radioprotectors
TRANSCRIPT
RADIOPROTECTORS
DR BHARTI DEVNANI
MODERATOR:-DR RITU BHUTANI
GOAL OF RADIATION THERAPY
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
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
WAYS TO IMPROVE THE PROTECTION OF NORMAL TISSUES
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
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
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
History of development of radioprotecters
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.
Two Radioprotectors in Practical Use
CompoundDose
(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-2721Amifostine
900 1.8 2.7Protector in radiotherapy
and carried by US astronauts on lunar trips
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.
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-PO3NH2-CH2-CH-
SH2PO3
777(700-864) 2.1 at 500mg/kg
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)
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-βHowever, the success with these compounds has also been limited.
AMIFOSTINE(WR-2721)
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
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).
METABOLISM OF AMIFOSTINE
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
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
WR-33278(Antimutagenic)
RADIOPROTECTION
Prevention of DNA damage
1.Condensation of DNA, thereby limiting potential target sites for free-radical attack
2.AnoxiaRapid 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
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
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
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
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 min---NO difference
<30 min--- Difference present
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.
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
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)
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
AMIFOSTINE
USE
IN RADIATION THERAPY
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).
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.
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
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
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
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.
StatusThe 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)
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.
Herbal radioprotectors
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
New Directions
Possibility of dose escalation of radiotherapy
Combination with novel drugs Hypofractionation
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.
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.
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)
New Directions
Possibility of dose escalation of radiotherapy Combination with novel drugs Hypofractionation
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.
New Directions
Possibility of dose escalation of radiotherapy Combination with novel drugs Hypofractionation
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.