1. TREATING LYMPHOEDEMA WITH LOW LEVEL LASER THERAPY Sandy Anderson 1, Neil Piller 1, Colin Carati 2, Bren Gannon 2 and Ann Angel* 1 Lymphoedema Assessment Clinic, Flinders Surgical Oncology Unit, Flinders Medical Centre 2 Microcirculation & Lymphology lab., Department of Anatomy, School of Medicine, Flinders University, South Australia and *RIAN Corp., Adelaide, South Australia. ALOHA

2. Capillary Fluid Balance ( textbook) Fluid leakage at arterial end of capillary, (via many small & a few large pores)Fluid leakage at arterial end of capillary, (via many small & a few large pores) Fluid resorption at venous end of capillaryFluid resorption at venous end of capillary Despite large efflux & influx, Nett transcapillary fluid leakage is smallDespite large efflux & influx, Nett transcapillary fluid leakage is small Small Fluid loss  lnterstitium  lymph  venous circulationSmall Fluid loss  lnterstitium  lymph  venous circulation Dynamic centre Filtration Resorption Arterial Venous Net Pressure (kPa)

3. V in  V out vascular/ lymphatic causes Edema V in  V out * vascular/ lymphatic causes * while swelling; when fully swollen, new steady state where V in = V out  Pc  Pl   Pl J = K P [ P C - P IF -  (  Pl -  IF )] K P &   K P &    V out VENOUS BLOCK/  CVP ( femoral / axillary vein thrombosis, hepatic cirrhosis HYPOPROTEINEMIA (nephrotic syndrome, protein-loosing enteropathy plasma-pheresis, Starvation) CAPILLARY INJURY (burns, sepsis, toxins, allergy, hepatic vein block) LYMPHATIC BLOCK/ INSUFFICIENCY (filariasis, Milroy’s disease Lymphangioectasia, lymphangiocarcinomatosis

4. Lymphedema = edema due to lymphatic malfunction Excess fluid extravasation overwhelmes lymphatic reserve capacity Excess fluid extravasation overwhelmes lymphatic reserve capacityOR Reduced interstitial fluid removal due reduced lymphatic function Reduced interstitial fluid removal due reduced lymphatic function (May be both) (May be both) Imbalance results in swollen interstitium Imbalance results in swollen interstitium& NEW balance where input = output NEW balance where input = output (otherwise swelling continues to increase)

5. Lymphedemasymptoms: heavy, painful ? hot itchy infection-prone disfiguring (social isolation) (mild example)

6. Fluid Fluxes - Plasma, Interstitium & Lymph (after Renkin 1986; Am J Physiol 250:H 706-710 ) ~ 67% of initial lymph fluid is resorbed to plasma in lymph nodes

7. Lymphoedema -clinical >20% rate after surgical dissection of the axilla: breast cancer (♀ & ♂) the groin: cervical cancer : prostate cancer radiotherapy increases risk (? ~70%) W.H.O.  150,000,000 world-wide

8. Post Mastecomy Lymphoedema Mild case of postmastectomy lymphoedema “normal” limb

9. PML pathology axillary clearance +/- Radiotherapy reduces lymph transport ability cannot meet lymph load swollen arm (+/- local trunk) often requires a trigger (infection, burn, bite, long flight, etc) massage, compression garments, pumps, skin care more recently, low level laser treatment treatment for PML

10. aim to determine the clinical efficacy of treating post-mastectomy lymphoedema with LTU-904 (Low Level Laser) in a placebo controlled, double blind trial.

11. LLLT unit Laser Therapy Unit LTU904H unit, RIAN Corp. Adelaide SA, Australia 904 nm, pulsed, 5kHz, 200 nsec, duty cycle 0.1% Average power 5 mW, peak power 5 W Spot size 0.2cm 2 Class 1 laser device (divergent aperture) NiCad power, rechargable

12. Trial design Inclusion Criteria PML Axillary clearance  radiotherapy ≥ 200ml difference in arm volume Exclusion Criteria Congenital LO Past trauma to area Recent infection Unable to measure Co-morbidities (inc 2 y cancer) Recruitment: Surgical Oncology Unit, Flinders Medical Centre Funding: Aust. Govt. START Grant to FUSA, (part funded by RIAN Corp.)

13. trial design week 0 4 7 11 15 18 22 26 visit active group placebo group placebo active active active double blind, placebo controlled, single cross over design

14. treatment protocol Treatment area - 17 points - 2 cm space grid, (0.2 cm 2 X 17 = 3.4 cm 2 ) Treatment time = 17 mins Total energy = 5.1 Joules Dosage = 1.5 J/cm 2 LTU-904H RianCorp Pty Ltd 200nsec pulse, 904nm, 5kHz, mean output 5mW

15. volume of limb - perometry extracellular fluid - bio-impedance ’tissue hardness’ – tonometry range of movement Common Symptoms (by Visual Analogue Scale) ADLs (activities of daily living) QOL (quality of life) objective assessment subjective assessment

16. results 64 Participants completed -27 received placebo followed by laser - 37 received 2 x 3 weeks laser

17. Limb volume : perometry Mod. 305S Perosystem Wuppertal ( tissue volume, by truncated cones approx n ; @ 4 mm interval )

18. change in affected arm volume after 1 mo 2 mo after 1 mo 2 mo after 1 mo 3 mo Rx Rx Rx placebo 1 x laser 2 x laser *

19. ECF : bio-impedance (InBody, Seoul) Multifrequency Electrical Impedance Cellular & extracellular paths Solves for L & R Upper limb Trunk L & R lower limb volumes 10 values, 2/region

20. ECF - bioimpedance significant improvements after 2 x laser in affected arm (maintained at 1 - 3 months) trunk (maintained at 1 - 3 months) unaffected arm

21. affected arm bioimpedance – ECF (less is better) placebo 1 x laser 2 x laser * after 1 mo 2 mo after 1 mo 2 mo after 1 mo 3 mo Rx Rx Rx bioimpedance ECF units

22. tonometry : tissue resistance (indentation @275 g/cm 2 cf 12.2g/cm 2 surrounding) Penetration depth Fixed weight probe Fixed area probe Unit must be vertical

23. tissue tonometry significant improvements with 2 x laser in upper arm (affected limb) at 1-3 months, but not forearm posterior thorax (maintained at 1 month)

24. Pain Tightness Heaviness Cramps Limb Temp difference Size difference Pins and Needles significant improvements in subjective assessment nsd between groups Range of Movement QOL / ADL

25. conclusion 2 x 3 weeks LTU-904H treatment (3/wk) - decreases affected limb volume - decreases whole upper body fluid - improves tonometry of upper arm and posterior torso over period 1-3 months after treatment

26. underlying effects of LLLT in LO ? LLLT reduces volume & ECF content of : affected arm, (unaffected arm), & adjacent trunk. - LLLT increases drainage through restructured tissue in the axillary region ? OR - LLLT reduces fluid inflow into affected arm ? ( ↓ capillary permeability / fluid efflux into interstitium) LLLT has a systemic affect (perhaps through immune stimulation)

27. Optical Sweep of interfering Ar 514 laser beams moves large particle, but not small ones size selectivity (size matters!) sweep Mechanism of Action? ? Mitochondria ? Physical effect Rubinov A N J. Phys. D: Appl. Phys. 36: 2317–2330 (2003) Physical grounds for biological effect of laser radiation

28. Rouleaux-busting (argon Laser, 154nm) Rouleaux capture Single beam 45deg Rouleaux busted by 45deg energy gradients Interfering beams off

29. Fin. Mahalo

30. Clinical Trial published: [ #2 slightly scrambled by Cancer (J)] 1. Carati CJ, Anderson SN, Gannon BJ, and Piller NB (2004). Low Level Laser as Treatment for Post-Mastectomy Lymphedema. Am J Oncology Review 3: 255-60 (invited Review article). 2. Carati CJ, Anderson SN, Gannon BJ & Piller NB (2003). Treatment of Post-Mastectomy lymphedema with low level laser therapy: a double blind, placebo-controlled trial. Cancer, 98: 1114-22.