1. Effect of Ionizing Radiation on Skin
The Good, the Bad, and the Ugly
BOG July 2015
Dr. Lokesh Viswanath M.D.
Professor & Head of Unit
Department of Radiation Oncology
Kidwai Memorial Institute of Oncology

2. Radiation Induced skin reactions
• Domains
Radiation
Induced
Skin
Reactions
During
Radiation
Therapy : Acute
Effects and Late
effects
Accidental
exposures :
Industrial/
wartime
Nuclear
exposures /
Open isotopes
Radiation
Workers /
Public
exposure
monitoring

3. Introduction : Radiation induced skin toxicities
• ~ 95% of patients receiving RT for cancer
• negatively affect the quality of a patient's life :
pain and premature interruption of RT
• ranges in severity from mild erythema to moist
desquamation and ulceration.
• ionizing radiation damage is somewhat similar to
atopic dermatitis
• a common form of eczema
• ~20% of children
• profound effect on the stratum corneum function
• increased transepidermal water loss

4. History
• Skin burn attributed to radiation : 1901
• Skin erythema : Holzkencht`s
chromoradiometer 1902

5. Radiation skin injury
• morphological
• functional changes
• The degree of radiation injury »
– Total radiation dose, Dose /Fr
– proportion of body irradiated
– volume of tissues irradiated
– time interval of the radiation dose received
(Fr/week, No of Day, OTT)

6. most radiosensitive cells in the body
– high proliferative index
– Tissue oxygen
• The most radiosensitive organ systems are :-
– bone marrow
– reproductive and gastrointestinal systems
– Skin ←
– Muscle
– Brain
– etc

7. function of skin
• effective barrier against the surrounding environment
– Physical
– immunological
• The epidermis
– stratifying layers of keratinocytes
– primary barrier and biosensor
• The dermis
– provide structural strength
– connective tissue produced by dermal fibroblasts.

8. Skin is susceptible to radiation damage
• continuously renewing organ
• rapidly proliferating and maturing cells
• highly radiosensitive
– basal keratinocytes
– hair follicle stem cells
– melanocytes
• Radiation skin injury
– immediate damage to basal keratinocytes and hair follicle stem
cells
– Inflammation
– 1st keratinocytes
• disruption in the self-renewing property of the epidermis
• repeated exposures do not allow time for cells to repair tissue or DNA
damage.
• continually destroyed with each fraction

9. Radiation skin injury: categorized
• Acute injury : within hours to weeks
• late injury (i.e., chronic) : months to years after
radiation exposure

10. Acute radiation skin toxicty
• primarily involves cellular alterations and inflammation in the epidermis
and the dermis.
Acute changes
1. Erythema
2. Edema
3. pigment changes
4. Depilation
histological analysis:
• Hyper-proliferation of the epidermis
• thickening of the stratum corneum
• Trans-epidermal water loss – Significantly increased (a measure for skin
barrier integrity)
• Severe radiation injury
– complete loss of the epidermis
– persistent fibrinous exudates
– edema.
– Re-epithelialization begins within 10–14 days after radiation exposure in the
absence of infection

11. one year after radiation exposure
• skin
– thin
– Hypo-vascularized
– Tight
– susceptible to trauma or infection
• Chronic radiation skin injury
– delayed wound healing
– delayed ulcers
– Fibrosis
– telangiectasias

12. Acute skin changes with localized
radiation dose
Acute skin effect Dose (Gy) Onset
Early transient
erythema
2 Hours
Faint erythema;
epilation
6–10 7–10 Days
Definite erythema;
hyperpigmenation
12–20 2–3 Weeks
Dry desquamation 20–25 3–4 Weeks
Moist desquamation 30–40 4 Weeks
Ulceration >40 6 Weeks

13. Threshold doses

14. Pathophysiology
RT Skin Injury is different for thermal burn
1. dose-dependent clinical pattern, which includes
dry desquamation at 12–20 Gy, moist
desquamation at 20 Gy, and necrosis at >35 Gy
2. radiation Skin injury are associated with opiate-
resistant chronic pain
1. most complicating factor is the unpredictable
successive inflammatory waves occurring weeks to
years after radiation exposure
2. difficult to delineate the radiation-injured tissue from
noninjured tissue
3. healing of radiation skin lesion is extensive and
unpredictable.

15. Risk factors
• patient-related factors :
– obesity, age, gender, chronic sun exposure, and smoking
– Older female patients
– ataxia telangiectasia and hereditary nevoid basal cell
carcinoma syndrome (Gorlin Syndrome) require dose
alterations or avoidance of radiation exposure
• AT = mutations in the ATM gene, are highly susceptible to
severe radiation dermatitis
• GS: irradiation of individuals could produce widespread
cutaneous tumors.
• Other disorders :
– connective tissue disorders (lupus, scleroderma), chromosomal
breakage syndromes (Fanconi's anemia, Bloom syndrome),
xeroderma pigmentosa, Gardner's syndrome, hereditary malignant
melanoma, and dysplastic nevus syndrome

16. Risk Factor 2
• Technical factors :
– radiation dose to skin
– irradiation site :
• most sensitive - anterior of the neck, extremities, chest,
abdomen, and face , hair follicles on the scalp and breast tissue
– fractionation timing
– total exposure time
– angle of radiation beam
• Other risk factors
– increased transepidermal water loss
– infiltration of pathogens or bacteria into the skin
– Host antimicrobial defenses are severely compromised by
radiation and/or skin trauma combined with radiation

17. Late skin effect
Dose (Gy) Onset
Delayed
ulceration
>45
Weeks after
radiation
Dermal
necrosis/atrophy
>45
Months after
radiation
Fibrosis >45
6 Months to 1 year
after radiation
Telangiectasia >45
6 Months to 1 year
after radiation

18. Skin immune response following radiation
• skin provides : immune surveillance > maintains
homeostasis and is poised to respond to environmental
insults.
– Key cells : Langerhans cells (LCs)
– keratinocytes : important role because : producing large
amounts of cytokines, * IL-1α and tumor necrosis factor-α
• The LCs + dermal dendritic cells (DCs) = antigen-
presenting cells
– uptake of antigens that may breach the skin barrier
• The dermis : mast cells & T cells :> radiation-induced
immune response

19. ionizing radiation incites signaling between the epidermis and dermis

20. • Keratinocytes, fibroblasts, and
endothelial cells in the skin
stimulate resident (i.e., LCs,
DCs, mast cells, T cells) and
circulating immune cells
• Numerous cytokines and
chemokines are produced in
response to these activation
signals, which act on the
endothelial cells of local
vessels, causing the
upregulation of adhesion
molecules
• Transendothelial migration of
immune cells, such as
neutrophils, macrophages, and
leukocytes, from circulation to
irradiated skin is considered a
“hallmark” of radiation-
induced skin injury
• Acute radiation skin toxicity
has been correlated with
increased formation of various
cytokines and chemokines,
most notably IL-1α, IL-1β,
tumor necrosis factor-α, IL-6,
IL-8, CCL4, CXCL10, and CCL2

21. late-radiation injury
• fibroblasts - fibrosis and other
• key mediators
• Transforming growth factor-β (TGFβ)
• Smad3
• vascular endothelial growth factor
• CCL11 (eotaxin)

22. acute radiation skin injury scoring systems
Score Observation
Radiation Therapy Oncology Group
0 No change over baseline
1 Erythema; dry desquamation; epilation
2 Bright erythema; moist desquamation; edema
3 Confluent moist desquamation; pitting edema
4 Ulceration, hemorrhage, necrosis
NIH CTCAE
0 None
1 Faint erythema or dry desquamation
2 Moderate to brisk erythema
3 Confluent moist desquamation
4 Skin necrosis or ulceration
Oncology Nursing Society
0 No change
1.0 Faint or dull erythema
1.5 Bright erythema
2.0 Dry desquamation with or without erythema
2.5
Small to moderate amount of moist
desquamation
3.0 Confluent moist desquamation
3.5 Ulceration, hemorrhage, or necrosis

23. Score Observation
Douglas & Fowler
0 Normal
0.25 50/50, Doubtful if any difference from normal
0.5 Very slight reddening
0.75 Definite but slight reddening
1 Severe reddening
1.25 Severe reddening with white scale; “papery” appearance of skin
1.5 Moist breakdown in one very small area with scaly or crusty appearance
1.75 Moist desquamation in more than one small area
2 Moist desquamation in 25% of irradiated area
2.25 Moist desquamtion in 33% of irradiated area
2.5 Moist desquamation in 50% of irradiated area
2.75 Moist desquamation in 66% of irradiated area
3 Moist desquamation in most of irradiated area
3.25 Moist desquamation in most of irradiated area with slight moist exudate
3.5 Moist desquamation in most of irradiated area with moist exudates; necrosis
Radiation dermatitis severity scale
0.0 Normal or none
0.5 Patchy faint/slight follicular eyrthema; faint hyperpigmentation
1.0 Faint and diffuse erythema; diffuse hyperpigmentation; mild epilation
1.5 Definite erythema; extreme darkening/hyperpigmentation
2.0 Definite erythema/hyperpigmentation with fine dry desquamation; mild edema
2.5 Definite erythema/hyperpigmentation with branny/scaly desquamation
3.0 Deep red erythema with diffuse dry desquamation; peeling in sheets
3.5
Violaceous erythema with early moist desquamation; peeling in sheets; patchy
crusting
4.0
Violaceous erythema with diffuse moist desquamation; patchy crusting; ulceration;
necrosis

24. Radiation Therapy Oncology Group : Late Skin
Toxicity Scoring
Onset Grade
0 1 2 3 4 5
Chronic None Slight
atrophy.
Patch
atrophy.
Moderate
telangiectasi
a. Total hair
loss.
Marked
atrophy.
Gross
telangiectasi
a.
Ucleration Death

25. management of radiation skin injury
Conservative
Medical
Line
Surgical

26. management of radiation skin injury
• washing with mild soap (open isotopes)
• using unscented, lanolin-free, water-based moisturizing
cream,
• corticosteroid and nonsteroidal creams appeared to reduce
the severity of skin reactions, there was no clear indication of
a preferred topical agent.
• Amifostine and oral enzymes emerged as somewhat effective
preventative agents
• pentoxifylline reduced late, but not acute, effects of radiation
on the skin
• Long treatment (3 years) of pentoxifylline and tocopherol
(i.e., vitamin E) significantly reduced radiation-induced
fibrosis.
– Unfortunately, cessation of pentoxifylline–tocopherol treatment
before 3 years resulted in a “rebound effect” and more severe
radiation-induced fibrosis

27. radiation mitigators
• Targeted gene therapy
• potential targets:
– TGFβ1 pathway inhibitor synthetic superoxide dismutase
– catalase mimetics recombinant IL-12 toll-like receptor
– 5 agonist inhibitors of cyclin-dependent kinases
• pravastatin reduced radiation skin injury by maintaining endothelial cell
function after radiation exposure by increasing endothelial nitric oxide
synthase
• Curcumin, a component of turmeric, has also demonstrated the ability
to reduce radiation skin toxicity through its potent antioxidant and anti-
inflammatory activities
• acceleration of radiation delayed wound healing in mice upon
stimulation of TGFβ-1 and basic fibroblast growth factor, suggesting that
the growth factor treatment may mitigate radiation skin injury.
• Stem cell therapy combined with surgical excision has demonstrated
success in improving wound repair of severe radiation
• mesenchymal stem cell injections around the lesion at the cutaneous
and muscular levels, as well as in the bed of the lesion under the skin
graft
• adipose tissue–derived stem cells also promote wound healing in mice

28. Grade 1

29. Grade 2

31. Length of skin reaction (cms)
Length of skin reaction
(CMS)
Number
(n=23)
%
Up to 5 16 69.6
5-10 4 17.4
>10 3 13.0
Mean  SD 5.48  4.07 cms
Up to 5
69.6%
5-10
17.4% >10
13.0%
Length of skin reaction (CMS)
AREA OF SKIN REACTION (Sq Cms)
AREA OF SKIN
REACTION (Sq Cms)
Number
(n=23)
%
Up to 10 12 52.2
11-20 6 26.1
>20 5 21.7
Mean  SD 18.04 25.72 Sq cms
11-20
26.1%
>20
21.7%
Up to 10
52.2%
AREA OF SKIN REACTION (Sq Cms)

33. Filgastrim Treatment Protocol
Step 1: Aseptic precautions were taken during the procedure – injection of a single
dose of 300 μg of Filgrastim was administered, subcutaneously in the
unirradiated normal skin around the periphery of the moist desquamation (2 or 4
quadrant zones).
Step 2: Proper wound care was advised – air drying and rest to the part of the body
that is affected for 2 to 3 days, mainly to prevent skin fold from rubbing against
the exposed skin and aggravating the lesion and to clothes from sticking to the
exposed skin wound.
Step 3: Sprinkling of Neosporin® – antibiotic powder (contains Neomycin &
Polymixin B sulfates & Bacitracin zinc) ever 6 hours was advised (instructions
were not to touch the exposed skin with cotton swab or apply ointments).
Step 4: Appropriate oral antibiotics (such as Amoxicillin & Cloxacillin for 7 days or
Ciprofloxacilllin with or without Tinidazole) when necessary were given to
patients
Step 5: Analgesic & anti inflammatory drugs: oral Ibuprofen if subject is symptomatic
for 1–2 days.

34. 0
2
4
6
8
10
12
14
16
18
20
Superficial epidermal
involvement
Deep
Depth of skin reaction
No.ofdaystoheal.

35. Number of Days required to Heal
No of Days required to
Heal
Superficial
epidermal
involvement
Deep Total
Up to 5 days 13 (76.5%) - 13(56.5%)
5-10 days 4 (23.5%) 3 (50.0%) 7 (30.4%)
>10 days - 3 (50.0%) 3 (13.0%)
Total 17 6 23
Mean  SD
(Min-max)
4.53  2.07
(2-9)
12.66  5.12
(7-20)
6.65 4.73
(2-20)
76.5
0
23.5
50
0
50
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
Percentages
Up to 5 days 5-10 days >10 days
Sup.epdermal invol.
Deep
Number of days required to heal

36. Time to heal (Literature Review)
Time (days) Mean Authors
Duo Derm 4-6 4.6 Margolin et al 1990
G V paint 5 - 22 11
Hydrocortisone
Cream
21 - 28 Chen et al 1997
Gel Dressing 7 - 14
N. Saline 30 - 35
Dermofilm
dressing
11 - 16 See et al 1998
Inj GCSF s/c 2-20 6.65 Lokesh .V et al 2006
superficial 2-9 4.53
deep 7-20 12.66

38. Female patient who completed 50Gy in 25 fractions radiotherapy for a Breast Cancer
presented with grade III moist dequmation in the Axillary fold (Superficial dermal
exposure) (1a). The patient was referred to us for cytokine therapy. The skin ulceration
healed in the next 4 days after GCSF injection (1b).

40. • shows a 55year male who completed treatment with external
radiotherapy 5000cG in 25 fractions on Telcobalt Machine for
a head and neck malignancy developed grade 3 moist
desquamation of the skin (Deep skin lesions). The picture
shows an unresolved desquamation in spite of gentian violet
application.
• same patient with remarkable resolution of lesion by day 5.
He was able to reassume treatment within a week

43. a Female patient who completed radiotherapy 50Gy in 25 fractions 5 fractions per week, for Cancer Cervix. She presented with grade III moist
desquamation of the skin with deep dermal exposure. The patient was referred to us for cytokine therapy. Picture 2 a - Before cytokine
injection, Picture 2 b - day 2, Picture 2 c – day3 , Picture 2 d – day4, Picture 2 e – day 5 Shows Complete healing.

44. Summary
• there is no effective treatment to prevent or mitigate
radiation skin injury.
Simple solutions to prevent:
• No touch policy
• Megavoltage X Rays for RT
• Advanced Radiation techniqes : IMRT , Rotational
Modulated Arcs etc
• Use of multiple beams
• careful RT contouring & planning
• use of higher energies in obese patients
• Protons
• Amifostine