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.