Radioprotectors

1. RADIOPROTECTORS DR BHARTI DEVNANI MODERATOR:-DR RITU BHUTANI

2. GOAL OF RADIATION THERAPY

3. According to the NCI workshop on normal tissue protection(Stone et al., 2004), interventions in the development of radiation effects classified as Prophylaxis/Protection Mitigation Treatment

4. DEFINITIONS Prophylaxis or protection Any measure applied before the threshold dose for the specific side-effect is reached. Mitigation Strategies used before the manifestation of clinical symptoms(latent phase) Treatment or management In the symptomatic phase to reduce the side-effects

5. WAYS TO IMPROVE THE PROTECTION OF NORMAL TISSUES

6. Rationales for using Radioprotectors Therapeutic ratio (TR) = TCP NTCP TCP = Tumor control probability NTCP= Normal tissue complication probability Efficacy/toxicity profile of radioprotector Agent R.T. efficacy against tumor T.R. The intrinsic toxicity of the radioprotector

7. IDEAL RADIOPROTECTOR Preservation of the anti-tumor efficacy of radiation Wide window of protection against all types of toxicity High theraputic ratio High efficacy/toxicity profile(Low intrinsic toxicity profile) Easy and comfortable administration Reasonable cost-effectiveness

8. Chemical Radioprotectors Radioprotector : A chemical compound that reduces the biologic consequences of radiation Some may protect whole animals as they cause vasoconstrictions/upset metabolism to <O 2 concentration. e.g. NaCn , CO, epinephrine, serotonin, histamine

9. Historically known fact NH 2 HS-CH 2 -CH COOH Problem was their toxicity nausea and vomiting General structure : i . A free SH group at one end ii. Strong basic function, i.e. an amine or guanidine at other

10. History of development of radioprotecters

11. A fter World War II, a development programme was initiated in 1959 by the U.S. Army at the Walter Reed Institute of Research to identify and synthesize drugs capable of conferring protection to individuals in a radiation environment, but without the debilitating toxicity of cysteine or cysteamine . Over 4,000 compounds were synthesized and tested.

12. Two Radioprotectors in Practical Use Compound Dose (mg/kg) Dose reduction factor Use 7 days (GI) 30 days ( Haematopoetic ) WR-638 Cystaphos 500 1.6 2.1 Carried in field pack by Russian army WR-2721 Amifostine 900 1.8 2.7 Protector in radiotherapy and carried by US astronauts on lunar trips

13. First breakthrough to reduce toxicity- covering the SH group with phosphate Toxicity of the compound decreased b/c the phosphate group is stripped inside the cell, and the SH group begins scavenging for free radicals.

14. Effect of adding a Phosphate-covering function on the free SH of Cysteamine Drug Formula Mean 50% lethal dose (Range) in mice Dose reduction factor MEA NH 2 -CH 2 -CH 2 -SH 343 (323-364) 1.6 at 200mg/kg MEA-PO3 NH 2 -CH 2 -CH-SH 2 PO 3 777(700-864) 2.1 at 500mg/kg

15. CLASSIFICATION 1. Free radical scavenging and cellular detoxification Amifostine (WR2721, Ethyol ) Superoxide dismutase Selenium 2. Modification of normal tissue oxygen levels Systemic hypoxia Local hypoxia 3. Epithelial cell-specific growth factors K eratinocyte growth factor (Dorr et al., 2001)

16. 4. Haemopoietic growth factors and cyt okines Interleukin-7 ( Bolotin et al., 1996), Interleukin-11 (Van der Meeren et al., 2002), Granulocyte-colony stimulating factor (G-CSF) ( Russel et al., 2000), Granulocyte, macrophage-colony stimulating factor (GM-CSF) ( Mettler and Guskova , 2001; Vose and Armitage , 1995), Stem cell factor (SCF) ( Zsebo et al.,1992), Antiapoptotic cytokine combinations ( Herodin et al., 2003) 5. Angiogenic growth factors FGF-1 and FGF-2 6. Vascular endothelial growth factor (VEGF) 7. TNF - α & TGF- β However, the success with these compounds has also been limited.

17. AMIFOSTINE(WR-2721)

18. Amifostine Introduction & History Metabolism Mec of action Pharmakokinetics Side effect profile Routes of administration Use in radiation oncology Head & neck cancer Lung cancer Pelvic cancers

19. Initially developed at the Walter Reed Army Research Institute,USA Under the Antiradiation Drug Development Program of the US Army Medical Research and Development Command ( Schuchter and Glick, 1993; Sweeney, 1979).

20. METABOLISM OF AMIFOSTINE

21. Amifostin (WR-2721) Phosphorothioate prodrug -inactive, does not readily permeate cells. Dephosphorylation by ALP(expressed on endothelial cell lining & proximal renal tubular cells) Active thiol (WR 1065) Oxidation Enter in cell by facillited diffusion WR – 33278(polyamine like disulphide metabolite) Radioprotection

22. MECHANISM OF ACTION

23. WR-1065 i . Free radical scavenging- Protects cellular membranes and DNA from damage ii. H 2 atom donation T o facilitate direct chemical repair at sites of DNA damage

24. WR-33278( Antimutagenic ) RADIOPROTECTION ACCELARETED RECOVERY

25. Why selective cytoprotection ? Diffrential expression of alkaline phosphatase in tumor tissue Hypovascularity & hypoxia Acidic environment of the tumor 100 folds decreased concentration in tumor tissue

26. Absorption - Not orally bioavailable . Distribution - Confined primarily to intravascular compartment. Rapidly cleared from Plasma Half life <1 min and >90% drug cleared plasma 6 min after admin. Active metabolite widely distributed in body tissues. Very little amifostine , or the metabolites WR-1065 and WR-33278, is excreted in urine 1 hour after injection. Once amifostine enters the plasma, it is rapidly metabolized and distributed in the tissues, whereas the excretion of the metabolic products is very slow

27. Differential uptake Extensive uptake is seen in:- Salivary glands Kidneys Intestinal mucosa Markedly lower uptake is seen in:- Tumour tissues Amifostine and metabolites do not cross the blood-brain barrier

28. Timing of administration Timely administration of amifostine is necessary. Amifostine before 30 min. of RT provide optimal benefit for cytoprotection of normal tissues. Single morning dose of amifostine provides superior radioprotection than with a single afternoon dose

29. >30 min---NO difference

30. <30 min--- Difference present

31. ROUTES OF ADMINISTRATION i.v . Amifostine At a dose of 200 mg/m2 daily, given as a slow i.v . push over 3 minutes,15–30 minutes before each fraction of radiation therapy Well hydrated and in supine position Antiemetics . B.P. should be measured before and immediately after the 3-minute amifostine infusion.

32. s.c . Amifostine s.c . injection of 500 mg of amifostine Nausea Fever/rash reaction Hypotension is less Endorectal 1,500 mg intra rectally 20 –30 minutes before each radiotherapy session Useful for pelvic irradiation Benefit demonstrated in a phase I study

33. SIDE EFFECTS Nausea, vomiting & other GI effects Transient hypotension- in 60%. Mean time of onset is 14 mins into infusion. BP reverts in 5-15 min. Infusion related :- flushing and feeling of warmth, Chills, Dizziness, somnolence, hiccups & sneezing Hypocalcemia in <1%- clinically asymptomatic by inhibition of PTH secretion Metallic taste during infusion Allergic reactions include rash, fever, and anaphylactic shock(TEN STS in6-9/100000)

34. Incidence and severity of amifostine -related adverse events vary based on the route of administration. I.V. route G reater risk for grade 3 or 4 hypotension s.c . route H igher incidence of fever and cutaneous reactions than with i.v . route

35. AMIFOSTINE USE IN RADIATION THERAPY

36. Head & Neck Cancers SCC of H&N 75% parotid gland was present in the fields Dose was 200 mg/m2 daily,15–30 minutes before each fraction of radiation therapy ( 1.8 –2.0 Gy /day, 5 days per week for 5–7 weeks, to a total dose of 50–70 Gy ).

37. Amifostine significantly reduced acute and late xerostomia and associated symptoms. Meaningful saliva production after 1 year was significantly higher with amifostine (72% versus 49%; p .003). At 1 year, with a median follow-up o f 20 months, the LR tumor control rates did not differ, and DFS & OS were comparable.

38. LUNG CANCER Factor studied Amifostine+RT RT alone P value Pnemonitis 9% 43% <0.001 Fibrosis 53% 28% <0.05 Esophagitis 4% 42% <0.001 CR or PR 75% 76% Antonadou et al. Dose:-340 mg/m2 15 minutes before irradiation. No evidence of tumor protection

39. MDACC trial (Komaki et al. ) : evaluated the cytoprotective role of amifostine for esophagitis and hematologic and pulmonary toxicities in a randomized study of patients with stage II or III non-small cell lung cancer receiving concurrent chemoradiotherapy . Did reduce incidence and severity of esophageal, pulmonary and hematologic toxicity. Did not affect survival

40. Pelvic malignancies Gasrointestinal mucositis Various routes of administration of amifostine ( i.v ., s.c . and intrarectal ) are effective. Intrarectal administration was more effective at reducing radiotherapy-induced rectal toxicities s.c . administration was more effective at reducing radiotherapy-induced urinary toxicities Combined route for optimal cytoprotection

41. Dermatitis Assessed in a retrospective analysis in which 100 patients with pelvic tumors treated with radiotherapy and amifostine were compared with 120 historical controls who did not receive amifostine 77% lower risk for radiation-induced dermatitis with amifostine use The severity of dermatitis was also significantly lower Among patients who received amifostine , only grade 1 dermatitis was noted.

42. Status The U.S. FDA has approved the i.v . use of amifostine in:- Patients with advanced ovarian cancer to reduce the cumulative renal toxicity associated with repeated administration of cisplatin . (1996) Patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands to reduce the incidence of moderate to severe xerostomia .(1999)

43. Issue of tumor protection A meta-analysis ( Sasse et al ., 2006) concluded that A mifostine does not affect the efficacy of radiotherapy To the contrary, patients receiving amifostine with RT achieved higher rates of CR presumably the result of fewer treatment interruptions because of reduced acute toxicity of the treatment.

44. Herbal radioprotectors

45. mitigators Compounds that mitigate damage caused by previous radiation exposure – different approach in management of radiation induced toxicity Leading drug under development – Palifermin Recombinant human keratinocyte growth factor Promote & hasten repair of t/t induced normal tissue damage Member of fibroblast growth factor family Rapid increase in basal cell proliferation Decreases RT & CCT induced injury to oral & GIT mucosa No interaction with tumor cells Phase II studies going on

46. More modest but achieveable goal is to use them to reduce side effects RTOG phase III RC trial ( Brizel et al.1998) : Amifostine reduced xerostomia without affecting early tumour control in H&N cancers. 15 min before radiation, 4 days each week, for 5 weeks. Three months after treatment, incidence of xerostomia significantly reduced. MDACC trial (Komaki et al. 2004): whether Amifostine reduced acute toxicity associated with concurrent chemoradiation . Amifostine twice a week at 20-30 min before doses of IV cisplatin , oral etoposide or irradiation. Did reduce incidence and severity of esophageal, pulmonary and hematologic toxicity. Did not affect survival

47. Why not used Protection of salivary glands could also be achieved by using intensity modulated radiotherapy uncertain to what extent amifostine protects against fibrosis and other dose-limiting late reactions the optimal dosage and schedule of amifostine has not been established. major concern related to radioprotectors remains the potential hazard of tumor protection. However,not even the trial conducted by Brizel et al,73 which recruited over 300 patients, has had sufficient statistical power to detect and quantify a possible tumor protective effect of amifostine . the lack of statistical power in these studies hinders any firm conclusions being drawn regarding tumor protection. T/t & toxicites cumbursome repeted puncture & hypotension

48. THANK YOU

49. New Directions Possibility of dose escalation of radiotherapy Combination with novel drugs Hypofractionation

50. New Direction:Possibility of dose escalation of radiotherapy Protracted overall treatment time results in a substantial compromise of RT efficacy because of rapid tumor repopulation starting within 3 weeks of RT. The dose intensity of RT and CCT may be an imp factor related to the efficacy of such a regimen in controlling local and disseminated disease.

51. New Direction:Possibility of dose escalation of radiotherapy In experimental studies ( Laaret al, Van der Wilt et al,Gridelli et al), it has been adequately proved that it was possible to increase the dose of chemotherapeutic agent by 1.5-2.2 times with an increase in anti tumor effect and reduction in toxicity with the use of amifostine .

52. New Direction:Possibility of dose escalation of radiotherapy Koukourakis et al ph I study of 24 pts using 500mg before carboplatin allowed increase in the dose with sig decrease in the incidence of esophagitis and diarrhoea (p=.01)

53. New Directions Possibility of dose escalation of radiotherapy Combination with novel drugs Hypofractionation

54. New Direction:Combination with novel drugs Combination of RT with Taxanes in NSCLC, topo isomerase inhibitors, irinotecan,liposomal doxorubicin and gemcitabine in HNC and NSCLC has resulted in improved local control but at the cost of severe mucositis leading to prolongation of treatment time or decrease in dose and thereby minimising the therapeutic benefit. Addition of Amifostine could increase the therapeutic index.

55. New Directions Possibility of dose escalation of radiotherapy Combination with novel drugs Hypofractionation