lhermitte’s phenomenon due to transient demyelination) 3-late (greater than 6 months following irradiation). Early and early delayed toxicities are normally reversible and spontaneously resolve whereas late toxicity is normally progressive and irreversible. Late injury is characterised pathologically by demyelination, vascular changes and ultimately necrosis
Evidence for Re-irradiation using various techniques 1-Conformal Radiotherapy 3D conventional radiotherapy using co-registered magnetic resonance imaging (MRI) has improved target definition and allows for a reduction of the dose to normal structures. Further developments such as IMRT (intensity-modulated radiotherapy) can improve this further by conformality at the target using multiple-modulated beams. For re-irradiation, the aim is not only to treat the area of recurrence with an adequate margin, but also to reduce as much as possible the total dose to critical organs at risk within the CNS, as, optic nerves or brainstem, making highly conformal
CT and MRI-fused planning images for a patient treated for a recurrent glioma. 10 years previously treated with 55 Gy in 30 fractions over 6 weeks. Re-irradiated with 30 Gy in 6 fractions over 2 weeks. CTV contrast enhancing volume on T1-weighted MRI. PTV = CTV ? 0.5 cm margin
Image showing 4-field conformal radiotherapy axial plan for the same patient
2-Stereotactic Radiosurgery/Fractionated Stereotactic Radiotherapy:- Stereotactic radiosurgery (delivered using the Leksell Gamma Knife, adapted linear accelerators, Cyber Knife and other devices) is a non- invasive, highly conformal radiotherapy technique. It allows very accurate dose delivery with the patient in a fixed head frame and multiple beam sources producing a steep dose gradient at the edge of the target, therefore allowing a highly precise dose to be delivered to tumour whilst sparing the surrounding normal tissues and organs at risk.
57-year-old patient with recurrent glioblastoma of theright temporal lobe anterior to the surgical resection cavity. The targeted volume was 12.3 ml. The patient was treated with SRS to a dose of 18 Gy prescribed to the 90% isodose line
3-Brachytherapy Most studies in the brain have used 125I or 192I. Placement of multiple sources of radiation around the surgical cavity is technically challenging to ensure an adequate and even dose distribution.
Dose and delineation Most recurrent glioma patients will have received the equivalent of 55–60 in 1.8–2 Gy per fraction when they were initially treated, and therefore not more than 40 Gy equivalent in a hypofractionated regimen should be delivered when re- irradiating, aiming to keep the total dose less than 100 Gy To optimise the outcome of radiotherapy treatment, improved target definition is of paramount importance. In this context, alternative biological imaging may improve the definition of the relevant target; for example, Amino Acid PET (SPECT)/CT/MRI image fusion to determine the gross tumour volume are currently under investigation.
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Radiobiology

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Radiobiology

  • 1.
    Reirradiation ; Backgroundstate of art and prespective part I : Principles Of Radiobiology By Ereny S. Poles Ass.lecutrer of clinical oncology, Assuit university
  • 3.
    • *Objectives: 1- Types ofradiation. 2- effect of radiation . 3- physical factors affecting radiobiology. 4- Tissue factor affecting radiobiology.
  • 4.
    10-9 10-8 10-710-6 10-5 10-4 10-3 10-2 10-1 1 10 102 103 104  rays X-rays U.V. v i s i b l e Infra Red Radio Waves Microwaves Short Waves T.V. Radio Radar IONIZING RADIATION NON-IONIZING RADIATION  (cms) E (eV) 1.24x107 1.24x102 1.24x10-13 ELECTROMAGNETIC RADIATIONS Photon E = h(energy = Planck’s const x frequency) = hc/ (c = speed of light,  = wave length)
  • 6.
    Ionizing radiation hasenough kinetic energy to detach at least one electron from an atom or molecule, creating ions Charged particles such as electrons, protons, heavy ions, alpha and beta particles are directly ionizing because they can interact directly with atomic electrons. In contrast, photons (x rays,  rays) and neutrons are chargeless and therefore more penetrating. They are indirectly ionizing.
  • 7.
    What we wantto penetrate???? What is our target ??????
  • 11.
    What is thebiological effect of radiation How it works *Biological effects of ionizing radiation are determined in large part by free radical *Since H2O is the major component in cells, the most common ionization event is radiolysis of water, producing reactive oxygen species (ROS) The most relevant water is within 2nm of the DNA and tightly bound *ROS produced include: H. - reducing; OH. - oxidizing; HO2 . - oxidizing (O2 + H.); H2O2 - oxidizing The net effect is oxidation of cellular constituents About 60% of DNA damage caused by x-rays is due to ROS About 75% of the indirect action of radiation is due to hydroxyl radicals (OH.)
  • 12.
    p+ e- photon p+ photon INDIRECT ACTION DIRECT ACTION Directand Indirect Action of Ionizing Radiation on DNA 4 nm 2 nm e- R. H2O OH .
  • 13.
    Ionization produces ions,ion radicals, and free radicals concentrated along tracks and especially at Bragg peak of primary and secondary electrons. They are highly reactive and cause damage to biological matter Ion formation – H2O+ and e- Excitation and H and OH radical formation ION RADICAL LIFETIME FREE RADICAL LIFETIME BREAKAGE OF BONDS CHEMICAL REPAIR / MISREPAIR ENZYMIC REPAIR / MISREPAIR EARLY BIOLOGICAL EFFECTS LATE BIOLOGICAL EFFECTS 10-18 10-12 10-6 100 106 SECS Absorption of energy Physical effects Chemical lesions Chemical repair Enzyme repair/lesion Cellular effects Tissue effects Systemic effect Hrs-Days Mins-Hrs 10-16 10-14
  • 15.
    10MvGamma rays 10MvProton , Neutron The Grayis the Physical Unit of Radiation • 1 GRAY, the unit of absorbed dose (1 joule / Kg), – Causes 1-2 x 105 ionization events / cell – 1% in DNA – A single cobalt 60 ray will deposit about 1mGy in a cell • Rad (Radiation Absorbed Dose) is the old unit = cGy
  • 16.
    Factors affect theeffect of radiation on tissue ?????? Radiation Tissue
  • 17.
    Physical Factors OfRadiation Affect Radiobiological Effect: 1.Linear Energy transfer ( LET) 2.Relative Biological Effectivness (RBE) 3.Oxygen Enhancement Ratio (OER)
  • 18.
    1- Linear EnergyTransfer: LET is average energy (dE) imparted by excitation and Ionization events caused by a charged particle traveling a set distance (dl) - LET = dE/dl (keV/ m)
  • 20.
    gamma rays deep therapy X-rays softX-rays alpha-particle HIGH LET Radiation LOW LET Radiation Separation of ion clusters in relation to size of biological target LINEAR ENERGY TRANSFER LET is average energy (dE) imparted by excitation and Ionization events caused by a charged particle traveling a set distance (dl) - LET = dE/dl (keV/ m)
  • 21.
    *What does mean?????? Irradiatedcolonies X- ray Neutron Alpha
  • 22.
    2- Relative biologicaleffectiveness: *Relative means comparison *Comparison between standard and variable *Here the standard is x-ray Dose of 250 kVp x-rays required to produce an effect Dose of test radiation required for the same effect
  • 24.
    • A doseof 1 Gy will give 2x103 ionization events in 10-10 g (the size of a cell nucleus). This can be achieved by: – 1MeV electrons •700 electrons which give 6 ionization events per m. – 30 keV electrons •140 electrons which give 30 ionization events per m. – 4 MeV protons •14 protons which give 300 ionization events per m. • The biological effectiveness of these different radiations vary! -ray ’-ray excitation ionization  particle excitation and ionization
  • 27.
    3-Oxygen Enhancement Ratio(OER) Why oxygen -Binds H radicals forming hydrogen peroxide H. + O2 HO2 . (+HO2 . ) H2O2 (+O2) -Binds electrons to give superoxide e- + O2 O2 - + (H2O) HO2 . + OH- -Binds organic radicals to form peroxides R. + O2 RO2 . (radical peroxide) RO2 . + R’ H ROOH + R’ (hydroperoxide) RO2 . + R’. ROOR’ (peroxide) Oxygen “fixes” the radical lesions in DNA in a form that can not be easily chemically repaired and therefore is a very powerful radiosensitizer.
  • 28.
    Oxygen Enhancement Ratio(OER) Dose required to produce a specific biological effect in the absence of oxygen Dose required for the same effect in its presence = OER varies with level of effect but can be 2.5 - 3 fold 1) Culture Cells ( 3) Count cells in hemocytometer 4) irradiate under oxic or hypoxic conditions 0 Gy 2Gy 4Gy 6Gy 5) Plate cells and grow for about 12 days . . . . . . . . 6) Count colonies Dose (Gy) S.F. 0 2 4 6 8 10 1.0 0.1 0.01 oxic hypoxic 2) Suspend Cells trysinization)
  • 29.
    -For low LETradiation the O.E.R. is 2.5-3.0 and in the higher range at higher doses - For neutrons, O.E.R is about 1.6 -The oxygen effect is greater for low LET than high LET radiation
  • 30.
    Linear Energy Transfer(LET keV/m) RBE (for cell kill) 1000 100 10 1 0 2 4 6 8 RBE Diagnostic X-rays Fast Neutrons Alpha Particles overkill 0.1 Co-60 gamma rays 0 1 2 3 4 OER OER OER is the inverse of RBE because OER depends considerably on the indirect action of ionizing radiation RBE is maximal when the average distance between ionization events = distance between DNA strands = 2nm RBE and OER as a function of LET
  • 31.
    Factors affect theeffect of radiation on tissue ?????? Radiation Tissue
  • 32.
  • 33.
  • 34.
    Cytogenetic damage isnormally assessed at first metaphase after irradiation. The type of cytogenetic damage depends upon where in the cell cycle the cell is when it is irradiated Chromosome aberrations G1 irradiation Both sister chromatids involved Chromatid aberrations S or G2 irradiation Usually only 1 chromatid involved
  • 35.
    Repairable Sublethal Damage X-or -radiation is sparsely ionizing; most damage can be repaired 4 nm 2 nm
  • 36.
    Single lethal hit Alsoknown as  - type killing 4 nm 2 nm Unrepairable Multiply Damaged Site It is hypothesized that the lethal lesions are large double strand breaks with Multiply Damaged Sites (MDS) that can not be repaired. They are more likely to occur at the end of a track
  • 37.
    At high dose,intertrack repairable Sublethal Damage may Accumulate forming unrepairable, lethal MDS Also known as  - type killing
  • 38.
    Yield of radiation-inducedchromosome damage Exchange-type “lethal” aberrations ≥ 2 hits required or 1 hit required P (2 hits) = D x D = D2 Y (yield) = k + D2 Y = k + D2 P( 1 hit) = D Y = D Y = D + D2 A plot of # “lethal” aberrations vs natural log S.F. showed that an average of 1 lethal lesion decreased survival by e. In other words, S.F. = e –(D + D2)
  • 39.
    Repairable Sublethal Damage Sub-lethal(or accumulated) damage results from accumulation of events that individually are incapable of killing a cell but that together can be lethal 4 nm 2 nm Unrepairable Multiply Damaged Site
  • 42.
    Cell Cycle andRadiosensitivity S.F. 20 16 12 8 4 0 0 .01 .1 1 Dose (Gy) LATE S EARLY S G1 PHASE G2/M PHASE Variations in sensitivity and in cell cycle arrest after irradiation could be important in radiation therapy, because fractionated irradiation can lead to sensitization by reassortment. The oxygen enhancement ratio (OER) does not vary much with the phase of the cell cycle. High LET responses are less affected by cell cycle phase than low LET radiation responses. G1 S G2 M Increasing radioresistance
  • 43.
    Chromatin Structure andRadiation Responses Compact chromatin is more radiosensitive than non-compacted Mitotic cells are 2.8 times more sensitive to DNA breaks than interphase cells ,have a lower OER (eg 2.0 compared with 2.8) and do not have much of a “shoulder” on their survival curve Actively transcribing genes are less sensitive to damage Radiation Damage to DNA is not randomly distributed. It varies with cell cycle phase and level of gene expression
  • 44.
  • 45.
    Tissue Type SACUTE RESPONDINGTISSUE LATE RESPONDING TISSUES (Responses seen during standard therapy) Gut Skin Bone Marrow Mucosa (Responses seen after end of therap Brain Spinal Cord Kidney Lung Bladder
  • 46.
    Repair of sublethaldamage spares late responding normal tissue preferentially Reassortment/Redistribution of cells in the cell cycle increases acute effects no influence on late effects increases damage to tumor Repopulation/Regeneration spares acute responding normal tissue preferentially no influence on late effects, danger of tumor repopulation Reoxygenation no influence on normal tissue responses increases tumor damage 4Rs OF RADIOBIOLOGY
  • 47.
    Two another importantdefinition regarding normal tissue response Latency Tolerance
  • 48.
    Latency *Different tissues takedifferent times to express damage (latency). This depends on their turnover time. Defined by the standard 6wks clinical treatment time
  • 49.
    0 2 46 8 10 12 14 16 18 Dose (Gy) BONE MARROW Day 30 PERCENT LETHALITY GUT Day 7 LUNG Day 180 100% 0% There is no Relationship between Latency and Tolerance Different tissues have different tolerances to irradiation and fail at different times (latency) after irradiation Latency is determined by cell turnover kinetics in a tissue. It is NOT an indicator of radiosensitivity. After moderate doses, gut fails first, then bone marrow, then lung, but the hematopoietic system is the most radiosensitive
  • 50.
    -Intrinsic cellular radiosensitivityand repair -Regeneration - Structural organization of tissues -Wound healing ability -Non-radiobiologically determined factors, for example medicolegal, psychological Tissue Tolerance Doses
  • 51.
    In gut, symptomsappear rapidly (2 weeks). This is the time taken for epithelial cells to traverse the villus and be shed into the lumen. Tolerance is about 50 Gy in 2 Gy fx for the small intestine and slightly higher for the large intestine. Lag time before the onset of radiation-induced proliferation in jejunum may be less than 24 hours. In colon and stomach, slightly longer. Regeneration and repair
  • 52.
    Segment of MouseGut Irradiated with Varying Doses 12.5Gy 14.0Gy 15.5Gy 17.0Gy a b c d XRT Day 13 Overt tissue response (e.g. ulceration) is dose-dependent with a threshold followed by a rapid increase in severity. a. Patchy breakdown of mucosa except in shielded mucosa at top of specimen. b. Ulcerated mucosa being resurfaced by near-confluent nodules regenerated from a large number of independently surviving jejunal clonogens. c. Severe ulceration but with about 60 discrete clonogenically-derived mucosal nodules. d. As for c. but only 4 regenerated nodules.
  • 53.
    Probability of anormal tissue complication NTCP = 1/(1+(D/ED50)-k where k is sensitivity - typically about 7 for most normal tissues ED50 is typically 50-60 Gy Probability of complication free cure = [TCP][1-NTCP] small differences in total dose are amplified in late responding tissues, which are more subject to change with dose per fraction than are acute effect tissue
  • 54.
    Probability of damage (%) 37 0 20 70 60 40 1030 50 80 D10 ~ 7.5% per Gy 90 0 20 80 60 40 100 Small differences in dose can have major biological effects Dose (Gy) Curves for the probability of a normal tissue complication NTCP in the clinic are generally steep compared with TCP curves A 20% increase in dose could cause a large increase in the incidence of complications
  • 55.
    Effect of DoseFractionation on Clonogen Survival in Jejunum Repopulation Redistribution Repair Regeneration is a major factor contributing to increased tolerance of acute responding tissues during fractionation
  • 56.
    Clinical Relevance ofRegeneration Mucositis appears 2 to 3 weeks after the start of a standard RT course. Regeneration begins at about 10 to 12 days, before evident mucositis. This can increase the tolerance of the mucosa by about 1Gy/day, which is equivalent to clonogenic cell number doubling every 2 days.
  • 57.
    Because of regeneration/repopulationin acute, but not late, normal tissue reactions during treatment: Protracting overall treatment time beyond the conventional 6 weeks may result in sparing (but tumors may also be spared) Decreasing overall treatment time to less than the conventional 6 weeks may result in more acute normal tissue reactions Treatment time has relatively little effect on responses in late effects tissues Regeneration/repopulation in late, normal tissue reactions after treatment, may allow recovery and make retreatment possible Clinical Relevance
  • 58.
    If the initialdose is close to the ED50, the remembered dose is high but if it is 75% of the ED50, only 25% is ‘remembered’. Mason et al., Int J Radiat Biol Phys 26:643, 1993 Spinal Cord Regeneration may be important in recovery of late responding tissues and retreatment tolerance Recovery also depends on time van der Kogel and Fawcett 200 100 0 0 20 40 60 80 100 Time between treatments (days) 50% initial treatment as % of tolerance dose 70% 95% Retreat ment ED50 as a % of initial ED50
  • 59.
    -The number ofclonogens make up a FSU and their organization in series or in parallel in a tissue, can affect “tolerance” By definition, for an FSU to survive, at least one clonogen must survive FSUs can be discrete structures, such as a nephron in kidney or a liver lobule, or diffuse with no clear demarcation, eg skin 2-Functional Subunits
  • 60.
    168 clonogens in12 FSUs 168 clonogens in 4 FSUs Which is more radiation resistant and by how much? Examples: Epilation occurs at a lower dose than desquamation - because hair has fewer clonogenic cells per FSU Hair depigmentation occurs at a lower dose than skin depigmentation because follicles contain fewer melanocytes.
  • 61.
    FSUs and VolumeEffects FSUs can be arranged in parallel eg. lung, liver, kidney In tissues that are intrinsically radiosensitive and rely on a large functional reserve: A low dose to a large volume can be hazardous but A high dose to small volume can be innocuous This is because function is determined by the amount of tissue that is not irradiated I.e. the “reserve function determines the “volume” effect, which will be large. FSUs can also be arranged in series eg. spinal cord, nerves In tissues that are intrinsically radioresistant, and where cell migration may help tissue recovery: A low dose to a large volume may be innocuous but A high dose to a small volume may be hazardous i.e. a strong volume effect over a short distance This is a ‘true’ volume effect
  • 62.
    Two types Tissues HierarchicalTissues Rich in stem cells and highly proliferative progenito cells that differentiate into functional differentiated cells. They have a high turnover rate and a high rate of cell loss. They respond rapidly to irradiation and fail when the precursor pool fails to generate enough differentiated cells. Examples are Gut, Skin, Bone Marrow, Mucosa Flexible tissues have a slow turnover rate and respond slowly to irradiation. They fail when there is enough cell loss to induce regeneration, which triggers an avalanche of cell death, generally after a long lag period. Examples are Brain, Spinal Cord, Kidney, Lung, Bladder
  • 63.
    Late Effects areComplex For example: Lung expresses damage in two major waves - pneumonitis and fibrosis. In mice, these vary with the strain and are genetically determined In brain, demyelination with white matter necrosis, edema, hemorrhagic necrosis, and atrophy are variably found.
  • 64.
    Conclusions The time toa normal tissue complication depends on the tissue turnover time. It is relatively independent of dose for hierarchical, but not flexible, tissues The time to and extent of regeneration in normal tissues also determines how much dose can be tolerated Tissue tolerance depends not only on intrinsic radiosensitivity of clonogens, but also on organization into FSUs, and the number of clonogens per FSU Volume effects are complex, but a major volume effect may be due to differences in FSU organization Late effects are complex, but there is some reason to think they may, to an extent, be reversible. The balance of cytokines and growth factors determine both regeneration and normal tissue complications
  • 65.
    Rirradiation to becontinued ……………………
  • 66.
    Reirradiation ; Backgroundstate of art and prespective part II : Reirradiation
  • 67.
    • *Objectives: 1- Reirradiation ofHead and neck. 2- Reirradiation of recurrent brain tumors. 3- Reirradiation of painful bone metastasis.
  • 68.
    • Last decadewitnessed major progress in management of pts with HNSCC due to – The addition of concomitant chemotherapy – Significant improvement in radiation techniques (IMRT) However, Vast majority of these occur in previously irradiated areas and thus poses a common challenge to H & N oncologists Reirradiation of Head and neck
  • 69.
    Treatment options forRecurrent HNC Resectable / Unresectable Resectable Unresectable - Traditionally a std of care for resectable tumour - However only 20 % pts are candidates for curative resection - Results of salvage surgery are poor - Poor response rates - Limited palliation and - No long term survival - Nearly all pts die of disease progression within months - Historically been avoided owing to concerns regarding toxicity - Radiation tolerance of the normal tissue is significantly reduced compared with the first treatment - However, more recently published data demonstrated the feasibility and effectiveness of reirradiation Re irradiation Surgery Palliative Chemotherapy
  • 70.
    • Most recurrencesare local and in field. • Mostly in high dose regions. • Distant mets incidence increases if both primary and nodal failure occurs.
  • 71.
    • Patients shouldbe carefully selected: – Favourable sites such as larynx and nasopharynx; – Small tumour size (< 3cm); – A relatively longer period since previous irradiation (preferably ≥6 months); – No major late complications due to initial RT.
  • 72.
    • PET CTbased planning may be required as it may be difficult to distinguish fibrosis and recurrent tumor on CT/MRI. • RT dose fractionation not > 2 Gy/#. • Incidence of soft tissue necrosis- 0 to 40% • Pt. nutrition- should be excellent
  • 73.
    • Re irradiationdose should be more than 58 Gy for better LRC, PFS and OS, in many studies (OS- 30% vs 6%) • Cumulative dose to target volume should be more than 100Gy (Either alone or combined with CT). • Cumulative RT dose not more than 130Gy @ 2Gy/#. • Radiation fields should be small. • Highly conformal techniques are usually required- IMRT, SRS, SRT, etc. • CTV should include only GTV and limited margins (1.5 to 2cm) or high risk areas – positive surgical margins or lymph nodes with extra nodal spread.
  • 74.
    • Cumulative dose– subcutaneous tissue= 110Gy , spinal cord= 50Gy. • More than 90% of the initial dose can be given to subcutaneous tissues after 6 weeks of initial radiation. • 60% of the initial dose effect is repaired by the spinal cord if treatment courses are separated by 1–3 years. • Risk of myelitis < 6% if # size – 1.8 to 2.0 Gy.
  • 75.
    • Better responseand OS if overall cumulative field of RT <125 cm2. • More reactions expected if cumulative field of irradiation > 70 cm2. • 2 year loco regional control rate- – 52% with IMRT – 20% with conventional 2D RT.
  • 76.
    Strictly involved fieldradiotherapy  No elective nodal irradiation  No elective Clinical Target volumes Target volume delineation
  • 77.
    • Mucositis ratesincrease by 30% • Severe late reactions- 1 year • Severe late reaction rate- 9 to 41% (mean 25%) • Speech is preserved ,swallowing function is the concern. • Males more tolerant to side effects • Most severe reactions in age > 80 years
  • 78.
    • Severe latetoxicities (0 to 48%) – 6 mths to yrs. • Endocrine dysfunction, • Dysphagia, • Trismus, • Decreased hearing, • Osteonecrosis, and • Chondronecrosis. • Fatal complications (0 to 16%) • Carotid artery rupture, • Brain necrosis, • Aspiration due to cranial nerve paralysis, • Pharyngeal dysmotility, and • Narcotic overdose
  • 79.
    2- Reirradiation ofpainful bone metastasis • Bone metastases are common manifestation in malignancy • It causes – Pain Spinal Cord Compression Hypercalcemia Fractures • Multidisciplinary Management is required
  • 80.
    1) When shouldpatients receive re-treatment with radiation to peripheral bone metastases? • Rates of re-treatment - 20% with single fraction as compared 8%with lengthier courses of treatment. • Normal tissue tolerance – limiting factor. • The presence of persistent pain in weight bearing or long bones would necessitate a re-assessment of pathologic fracture risk.
  • 81.
    2) When shouldpatients receive re-treatment with radiation to spine lesions causing recurrent pain? • Sites of recurrent pain in spine bones - palliated with EBRT re-treatment, but no conclusive data regarding dosing and fractionation. • If the re-irradiated volume contains the spinal cord, sum of the BEDs of earlier RT to estimate the risk of radiation myelopathy.
  • 82.
    • Few retrospectivesstudies - good pain control with a limited risk of side effects following re-irradiation with single fractions between 4 Gy and 8 Gy. • Radiation myelopathy - 3% when : 1. Sum of two BEDs – 135.5 Gy (a/b = 2Gy for spine, according to LQ model) 2. Neither single course BED > 98 Gy. 3. Interval not less than 6 months
  • 83.
    3) What promisedoes highly conformal radiotherapy hold for the primary treatment of painful bone metastasis? • Stereotactic body radiation therapy (SBRT). • Dosage and target delineation yet to be fully defined • Given under clinical trials and should not be the primary treatment of vertebral bone lesions causing spinal cord compression.
  • 84.
    • Aims atidentifying who may achieve more durable pain relief or overall failure-free survival with SBRT. • Late toxicities can occur such as : o Radiation myelopathy – in previously untreated patients o New or progressive vertebral compression fractures o Esophageal and bronchial problems
  • 85.
    4) When shouldhighly conformal radiotherapy be considered for re-treatment of spine lesions causing recurrent pain? • No definitive data to specify the proper patient selection criteria. • Re-treatment to spine lesions with SBRT may be feasible, effective, and safe. • Limited to the setting of clinical trial participation • No evidence of superiority of SBRT over conventional EBRT with respect to pain control. • May lead to unexpected side effect risks.
  • 86.
    3-Reirradiation of recurrentbrain tumors. *The current standard of care for glioblastoma multiforme (GBM) is radiotherapy with concurrent and adjuvant temozolomide. *This is associated with a5-year overall survival of 9.8% versus 1.9% with radiotherapy alone. *Because of the infiltrating nature of gliomas, they frequently recur and despite an increase in survival rates the majority of patients progress within 1–2 years. *With regards to anaplastic astrocytomas and low grade gliomas the time to local recurrence is longer, but the majority ultimately also recur.
  • 87.
    *Salvage therapy isindicated in the majority of recurrent gliomas, and most patients receive chemotherapy or surgery at relapse *Re-irradiation for brain tumours is now attracting more interest as our understanding of the tolerance of the brain evolves. *Developments in radiation technology and imaging also mean that highly accurate targeting of biologically relevant tumour volumes is possible.
  • 88.
    The Biology ofLate Central Nervous System Toxicity: CNS toxicity following irradiation has been divided into three phases:- 1-early (days–weeksafter), 2-early delayed (1–6 months after and includes somnolence syndrome and Lhermitte’s phenomenon due to transient demyelination) 3-late (greater than 6 months following irradiation). Early and early delayed toxicities are normally reversible and spontaneously resolve whereas late toxicity is normally progressive and irreversible. Late injury is characterised pathologically by demyelination, vascular changes and ultimately necrosis
  • 89.
    Evidence for Re-irradiationusing various techniques 1-Conformal Radiotherapy 3D conventional radiotherapy using co-registered magnetic resonance imaging (MRI) has improved target definition and allows for a reduction of the dose to normal structures. Further developments such as IMRT (intensity-modulated radiotherapy) can improve this further by conformality at the target using multiple-modulated beams. For re-irradiation, the aim is not only to treat the area of recurrence with an adequate margin, but also to reduce as much as possible the total dose to critical organs at risk within the CNS, as, optic nerves or brainstem, making highly conformal
  • 90.
    CT and MRI-fusedplanning images for a patient treated for a recurrent glioma. 10 years previously treated with 55 Gy in 30 fractions over 6 weeks. Re-irradiated with 30 Gy in 6 fractions over 2 weeks. CTV contrast enhancing volume on T1-weighted MRI. PTV = CTV ? 0.5 cm margin
  • 91.
    Image showing 4-fieldconformal radiotherapy axial plan for the same patient
  • 92.
    2-Stereotactic Radiosurgery/Fractionated Stereotactic Radiotherapy:- Stereotacticradiosurgery (delivered using the Leksell Gamma Knife, adapted linear accelerators, Cyber Knife and other devices) is a non- invasive, highly conformal radiotherapy technique. It allows very accurate dose delivery with the patient in a fixed head frame and multiple beam sources producing a steep dose gradient at the edge of the target, therefore allowing a highly precise dose to be delivered to tumour whilst sparing the surrounding normal tissues and organs at risk.
  • 93.
    57-year-old patient withrecurrent glioblastoma of theright temporal lobe anterior to the surgical resection cavity. The targeted volume was 12.3 ml. The patient was treated with SRS to a dose of 18 Gy prescribed to the 90% isodose line
  • 94.
    3-Brachytherapy Most studies inthe brain have used 125I or 192I. Placement of multiple sources of radiation around the surgical cavity is technically challenging to ensure an adequate and even dose distribution.
  • 95.
    Dose and delineation Mostrecurrent glioma patients will have received the equivalent of 55–60 in 1.8–2 Gy per fraction when they were initially treated, and therefore not more than 40 Gy equivalent in a hypofractionated regimen should be delivered when re- irradiating, aiming to keep the total dose less than 100 Gy To optimise the outcome of radiotherapy treatment, improved target definition is of paramount importance. In this context, alternative biological imaging may improve the definition of the relevant target; for example, Amino Acid PET (SPECT)/CT/MRI image fusion to determine the gross tumour volume are currently under investigation.
  • 96.