Rt in lymphoma

1. By Dr. Rajib Bhattacharjee RT in LYMPHOMA

2. RT in Non Hodgekin's Lymphoma

3. Non Hodgkin's lymphoma - Definition Heterogenous group of lymphoid malignancy other than Hodgekins lymphoma , acute or chronic lymphocytic leukemia, and the immunoglobulin synthesising lymphoproliferative disease like multiple myeloma, Waldenstroms macroglobulinemia, heavy chain disease, hairy cell leukemia and is charecterised by abnormal clonal proliferation of B cells, T cells and NK cells

4. lymphocytes the rule bender Normally, radiosensitive cells die a mitotic death and cells that devide less are radioresistant but Lymphocytes seldom devides Lymphocytes die an interphase death still Lymphocytes are one of the most radiosensitive cells

5. Lymphomas are sensitive Lymphomas are uniquely sensitive to ionising radiation. Sensitivity of the tumor exceeds that of the sarrounding normal tissues. Larger radiation fields can be used

6. Dose of RT when used alone Experiences in Stanford, Princess Margaret Hospital and University of Florida. DLBCL- For medium and large bulk disease- 40Gy @ LCR of 80% For smaller vol- LCR > 90% with lower dose FL- Low grade- 30 Gy @ LCR > 90% High grade- 30-50 Gy @ LCR > 95% (Tumor size > 6cm 40 Gy as CMT) (Small tumors- 30 Gy is not required

7. RT dose as a part of CMT CMT- RCHOP/CHOP RT Experience of the Vancouver group, MDAnderson, Krol et al, Duke university as well as the BNLI phase III data indicates Optimal RT dose as CMT 30 Gy PET +ve disease post CT 40 Gy

8. WHO classification of mature Lymphoid Neoplasms

9. Most common Histologic types DLBCL 33% FL 22% MZL 10% PTCL 10% CLL/SLL 7% MCL 7%

10. The Ann Arbor/Cotswolds staging classification

11. INTERNATIONAL PROGNOSTIC INDEX (IPI) International NHL Prognostic Factors Project Factors Included: Age > 60 years Stage III to IV > 1 Extranodal Site Performance Status 2 LDH > normal

12. DLBCL Stage I & II RCT EVALUATING CONSOLIDATION RT IN EARLY STAGE DLBCL

13. DLBCL Stage III & IV DLBCL Bulky disease CR with CHOP RT(40-50 Gy) No RT (To prior sites of bulky ds) 72% FFS 35% 81% OS 55% #Aviles et al MD Anderson showed CMT produced improved LCR(89% vs 52%) , PFS(85% vs 51%) but there was no effect on OS (87% vs 81%)

14. FL Stage I & II Radiation therapy-selected phase II trials

15. Conclusions High 5 & 10 year OS 75% - 90%. Early deaths from lymphoma were rare. Low FFS 40% - 80%. FFS was better in stage I disease. LCR > 90% with doses of 24-30 Gy Field sizes No evidence of improved survival with increased field size. Long median survival. Leading cause of death Relapse

16. FL Stage III & IV Advanced FL (n=118) CVP IFRT No RT @ involved nodal sites (35-45 Gy) 66% FFS 33% 80% OS 40% #Aviles et al FL Stage III (n=66) TLI(n=61) TBI(n=5) Dose - 40-48 GY FFS CSS OS 35% 58% 35% Limited stage III disease FFS CSS 88% 100% #Stanford

17. Radioimmunotherapy I-131 Tositumomab Yttrium-90 Ibritumomab beta & gamma emitter beta emitter Both are FDA approved. Effective in chemo and rituximab resistant cases.

18. Extranodal MZL MALT Lymphoma Very responsive to RT Dose 30 Gy LCR OS FFS (@ 5 years) 97% 96% 76% Lymphocyte homing B/L organ involvement Treatment - local RT to both paired sites

19. Other histologic types Localised PTCL Localised SLL Localised MCL CT f/b RT RT RT (40 Gy) (30 Gy) (30-35 Gy)

20. Dose summery

21. Stem cell transplantation Autologous & Allogenic HDC with Autologous stem cell rescue Allogenic SCT additionally mounts an immunogenic attack on malignant cells TBI conditions the patient for subsequent transplant Indications in NHL DLBCL- High risk DLBCL- Relapse or refractory FL- Relapse

22. Total Body Irradiation Utility Immunosuppression (lymphocytic cell kill) to allow engraftment of donor marrow Eradication of malignant cells ( Leukemia, lymphomas, & some solid tumors) Eradication of cell population with genetic disorders ( e.g. Fanconis anemia, Thalassemia major)

23. Treatment aids Special TBI stands or tables are often used to aid in immobilization, placement of organ shields, and patient support and comfort

24. Treatment program Myeloablative treatment program fractionated or hyperfractionated regimens over days decrease toxicity & treatment time Dose 10-13.5 Gy; 1.2-2 Gy/# once or twice a day Shielding checked with portal images Non myeloablative treatment program Dose - 2 Gy in a single #. Shield - not required.

25. Principles The higher the energy, the lower the dose variation (excluding the effects of the build-up region and tissue inhomogeneities). The larger the treatment distance, the lower the dose variation. The larger the patient diameter, the larger the dose variation.

26. Principles AP/PA treatment yields a variation not larger than 15%. Lateral opposed beams exhibits a greater dose variation The radiation dose delivered throughout the patient body varies mainly due to the variation in patient thickness. Dose non uniformity within 10% of the prescription dose desirable for best clinical results.

27. AP/PA Technique (MSKCC) Patient in standing position Shielding and boosting possible SSD - >3 m The shielding on acrylic box tray at short distance from surface The tray (1cm thick) also act as beam spoiler to build up skin dose Poor reproducability

28. Treatment room

29. Technique AP/PA Field 2 cm PMMA(Perspex) screen Anterior field- patient faces the machine Posterior field- patient faces the wall Individualized lead lung compensators Paraffin jelly bolus bag around the neck

30. DOSIMETRY Doses are measured during 1st # All TLDs only on anterior surface except chest TLDs Gives entry & exit doses

31. Lateral field technique (Duke university) Position- sitting Lateral parallel opposed fields Arms resting by the side- shadow the lungs Aluminium compensators for head, neck, lungs & neck

32. Pros & cons TBI Techniques AP Technique Lateral field technique Advantages Minimizes patient thickness at central axis of the beam Easy set up Comfortable for patients disadvantages Poor reproducability Lung blocks needed Dose inhomogeneity Lateral tissue effect

33. Reduced intensity conditioning regimen In the 1990s, feasibility of reduced-intensity conditioning (RIC) regimens consisting of lower-dose TBI and/or udarabine considered Cytotoxic effect from such regimen is minimal tumor cell death mainly due to graft vs tumor effect McSweeney et al. employing 2 Gy delivered as a single dose, with or without udarabine, with cyclosporine and mycophenolate mofetil as GVHD prophylaxis in older patients # Blood 2001; 97: 33903400 Other group use 2 Gy, single-dose, low-dose rate (7 cGy/min) TBI in the setting of both related and unrelated donor transplantation # Blood 2004; 104: 961968. # J Clin Oncol 2005; 23: 19932003.

34. In a nutshell Myeloablative conditioning regimen in lymphoma Dose 10-13.5 Gy, 1.2-2 Gy/# once or twice a day Technique- Standing technique #MSKCC Sitting technique #Duke University translational technique Lung shield after 8-9 Gy Side effects- myelosuppression ovarian ablation male sterility cataract

35. RT in palliation Dutch trial indolent lymphoma (mostly FL) 4 Gy in 1-2 # ORR-92% CR-61% PR-31% Similar results in French trial Spinal cord compression 30 Gy in 2Gy/# Aggressive lymphoma 2Gy in 2# ORR- 50-80%

36. Primary extranodal lymphomas

37. Gastric DLBCL Radiation dose Surgical resection - 25 Gy Without resection - 30 50 Gy CR to CT - 30 Gy Persistant ds to CT 40 Gy Radiation field encompass the entire stomach and perigastric lymph node along with any other involved nodal areas. Field arrengement - Parallel opposed antero- posterior field.

38. Gastric MALT Lymphoma Indication H. pylori ve failure to antibiotic therapy Radiation dose -- 25 -30 Gy

39. Intestinal MALT Lymphoma Post operative WAI Radiation dose 20-25 Gy in 1-1.25 Gy/# CT based planning to save kidney & liver critical Cross table laterals for treatment of mesenteric adenopathy

40. Whole abdomen irradiation Indication widespread abdominal involvement stage II Technique parallel opposed anterior and posterior field. Border - Diaphragm to superior portion of pelvis or inferior portion of obturator foramen Shielding illiac bones, femoral head, right lobe of liver, kidney( >18 Gy) 3D Planning desirable

41. Head & neck lymphomas Waldeyers ring Thyroid Salivary glands Nasal cavity Paranasal sinus Orbit

42. Waldeyers ring CT f/b IFRT Salivary glands MZL RT alone Nasal cavity NK/T cell variety concurrent CT/RT Paranasal sinus CMT Radiation dose DLBCL CR- 30 Gy; No CR-30-40 Gy Indolent histologies RT alone @ 30 Gy NK/T cell 40-50 Gy + CT Field size Involved region with generous margin No prophylactic node irradiation

43. Orbital lymphomas Treatment principle MZL RT alone(20-30 Gy) DLBCL CT f/b IFRT(30 Gy) Field arrengements Entire orbit treated Single anterior field or wedge pair Lens shield to prevent cataract

44. Extranodal lymphomas of other sites Testes CT + IT MTx prophylaxis + RT to C/L Testes & para-aortic and pelvic nodes Bone DLBCL - CT f/b IFRT (30-40 Gy) Lung MZL(BALT Lymphoma) RT(20-30 Gy) DLBCL Incomplete resection CT f/b RT Breast DLBCL CT f/b whole breast RT(30 Gy) MZL/FL RT alone(26-30 Gy)

45. Primary CNS Lymphoma Historically treated with whole brain RT but produced poor results. Tumor initially responds but regrows. High radiation dose in the vicinity of 45 Gy produce unacceptable neurotoxicity MSKCC reduced the dose to 23.4 Gy for patients achieving CR to Rituximab & MTx based CT. OS 67% & PFS 57% Current treatment reccomendations High dose MTx + CT + Whole brain RT(24 Gy)

46. Primary cutaneous lymphoma

47. WHO-EORTC Classicication

48. ISCL/EORTC revisions to Mycosis Fungoidis staging

49. Mycosis fungoides-Treatment Skin directed therapys- Topical agents-corticosteroids, nitrogen mustard, bexarotene gel Phototherapy- narrow band ultraviolet B psoralen + UVA (PUVA) Local superficial irradiation

50. Local superficial irradiation Indication minimal disease Treatment fields entire lesion with 1-2 cm margin Treatment beam megavoltage electrons(6-16 MeV) or Orthovoltage X rays Treatment dose 20-40 Gy in 10-15 # Side affects mild darmatitis, local alopecia, pigmentation changes

51. Conventional RT 20 patients ( 110 lesions) RT for cutaneous MF Superficial X-ray, Co60, electron beam Plaque (50%), tumor3 cm(27%) # Cotter et al. ( IJROBP 1983;9 :1477)

52. Micaily et al. 18 patients with unilesional MF Local electron beam irradiation only Median dose 30.6 Gy 10 Yr relapse free SR = 86.2% 10 Yr overall SR = 100% #IJROBP 1998;9:475 TSEBT is not indicated for unilesional MF.

53. Indications of TSEBT TSEBT can be used in any stage of cutaneous lymphoma except minimal disease

54. TSEBT Only in major radiotherapy centers Aims to irradiate the patients whole skin With the prescribed radiation dose by proper choice of electron energy Dose to epidermis and upper dermis Sparing deep dermis & subcutaneous tissues First used by Trump et al using a van de Graaff generator. #Trump et al. Am J Roentgenol.1953;69:623 Stanford technique # Page et al. Radiology.1970:94;635

55. Current techniques of TSEBT Translational techniques patient is translated on a stretcher through an electron beam of sufficient width to cover the patients transverse dimensions; Large electron field techniques a standing stationary patient is treated at a large SSD with a single large electron beam or a combination of large electron beams; Rotational techniques patient is standing on a rotating platform in a large electron field.

56. Large electron field techniques Large electron fields produced by Scattering electrons through wide angles large treatment distances Field made uniform over the patients height Vertically combining multiple fields Vertical arcing Circumferential coverage of body surface 4-6 fields directed from equally spaced angle

57. Field flatness Low energy electron beam : considerably widened by scattering in air. E.g. 6 MeV narrow beam, after passing 4 m of air, achieves a Gaussian intensity distribution with a 50% to 50% width of appx. 1 m. By combining such fields at 50% isodose lines, large uniform fields can be created.

58. X-ray contamination Limiting factor in TSEBT Contributed by bremsstrahlung interactions Exit window of linac, scattering foil, ion chamber, collimators, air & the patient. Reduced by Modification of accelerator Angling beam 150 above & below horizon

59. Techniques Stanford technique Six fields (ant, post, four obliques) Positioned 600 apart around the patient Each field: 2 component with respect to horizon

60. Techniques Multiple field arc technique ( Minnesota) Beam describes an up-and-down arc Gantry rotates analogous to pendulum Advantage: dose uniformity along vertical plane Disadvantage: higher X-ray contamination # Sewchand et al. Radiology 1979;130:493

61. Modified Stanford Technique Six field technique Beam 6-9 MeV electrons Patient stands behind a polycarbonate screen Source to surface distance 4 m Cycles 2 days 6 positions 3 positions/day 2 Gy/cycle 2 cycles/week Positions day1- anterior, right posterior oblique, left posterior oblique day2- posterior, right anterior oblique, left anterior oblique

62. TSEBT Treatment positions

63. Modified Stanford Technique Dual field technique-superior & inferior field Dose: 36 Gy in 2 Gy/cycle, 2 cycles/week for 9 weeks (CR 94%) Treating 3 fields /day 4-day-per-week dose schedule Boost - 15-20Gy ;1-2Gy/# to soles of feet, scalp, perineum and inframammary area.

64. Dual field technique

65. Supplemental treatment Sites- scalp, perineum, soles Dose 20-28 Gy @ 4mm depth Beam- 120 KV superficial photon with HVL 4.2mm Al, or low energy electrons(6 MeV) with 1 cm bolus for sole & perineum Scalp angled electron reflector above the patient, or by supplimental boost. Thick cuteneous tumors & skin folds due to body habitus may require supplimental dose.

66. EORTC Technical reccomendations

67. TSEBT Side effects Acute-pruritus, cutaneous erythema xerosis, dry desquamation, edema, blister, alopecia nail changes, hypohydrosis, mucosal dryness, gynaecomastia(rare) Chronic-cataract, chronic xerosis dystrophic nails, seccondary skin cancers Prevention - blocking of eyes,lips,hands, fingernails,feet & testes

68. TSEBT stage T1 T2 T3 T4 Clinical efficacy CRR>90% Recurrence after TSEBT is usually

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