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Gowtham's 3rd radiobiology
This document discusses the clinical response of normal tissues to radiation. It begins by explaining the inherent radiosensitivity of different tissues based on Casarett's and Michalowski's classifications. It then discusses the kinetics of normal tissue radiation injury, including acute, subacute, late responses. It explains how tissue organization into functional subunits and volume effects impact the response. The document outlines factors like regeneration and retreatment tolerance. It briefly introduces quantitative guidelines from projects like QUANTEC and LENT/SOMA for evaluating normal tissue effects from radiation therapy.
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Gowtham's 3rd radiobiology
- 1. Clinical Response of NormalTissues Presenter : Dr. Gowtham Manimaran Moderator : Dr. Charu Garg
- 2. Contents Concepts – Molecularand cellular aspects Introduction Inherent tissue Radiation sensitivity - Casarett’s Classification - Michalowski’s population Kinetics of Normal tissue Radiation injury - Acute , Subacute, Late responses Tissue Organisation - Functional subunits(FSUs), Volume effects Regeneration Retreatment - ‘Remembered’ dose QUANTEC , LENT , SOMA
- 3. Cell death • Majorand desired outcome of RT is cell death but occurs in several different ways. • Final cellular outcome of RT will depend in part upon how cells and tissues “perceive damage” through internal and external sensors (hypoxia , cytokines, cell-cell , cell -matrix interactions) Mitotic death Apoptosis Necrosis Autophagy Senesence
- 4. Growth Factors • IL-1 acts like radioprotectant of hematopoietic cells • TNF cytotoxic agent , protects hematopoietic cells and sensitises tumour cells to radiation (regulated at transcription level ) • Basic fibroblast growth factor induces endothelial growth , inhibits radiation induced apoptosis and confers protection against microvascular damage. (produced more in larger blood vessels in response to stress ) • PDGFincreases damage to vascular tissue • TGF ß fibrosis , related late changes are attributed to it , they downregulate IL-1 , TNF and may cause increase damage to hematopoietic stem cell. (high systemic levels have shown to critically impact outcome)
- 5. Bystander effects • Radiation-inducedbystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. • These effects include DNA damage, chromosomal instability, mutation, and apoptosis.
- 6. Abscopal effects • Localanticancer radiotherapy may have not only delayed effects but also distant ones • Treatment directed at a tumour at one site can in fact profoundly affect tumours at other locations in the body through an effect which R.J. Mole described more than 60 years ago as the abscopal effect • Due to activation of antitumor immune response involving adaptive immunity.
- 7. Introduction • Effects ofradiation on normal cells is either by their killing action (by direct DNA damage ) or other mechanisms like cytokine mediated , adaptive immunity related ,cell signalling pathways . • Normal tissue - complete integrated structure , balance between cell death and birth • Response to damage governed by 1. Inherent cellular radiosensitivity 2. Kinetics of the tissue 3. The way cells are organized in the tissue
- 8. 1. Inherent tissueradiosensitivity • Radiosensitivity of various tissues have been studied in detail based on histopathological observations. • Radiosensitivity vs radioresponse • G2-M phase most sensitive phase to radiation (especially M phase) • This gave rise to several classification systems, Casarett’s classification Michalowski’s classification
- 9. Casarett's Classification ofMammalian Cell Radiosensitivity
- 10. Exception : • Smalllymphocyte : They defy all laws and systems of classification They are believed to never divide at all but they disappear from blood even after very small doses of radiation
- 11. Michalowski Classification Tissues followeither a hierarchical (H) or flexible (F) model Within tissues 3 distinct categories of cells Stem cells continuously divide and reproduce to give rise to both new stem cells and cells that eventually give rise to mature functional cells. Functional cells, which are fully differentiated; they are usually incapable of further division and die after a finite life span, though the life span varies enormously among different cell types. Example- circulatory granulocytes Between these two extremes are maturing partially differentiated cells ; these are descendants of the stem cells, still multiplying as they complete the process of differentiation. In the bone marrow, for example, the erythroblasts and granuloblasts represent intermediate compartments
- 12. H-type & F-typepopulations • Hierarchical (H-type) populations- The cell types that progress from the stem cell through the mature cell with nonreversible steps along the way Eg: bone marrow, intestinal epithelium, epidermis. • Flexible tissue(F-type) populations- The cell lines in which the adult cells can under certain circumstance be induced to undergo division and reproduce another adult cell. Eg: include liver parenchymal cells, thyroid cells and pneumocytes. • Many tissues are hybrids of these two extreme models with most cells able to make a few divisions and minority behaving as stem cells
- 13. 2. Kinetics ofnormal tissue • Rate of tissue turnover i.e (rate of loss vs regeneration) is as important as size of dose per fraction for defining response to radiation. • Tissues dose responses are characterised by their different a/ß ratios (Late effects more sensitive to changes in fractionation than early effects) Early effects Consequential late effects Subacute Late effects
- 14. Acute Responses/effects • Early(acute) effects result from death of large number of cells and occur within a standard of 6-8 weeks / even days after irradiation in tissues with rapid rate of turnover • Repaired rapidly because of rapid proliferation of stem cells • May be completely reversible Examples: • Epidermal layer of skin • Gastrointestinal epithelium • Hematopoietic system • Severity of acute injury increases with dose
- 15. Consequential late effects •A severe acute radiation may deplete the complete stem cell population leading to nonspecific late (consequential) changes which may remain as a chronic injury . Eg: 1. stenosis as a consequence to mucosal ulceration of the bowel (unable to regenerate heals by fibrosis) 2. Bone marrow suppression following intense fractionation 3. Fibrosis /necrosis of skin consequential to early reaction of desquamation
- 16. Subacute effects • Occurringduring 3 months to 6 months of completion of Radiation treatment • Symptoms often reversible but might progress to severe damage and even death • Eg: Lhermitte syndrome ,Radiation pneumonitis
- 17. Late effects • Occurringeven after 6 months of completion of Radiation treatment. • Eg: Lung, Kidney, Heart, Central nervous system • The damage might improve but never completely repaired and are mostly fatal • Late effects are more sensitive to increase in dose per fraction • An issue of growing clinical importance ! – can it be reversed/treated ? Eg: Captopril , an ACE inhibitor has shown to slow radiation nephritis and lung fibrosis in rats • Reflection of dysregulated immune homeostasis – reestablising it is the only way for complete treatment
- 18. 3. Tissue organisation •FSU (Functional subunits) - Defined as a tissue unit able to recover from one surviving clonogen. • FSUs depends on survival of one or more clonogenic cells within them and tissue survival in turn depends on the number and radiosensitivity of these clonogens. 1. Structurally defined FSUs: Ex : Kidney Nephrons are the FSUs , but dose tolerance for kidney depends more upon the number of tubule/stem cells per nephron than the number of nephrons Other examples with clear demarcation are : salivary glands, pancreas , sweat glands , mammary epithelium , spinal cord , nerve tracts 2. Undefined FSUs: Ex: Dermis , mucosa , gut epitheliumclonogenic cells can migrate between FSUs • Exception : Jejunum
- 19. Serial organs : •complications occur even when small segments of the organ are damaged. Ex: Spinal cord , brain stem , optic nerve ,chiasma Parallel organs : • sub-volumes of the organ function relatively independently • Complications develop when critical volumes are injured.Hene the volume of tissue exposed to radiation is more important Ex: Lungs , liver , kidney
- 20. Volume Effect in Radiotherapy •Traditionally , we reduce total dose when treating large volumes of normal tissue • In reality , the concept of decreasing dose with increasing volume has little radiobiologic basis , except in specific circumstances • Ex :Tissues with FSUs arranged in series like spinal cordloss of one FSUs may result in a state of injury irrespective of the other FSUs
- 21. Other Volume effects: (not related to cell death) • A small area of injury is tolerated better than a large area of the same severity. Pain, fluid leakage, and inflammation worse, healing slower • Dose heterogenecity across the field. • If organ “reserve” is obliterated as volume is increased (e.g., lung, salivary gland). This is not a true volume effect because sequelae are determined by the volume and functional status of the tissue excluded from the treatment volume, not the volume irradiated.
- 22. Regeneration • In acuteresponding cells , repopulation starts early because cell loss in rapid. • The current standard protracted treatment times confer a benefit by allowing regeneration of acute responding tissues. • When attempts are made to accelerate treatment , acute responses become more severe and dose limiting. • Mitigators of radiation damage capable of accelerating recovery are being used Ex: G-CSF, GM-CSF ,KGF (keratinocyte growth factor)
- 23. Tolerance to retreatment •According to conventional wisdom , heavily irradiated tissue cannot be retreated because of irreversible vascular damage • But although prior RT may decrease tissue tolerance , retreatment is often possible and may be better tolerated . • Factors determing : Tissue at risk Amount of initial cell depletion Time elapsed since treatment extent of regeneration
- 24. QUANTEC Quantitative Analysis ofNormal Tissue Effects in the Clinic Published in the International Journal of Radiation Oncology, Biology, and Physicsin 2010 (IJROBP) 64
- 26. Implications of QUANTEC •Different mechanisms for radiation-induced injury in different organs • Serially arranged organ have steep dose–response curves at doses beyond an apparent critical threshold • Several neural structures exhibit a similar threshold dose for injury,so there is common mechanism of injury • Organs that are classically considered structured in parallel (e.g., lung, liver, parotid, and kidney, analogous to electrical circuits) experience injury at far lower doses and have more gradual dose–response curves compared to series organs • QUANTEC better quantify the relationship between dose –volume parameters and clinical outcomes. 66
- 27. LENT AND SOMA •European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG), formed working groups to update their system for assessing late injury to normal tissues • This led to the Late Effects of Normal Tissue (LENT) conference in 1992This conference led to the introduction of the SOMA • SOMA is an acronym for subjective, objective, management criteria with analytic laboratory and imaging procedures
- 28. Central Nervous System- SOMA62
- 29. LENTand SOMA ScoringSystemand Grading Categories Grade I Grade II Grade III Grade IV Subjective (pain) Occasional and minimal Intermittent and tolerable Persistent and intense Refractory and excruciating Objective (neurological defect) Barely Detectable Easily Detectable Focal Motor sign, vision and disturbances Hemiplegia, Hemisensory defect Management (pain) Occasional nonnarcotic Regular nonnarcotic Regular narcotic Surgical intervenrion Analytic (CT, MRI, Lab Tests)
- 30.
Editor's Notes
- #4 Mitotic death after irradiation was observed first in 1956 by Puck and Marcus.Most commonest type of cell death. M phase, chromothripsis can catastrophic shattering event Apoptosis – interphase death ex :lymphocytes , salivary gland , thyroid , intestinal crypts (not always intrinsic (bax , bak) also with extrinsic (TNF , death domain) Necrosis – cell membrane integrity lost , cells swell , lysosomal enzymes released necroptosis (TNF alpha) , pyroptosis (IL-1 BETA, IL -18) Autophagy – seen in nutrition deprivation , internalise their own cellular organelles Senescence – production of antiproliferative cytokines like IL 6 , TDG BETA-->collagen formation leading to long standing effects
- #6 Mothersill et al.6,7 These findings suggest that the direct effect of fractionated radiotherapy would be to spare the tissues receiving the direct dose, whereas the unirradiated cells that receive signals from nearby irradiated tissue would respond to each fraction as a unique dose. As a result, over a very large dose range, fractionating the dose does not result in any sparing effect for adjacent cells that receive bystander signals rather than direct doses. Again, this effect would be likely to negatively affect the therapeutic ratio. For this reason, it is essential to evaluate the effect of fractionating doses in an in vivo model.
- #10 Vegetative Intermitotic Cells.(VIM)-Undifferentiated rapidly dividing cells which generally have a quite short life Differentiating Intermitotic Cells (DIM)-Actively mitotic cells with some level of differentiation. Spermatogonia are a prime example as well as midlevel cells in differentiating cell lines.Have substantial reproductive capability but will eventually stop dividing or mature into a differentiate cell line Reverting Postmitotic Cells (RPM)-Does not normally undergo division but can do so if called upon by the body ex :liver , kidney Fixed Postmitotic Cells (FPM) Most resistant to radiation Highly differentiated and lost ability to divide May have long (neurone) and short life span (granulocyte)
- #11 Clinically lymphopenia caution of adding prophylactic antibiotics (trimethoprim–sulfamethoxazole (TMP/SMX) –gastric tolerance and broad spectrum) They die an interphase death
- #17 Lheremitte syndrome – after spinal cord irradiation , due to diffuse demyelination Radaition pneumonitis -Radiation pneumonitis: Atypia of type II pneumocytes Alveolar wall edema Infiltration of inflammatory cells in the interstitium Aggregation of alveolar macrophage Hyaline membranes lining alveolar ducts and alveoli Pathophysiology Two separate and distinct mechanisms are involved in the pathogenesis of acute radiation pneumonitis. The first, classical radiation pneumonitis, involves direct toxic injury to endothelial and epithelial cells from the radiation. The accumulation of leukocytes distorts the normal alveolar structures resulting initially in an acute aveolitis at the site of radiation. The alveolar macrophage is thought to play a central role in the subsequent development of fibrosis. The second mechanism, sporadic radiation pneumonitis, results in an "out-of-field" response. This is thought to be an immunologically mediated process resulting in bilateral lymphocytic aveolitis.
- #18 Caution for late and subacute !!! – because both appear after completion of treatment mostly hence dose adjustment is obviously not an option Now a days due to advances in medicine average life span has increased which also a reason for apparent increase in late effects!!
- #19 Definition of clonogenic cell – a survivor that has retained its reproductive ability and is able to proliferate indefinitely to produce a large colony of clones are called clonogenic. Crypts of jejunum (structurally well defined but surviving crypts can/do migrate from one crypt to another to repopulate depleted neighbors
- #20 DVHs do not represent all organ-specific spatial radiation dose information, hence assume all regions are of equal functional importance, and they often do not consider fractionation schemas. Spinal cord conventional : 45-50 Gy Optic Chiasma and nerve : Dmax <55 Gy B/L whole kidney - Dmean < 15-18 Gy - V12 < 55% , V20 <32% , V23 <30% , V28 < 20%
- #21 Curve A relates to a normal tissue in which the functional subunits are not arranged serially regardless of whether one or all subunits are exposed (i.e., regardless of field size). It also applies to a normal tissue in which functional subunits are arranged serially if only one subunit is exposed (i.e., if the field is small). Note that the curve is relatively shallow (i.e., the probability of a complication rises relatively slowly with dose). Curves B and C refer to a tissue with serially arranged functional subunits; the complication curve gets steeper and moves to lower doses as the treatment field size increases.
- #22 Increased toxicity with bleomycin, cyclophosphamide
- #23 KGF – palifermin60 ug /kg/day GM-CSF SARGRAMOSTIM , REGRAMOSTIM G CSFpegfilgastrim , filgastrim
- #24 (high prior doses , a short interval , slow regeneration will reduce retreatment toelrance)