1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Molecular Pharmacology

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Extravasation of a cytotoxic is an emergency Emergency cases require clear instructions

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria DOCUMENTATION OF EXTRAVASATION General documentation: patient data and involved hospital staff Drug documentation: drug and application data, other cytostatics, extravasation symptoms Interventions: measures and antidotes Patient instruction

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria PATIENT INSTRUCTION Verbal and written instructions Check patient’s compliance, e.g. for care and follow-up Make sure that the patient calls in case of extravasation related side-effects, i.e. pain, swelling, changes in skin colour

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria GENERAL TREATMENT Non-vesicant drugs Irritant and vesicant drugs SPECIFIC MEASURES AND ANTIDOTES Heat vs. cold Pharmacologic intervention Surgical intervention

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria VESICANT: Agent with the potential to cause cellular damage and tissue destruction IRRITANT: Agent that may produce a variety of symptoms without necrosis NON-VESICANT: Agent devoid of significant irritant or vesicant effects DEFINITIONS

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria GENERAL TREATMENT: NON-VESICANT DRUGS 1. Stop infusion 2. Put on gloves 3. Carefully aspirate to withdraw some of the extravasated drug: do not apply pressure! 4. Remove the cannula 5. Elevate the affected limb above heart level 6. Document the extravasation: delineate the infiltrated area, complete the extravasation form 7. Instruct the patient

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria GENERAL TREATMENT: IRRITANT or VESICANT DRUGS 1. Stop infusion 2. Put on gloves 3. Carefully aspirate to withdraw some of the extravasated drug: do not apply pressure! 4. If blistering occurs: aspirate from the bleb with a thin needle (G26) 5. Remove the i.v. cannula if no antidotes are to be administered 6. Elevate the affected limb above heart level 7. Give specific antidotes if available 8. Document the extravasation 9. Instruct the patient 10. Seek advice of a plastic surgeon within 72 hours if the drug is classified as vesicant

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria DO NOT APPLY: Pressure on infiltrated tissue ! Moist compresses or fomentations ! Alcoholic compresses !

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria SPECIFIC MEASURES AND ANTIDOTES Topical cooling Topical heating Topical dimethylsulfoxide (DMSO) Subcutaneous hyaluronidase Intravenous or subcutaneous sodium bicarbonate Intravenous or subcutaneous sodium thiosulphate Subcutaneous dexamethasone or topical hydrocortisone Surgical intervention

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TOPICAL COOLING Mechanism: Vasoconstriction Reduced cellular uptake, e.g. doxorubicin Reduced cytotoxicity, e.g. doxorubicin, cisplatinum, bleomycin, carmustine Localization of extravasated drug to the infiltrated tissue area Advantage: Simple to use Negligible side-effects

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Disadvantage: Enhanced cytotoxicity of vinca alkaloids in the mouse Example: Anthracyclines Treatment: Start immediately after extravasation Initiate with cooling at least one hour Continue for 72 hours several times a day (minimal cooling period: 15 minutes) TOPICAL COOLING

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TOPICAL HEATING Mechanism: Vasodilation Increased local blood flow and drug absorption Advantage: Simple to use Negligible side-effects Disadvantage: Enhanced cytotoxicity of cisplatinum, bleomycin, carmustine (in vitro), and doxorubicin (in vitro and in the mouse)

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Example: Vinca alkaloids Treatment: Apply warm compresses for 20 minutes Repeat every 6 hours for 48 hours TOPICAL HEATING

15. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TOPICAL DMSO Mechanism: Vasodilation Rapid penetration of tissues Excellent solvent for many drugs Concentrated DMSO increases the permeability of tissues and reduces the local drug concentration Anti-inflammatory Scavenger of free radicals Reduces the cytotoxicity of cisplatinum in vitro

16. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Advantage: Simple to use Negligible side-effects Disadvantage: Unpleasant garlic odour in the breath Burning sensations and erythema are sometimes experienced TOPICAL DMSO

17. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Example: Anthracyclines Treatment: Paint infiltrated area with DMSO (99%) every 8 hours Air dry Apply at least for 7 days TOPICAL DMSO

18. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria SUBCUTANEOUS HYALURONIDASE Mechanism: Enzymatic degradation of hyaluronic acid and increased drug absorption from infiltrated tissue Synergism with heat postulated Advantage: Negligible side-effects Disadvantage: Invasive treatment

19. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Example: Vinca alkaloids Treatment: Inject 150 - 900 IE Hyaluronidase subcutaneously around the affected area SUBCUTANEOUS HYALURONIDASE

20. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria SODIUM BICARBONATE (sc or iv) Mechanism: Increases the local pH Chemical degradation of some cytostatic agents, e.g. carmustine Disadvantages: Invasive procedure with a vesicant antidote Example: Carmustine, treosulfan SINCE SODIUM BICARBONATE IS A VESICANT, IT SHOULD NOT BE ADMINISTERED AFTER EXTRAVASATION !

21. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Mechanism: Chemical inactivation of some cytostatic agents, e.g. cisplatinum scavenger of radical oxygen species Advantage: Negligible side-effects Disadvantage: Invasive procedure SODIUM THIOSULPHATE (sc or iv)

22. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Example: Mechlorethamine Cisplatinum Treatment: Infiltrate sodium thiosulphate subcutaneously (2% - 6.7%) or Administer 4 ml sodium thiosulphate intravenously (10%) ALTHOUGH THE USE OF SODIUM THIOSULPHATE IS WIDELY ACCEPTED IN THE LITERATURE, THERE IS ONLY LIMITED EVIDENCE OF ITS EFFICACY ! SODIUM THIOSULPHATE (sc or iv)

23. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CORTICOSTEROIDS Mechanism: Anti-inflammatory Advantage: Negligible side-effects Disadvantage: Enhanced cytotoxicity of vinca alkaloids in the mouse

24. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Treatment: Administration of 100 mg hydrocortisone subcutaneously or intravenously Topical application of 1% hydrocortisone cream EXTRAVASATION IS RARELY ACCOMPANIED BY INFLAMMATION, THUS DISCOURAGING THE USE OF CORTISOSTEROIDS ! CORTICOSTEROIDS

25. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria OTHER AGENTS Heparin N-Acetylcysteine Chondroitinsulfatase 3,5-Dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl (DHM3) Tetrachlorodecaoxygen anion complex (TCDO) Retinol (vitamin A)  -Carotene Pyridoxine (vitamin B 6 ) Ascorbic acid (vitamin C)  -Tocopherol (vitamin E)

26. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CONCLUSIONS Poor design and inaccurate descriptions reduce the benefit of several case reports or even clinical studies Some promising experimental agents (e.g. DHM3) have not been adapted to the clinical situation Even „consensus“ procedures may suffer from scarce clinical evidence of their efficacy (e.g. the use of sodium thiosulphate after extravasation of cisplatinum)

27. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria In contrast to sodium bicarbonate, the successful use of DMSO, hyaluronidase, cooling, and heating is well documented Joint efforts to unravel systematically the vesicant potential of some of the older drugs and the incoming new agents are highly desirable CONCLUSIONS