TBI.ppT . DR ANJALIKRISHNA , PG RESIDENT AIIMS GKP

TOTAL BODY IRRADIATION

1. Total Body Irradiation(TBI) Dr ANJALIKrishna NP PG ReSIDENT Dept of RadiOTHERAPY AIIMS GORAKHPUR

2. Overview Concept Indications Doses Pre-requisites of TBI Performance of TBI in CMC Treatment Planning Toxicity Total Marrow Irradiation

3. History of TBI Year Event 1907 X ray Bath 1940-1950 Lymphoma/Solid tumors with disseminated disease 1960 First exploration of BMT- Nobel Laureate E Donnall Thomas 1970-1980 TBI with low dose 1977 TBI Myelo abalative 2005 Total Marrow Irradiation

4. Definition When radiation is given in a way to cover the whole body, is called total body irradiation, or TBI.

5. TOTAL-BODY IRRADIATION—RADIOBIOLOGY 5

6. Radiobiologic Effects on the Normal Hematopoietic System Successful hematopoietic stem cell engraftment requires: (a) Eradication of the recipient bone marrow. (b) Immunosuppression to prevent rejection of donor stem cells in the case of an allo -SCT . (c) relative sparing of the recipient’s bone marrow stromal cells. 6

7. Concept of TBI One of main component in interdisciplinary treatment of hematological malignancies Enables myeloablative high dose therapy (HDT) immunoablative conditioning therapy prior to stem cell transplantation

8. High dose Therapy (HDT) Intensive chemotherapy High dose Total Body Irradiation (TBI) Transplantation of HLA compatible blood or marrow stem cells (HSCT), and Supportive care under sterile conditions during the aplastic phase .

9. Myeloablative therapy: The irreversible elimination of the clonogenic malignant cells - therapeutic task of high dose TBI in treatment.

10. Immunoablative conditioning treatment: The induction of immuno-suppression is the conditioning task of TBI in allogeneic haematopoietic stem cell transplantation to enable successful engraftment .

11. Indications Certain indications: Leukaemias in adults and childhood : - Acute lymphoblastic leukaemia (ALL), - Acute myeloid leukaemia (AML), - Chronic myeloid leukaemia (CML), - Myelodysplastic syndrome (MDS). Optional indications: Solid tumors in childhood: - Neuroblastomas - Ewing sarcomas - Plasmocytomas / multiple myeloma. In clinical test: - Hodgkin`s disease - Non-Hodgkin`s lymphomas

12. Dose used in TBI High Dose TBI Low dose TBI

13. High Dose TBI Prescription:  4-10Gy in single fraction 10-14Gy in 8 fractions Typically delivered BID (twice daily) Intent:  Immunosuppression Killing lymphocytes and destroy bone marrow reduces graft rejection in bone marrow transplant. Associated Diseases:  Aplastic Anemia 13

14. High dose TBI- Dose prescription Disease Dose Fractions Dose Rate Reference AML ALL CML Lymphoma MM 13.2 Gy 8 # , twice daily 10 cGy /min Dusenbery et al. (Minnesota) 13.5 Gy 6 #, twice daily 3.25cGy/min Blaise et al. (GEGMO) 12 Gy 6 #, twice daily NR Clift et al. (Seattle) 10-12 Gy 1-8 times/day 3.25cGy/min Devergie et al. (SFGM) 8 Gy 4 # Not mentioned Moreau et al. (IFM)

15. Low Dose TBI Prescription:   2Gy in single fraction Intent:  Cytoreduction Associated Diseases Eliminating malignant cells : Leukemias Lymphomas Eliminating cells with genetic disorders : Fanconi’s Anemia Thalessemia Major 15

16. Low dose TBI- Dose prescription Disease Dose Fractions Dose Rate Reference AML CML Lymphoma MDS 2 Gy 1 Fraction 7 cGy /min Hegenbart et al. 5.5 Gy 6 #, twice daily 27.6 – 36.4 cGy /min Hallemeier et al 4 Gy 1 fraction NR Schmid et al. 2.5 Gy 2 #, twice day NR Badros et al. (Arkansas)

17. Pre- requisites for TBI Interdisciplinary approach Radio-oncologists, medical physicists and haemato-oncologists RT and transplantation must be in same centre Conditions with a low risk of infections is recommended

18. Position Patient lies supine Length of patient - not more than 140 cm If length greater than 140 cm – legs folded with pillow tucked between both legs Arms flexed and placed near to chest wall Knees adjoined together, wrapped Positioned at extended SSD of 300 cm

19. Total body irradiation (TBI) stand . A stand is commonly used to help position patients for TBI with photons and electrons. Common features of TBI stands include : handgrips and a seat to help support the patient. (B) the harness used to prevent the patient from falling in the case of fatigue and/or fainting. (A taken at University of Virginia, December 2011. B, courtesy of Radiation Products Design, Inc) 19

20. POSITIONING DURING TBI The patient lying on the side - utilizing opposing beams at large distance (4-6 m).

21. Measurements Skull Neck Shoulder Chest Abdomen Thigh Knee Calf Ankle

22. Higher energy is generally improves homogeneity. Source: AAPM TG-29

23. Target volume All malignant cells including those circulating as well as the whole cellular immune system. The Whole Body, including Skin Organs with a high risk of recurrence (“homing phenomenon”) & meninges, testes, may require additional local radiotherapy.

24. Treatment Planning AIM – homogenous high dose delivery with sparing the organs at risk

25. Dose specification The total dose to the target volume Reduced dose to the lungs The number of fractions The lung dose rate.

26. Dose ref points The dose reference point (+) for dose specification to the target volume is defined at mid abdomen at the height of the umbilicus according to an international consensus

27. Dose reference points D reference, Target Vol Lung Ref pt

28. The dose reference points (∗) for lung dose specification are defined as mid points of both lungs. The lung dose is defined as the mean of the dose at both lung reference points. Corresponds to the minimum dose to the lungs.

29. Prescription of dose and fractionation of TBI No general recommendation can be given. 12 Gy in 6 fractions – considered standard PETERS LJ (1980) : The radiobiological bases of TBI. Int J Radiat Oncol Biol Phys 6: 785. Single fraction TBI - too many complications have been observed. In fractionated TBI the total dose ( DRef ) has to be increased by 20-25 % compared to single fraction irradiation.

30. Radiobiology of TBI SF2 calculated for leukemia for 7 x 2 Gy regimen Range of 10 -2 to 10 -21 Average case – median of 10 -5 clonogenic cells are eliminated which corresponds to residual disease after good remission T E Wheldon : Radiobiological basis of TBI. The British Journal of Radiology, 1997

31. Calculation of Mid-plane dose Based on umbilical level separation Parallel Opposed lateral Beams Dose per fraction MU = ___________________ DR at Ext SSD * PDD ( Ud )

32. Does treatment with this MU s alone deliver homogeneous dose to entire body ?

33. Optimization of Dose The homogeneity of dose in the target volume The effective sparing the lungs

34. DOSE MODIFIERS Influences of irregular body contours have to be compensated. For bilateral TBI - a tissue compensators are used in front of and next to head, neck and legs.

35. TBI AAPM Report 17

36. Calculation of compensator thickness HVL _________ * ln Io/I 0.693 Thickness (t) = I = I o e - m t

37. 2. Increasing the dose to parts of the target volume For build-up, for higher energy photons : scatter screen (spoiler) has to be positioned close to the patient. In long term irradiation, remotely positioned dose modifyers are not recommended due to repositioning and increased verification problems .

38. 3 . Dose homogenization in parts of the target volume with reduced dose : Thoracic wall receives a lower dose due to lung shielding. Additional irradiation however is not used. Equivalent homogeneous dose is reduced by only 5% (1-7%), e.g. from 12 Gy TBI dose with 9 Gy lung dose to 11.5 Gy equivalent homogeneous dose – probability of cell kill is not reduced

39. 4. Fluence flattening Fluence modifying techniques can be used for dose homogenization E.g. in wide angle collimator or sweeping beam TBI or a wedge filter for oblique incidence of the beam.

40. Sparing the lungs 1. Dose reduction in the lung: To 80% of the prescribed target dose Primary radiation fluence had to reduced by 60-70 %. Shape and thickness of sheilds must be planned Skin-fixed shieldings : stacks of lead rubber cut-outs, lead-moulds or stacks of thin lead sheets (for high energy photons, the lead has to be covered by low density material). 2 . Reduction of dose rate: For accelerators: A Lower dose rate

41. Treatment delivery Delivered in the position which measurements are taken. Under sterile conditions . In vivo dosimetry is done on first day with Semiconductor diodes.

42. Other modalities of TBI

43. Immediate Toxicity Symptom Single fraction TBI Fractionated TBI Nausea& Vomiting 45 43 Parotid gland pain 74 6 Xerostomia 58 30 Headache 33 15 Fatigue NR 36 Ocular dryness 16 NR Esophagitis NR 4 Loss of apetite NR 16 Erythema NR 41 Pruritis NR 4 Diarrhea NR 4 Fever 97 NR

44. Late toxicity Salivary glands (22%) – Xerostomia , dental caries, tooth abnormalities Pneumopathy(10-20%) – Doses greater than 9.4 Gy and single dose TBI increase risk. Cardiac toxicity (2-3%) – Rare, in pts who had anthracycline based chemotherapy Hepatotoxicity / Venoocculusive disease (70%) – doses greater than 13.2 Gy Catracts - MC complication. Asso . steroid use and cranial irradiation Kidney Dysfunction - 17% Hypothyroidism – 25 % Growth abnomalities in children Sterility and endocrine abnormalities Secondary MDS or AML ( 1 % at 20 months and 24% at 43 months)

45. Targeted TBI – TMI and TMLI Total marrow irradiation TMI skeletal bone. Conditioning regimen for multiple myeloma. Total marrow and lymphoid irradiation (TMLI) bone, major lymph node chains, liver, spleen, and sanctuary sites, such as brain. Conditioning regimen for myeloid and lymphoid leukemias.

46. Colour wash for tomotherapy planned TMI

47. DVH curves for TMI

48. Advantages of TMI Escalate the dose to bone (& containing marrow) up to 20 Gy , while maintaining doses to normal organs at lower levels than in conventional TBI to 12 Gy . Jeffrey Y. C. Wong et al. Targeted Total Marrow Irradiation Using Three-Dimensional Image-Guided Tomographic Intensity-Modulated Radiation Therapy: An Alternative to Standard Total Body Irradiation, Biology of Blood and Marrow Transplantation 12:306-315 (2006)

49. OVERVIEW Total Body Irradiation (TBI) involves giving a high uniform dose to the whole body using photon fields and is the subject of AAPM Task Group 29. TBI is most commonly prescribed as preparation for hematopoietic cell transplant (HCT) commonly referred to as bone marrow or stem cell transplant. TBI improves HCT by suppression of the immune system, thereby reducing the likelihood of  Graft Versus Host Disease . TBI is also able to eradicate the malignant hematopoietic cells or those effected by genetic disorders. 49

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