This document discusses radioprotectors and focuses on amifostine. It provides background on amifostine's development, metabolism, mechanism of action, pharmacokinetics, side effects, and approved uses in radiation oncology to reduce toxicity in head and neck cancer and lung cancer patients. It notes that amifostine does not appear to protect tumors from radiation based on clinical studies. The document concludes by discussing potential new directions for amifostine including using it to enable dose escalation of radiation therapy or combination with novel drugs, and exploring its use to allow hypofractionated radiation schedules.
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
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.
8. 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
9. Historically known fact
NH2
HS-CH2-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
11. After 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 NH2-CH2-CH2-SH 343 (323-364)
1.6 at
200mg/kg
MEA-PO3
NH2-CH2-CH-
SH2PO3
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
Keratinocyte growth factor (Dorr et al., 2001)
16. 4. Haemopoietic growth factors and cytokines
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.
18. Amifostine
Introduction & History
Metabolism
Mec of action
Pharmakokinetics
Side effect profile
Routes of administration
Use in radiation oncology
1. Head & neck cancer
2. Lung cancer
3. 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).
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)
OxidationEnter in cell by facillited
diffusion
WR – 33278(polyamine like disulphide metabolite)
Radioprotection
22. WR-1065
i. Free radical scavenging-
Protects cellular membranes
and DNA from damage
ii. H2 atom donation
To facilitate direct chemical
repair at sites of DNA damage
23. WR-33278(Antimutagenic)
RADIOPROTECTION
Prevention of DNA damage
1.Condensation of
DNA, thereby limiting potential
target sites for free-radical
attack
2.Anoxia
Rapid consumption of O2 leads
to induction of cellular anoxia
ACCELARETED RECOVERY
Upregulates the expression
of proteins involved with
DNA repair
Inhibits Apoptosis, by Bcl-2
and hypoxia-inducible
factor-1
Enhanced cellular
proliferation
24. 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
25. 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
26. 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
27. 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
30. 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.
31. 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
32. SIDE EFFECTS
1. Nausea, vomiting & other GI effects
2. Transient hypotension- in 60%. Mean time of
onset is 14 mins into infusion. BP reverts in 5-
15 min.
3. Infusion related :- flushing and feeling of
warmth, Chills, Dizziness, somnolence,
hiccups & sneezing
4. Hypocalcemia in <1%- clinically asymptomatic
by inhibition of PTH secretion
5. Metallic taste during infusion
6. Allergic reactions include rash, fever, and
anaphylactic shock(TEN STS in6-9/100000)
33. Incidence and severity of amifostine-related
adverse events vary based on the route of
administration.
I.V. route
Greater risk for grade 3 or 4 hypotension
s.c. route
Higher incidence of fever and cutaneous
reactions than with i.v. route
35. 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).
36.
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 of 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
Amifostine 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.
45. 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
46.
47.
48. New Directions
Possibility of dose escalation of
radiotherapy
Combination with novel drugs
Hypofractionation
49. 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.
50. 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.
51. 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)
52. New Directions
Possibility of dose escalation of radiotherapy
Combination with novel drugs
Hypofractionation
53. 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.
54. New Directions
Possibility of dose escalation of radiotherapy
Combination with novel drugs
Hypofractionation
55. New Directions:
Hypofractionation
Despite established efficacy, it is an
abandoned form of treatment because of high
rate of severe late sequelae.
Neverthless, large fraction (4-5Gy) may be
more active in certain conditions where tumor
has low radiosensitivity.
If Amifos c’d maintain a low rate of radiation
toxicity, then hypofractionation c’d become
treatment of choice for certain tumors.
Editor's Notes
More than 4,000 sulfhudryl-containing substances with radioprotective properties were tested, but only the agent WR-2721, later known as amifostine, was found to exhibit acceptable toxicity.
Buentzel et al. amifostine was administered > 30 minutes before CRT, demonstrated no significant difference in the incidence of grade2 acute or chronic xerostomia or grade 3 oral mucositis b/w patients receiving i.v.amifostine and those receiving placebo
Studies(Brizel et al) in which amifostine was administered within 30 minutes of radiotherapy have shown promise with regard to protection from acute and chronic xerostomia