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Radiotherapy-Induced Dermatologic Toxicities
Jennifer Nam Choi, MD
Yale University School of Medicine
Department of Dermatology
Yale Cancer Center
New Haven, CT
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Disclosure of Relevant Relationships with Industry
Jennifer N. Choi, MD
Radiotherapy-Induced Dermatologic Toxicities
I do not have any relevant relationships with industry.
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Radiotherapy Reactions and Complications
Acute
Chronic
From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.
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Radiotherapy Reactions and Complications
Acute Dry desquamation, moderate erythemaMoist desquamation and mild bleeding
Chronic
From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.
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Radiotherapy Reactions and Complications
Acute
Chronic
From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.
RadiationDermatitis
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Locations Most Associated with Radiation Dermatitis
• Head/Neck • Chest wall
◦ Breast◦ Lung
• Genitourinary◦ Uterine◦ Cervical
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Grading System of Radiation Dermatitis
• National Cancer Institute (NCI)• Radiation Therapy Oncology Group (RTOG)• World Health Organization (WHO)• European Organization for Research and Treatment
of Cancer (EORTC)
NCI-Common Terminology Criteria for Adverse Events v3.0
Adverse Event Grade 1
Rash: dermatitis associated with radiation
Faint erythema or dry desquamation
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Grading System of Radiation Dermatitis
• National Cancer Institute (NCI)• Radiation Therapy Oncology Group (RTOG)• World Health Organization (WHO)• European Organization for Research and Treatment
of Cancer (EORTC)
NCI-Common Terminology Criteria for Adverse Events v3.0
Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Rash: dermatitis associated with radiation
Faint erythema or dry desquamation
Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin folds and creases; moderate edema
Moist desquamation other than skin folds and creases; bleeding induced by minor trauma or abrasion
Skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site
Death
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Acute: Radiation Dermatitis
• Erythema• Xerosis
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Acute: Radiation Dermatitis
• Erythema• Xerosis• Hyperpigmentation• Dry desquamation• Pruritus• Moist desquamation• Pain
• 2-4 weeks, 20-25 Gy• 80-90%
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Acute: Radiation Dermatitis
• Erythema• Xerosis• Hyperpigmentation• Dry desquamation• Pruritus• Moist desquamation• Pain
• 2-4 weeks, 20-25 Gy• 80-90%
• Severe reactions:◦ Total radiation dose◦ Dose per fraction◦ Overall treatment time◦ Beam type and energy◦ Surface area of skin
exposed◦ Chemotherapy
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Breast Irradiation
A. Radiation Beam
B. Radiation Beam
C. Breast
D. Ribs
E. Heart
F. Lungs
G. Vertebrae
H. Sternum (breast bone)
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Breast Irradiation
• BOOST AREA: location of extra radiation to the lumpectomy site after the initial course of radiation
• May outline area to direct the radiation beams using: ◦ Tattoos◦ Adhesive tape
• Remains on skin for entire duration of treatment e.g. 4 to 8 weeks
• Not permanent
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Radiation Dermatitis Management
• Controversial
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Study Descriptions and Trial Outcomes on Preventing Acute Radiation Skin Reactions
Author (Year) Treatment Arms Study Design Outcomes Assessed
Topical Steroids
Bostrom (2001)1 0.1% MMF + emollient
RCT/patient/double-blind
Max erythema score; total erythema index
Schmuth (2002)2
0.1% MPA
0.5% dexpanthenolRCT/patient/double-blind
Mean severity score
Løkkevik (1996)3
Dexpanthenol (cream vs none)
RCT/treatment/single-blind
Erythema grade
Washing Practices
Roy (2001)4 Soap + water; no washing
RCT/patient/single-blind
Max erythema score; Max moist desq score
Campbell (1992)5
No bolus /bolus + water, and/or soap
RCT/patient/open Mean erythema score
Westbury (2000)6
Normal hair washing; No hair washing
RCT/patient/openDegree of erythema/desq
Sucralfate or Derivatives
Lievens (1998)7 Oral sucralfate; Placebo
RCT/patient/double-blind
Time to mean dermatitis scores
Evensen (2001)8 NaSOS gel; Placebo
RCT/treatment/double-blind
Mean erythema score; Mean desq score
Maiche (1994)9 Sucralfate cream; Placebo
RCT/treatment/double-blind
G2 reaction
1 Bostrom A et al, Radiother Oncol 2001; 2 Schmuth M et al, Br J Dermatol 2002; 3 Løkkevik E et al, Acta Oncol 1996; 4 Roy I et al, Radiother Oncol 2001; 5 Campbell IR et al, Clin Oncol 1992; 6 Westbury C et al, Radiother Oncol 2000; 7 Lievens Y et al, Radiother Oncol 1998; 8 Evensen JF et al, Acta Oncol 2001; 9 Maiche A et al, Acta Oncol 1994.
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Study Descriptions and Trial Outcomes on Preventing Acute Radiation Skin Reactions
Author (Year) Treatment Arms Study Design Outcomes Assessed
Biafine Cream
Fenig
(2001)1
Biafine ointment; Lipiderm ointment; No treatment
RCT/patient/open Degree of skin reaction
Fisher (2000)2
Biafine ointment; Best supportive care
RCT/patient/openMax skin reaction score; Duration of dermatitis
Pommier (2004)3
Calendula ointment; Biafine cream
RCT/patient/single-blind
Acute skin toxicity
Oral Enzymes
Gujral (2001)4
Wobe-Mugos enzyme; No treatment
RCT/patient/openMean max extent of skin reaction
Dale
(2001)5
Wobe-Mugos enzyme; No treatment
RCT/patient/openMean max extent of skin reaction
Kaul
(1999)6
Wobe-Mugos enzyme; No treatment
RCT/patient/single-blind
Degree of skin reaction and biopsy scores
AmifostineDunst
(2000)7
Radiochemotherapy with/without IV amifostine
Non-randomized controlled trial/patient/open
Mean erythema score
1 Fenig E et al, Oncol Rep 2001; 2 Fisher J et al, J Radiat Oncol Biol Phys 2000; 3 Pommier P et al, J Clin Oncol 2004; 4 Gujral MS et al, Cancer Chemother Pharmacol 2001; 5 Dale PS et al, Cancer Chemother Pharmacol 2001; 6 Kaul R et al, Indian J Cancer 1999; 7 Dunst J et al, Strahlenther Onkol 2000.
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Study Descriptions and Trial Outcomes on Preventing Acute Radiation Skin Reactions
Author (Year) Treatment Arms Study Design Outcomes Assessed
Topical Acid Cream
Liguori (1997)1
Hyaluronic acid cream; Placebo
RCT/patient/double-blind
Skin reaction score
Halperin (1993)2
Ascorbic acid cream; Placebo
RCT/treatment/double-blind
Mean toxicity score
Aloe Vera
Heggie (2002)3
Aloe vera cream; Aqueous Cream
RCT/patient/double-blind
Erythema
Olsen
(2001)4
Mild soap + aloe vera gel; Mild soap
RCT/patient/single-blind
Time to erythema
Williams (1996)5
Aloe vera gel + Placebo; Aloe vera gel + No treatment
RCT/patient/double-blind (trial 1)/open (trial 2)
Max severity of skin reaction
Chamomile Cream vs Almond
Ointment
Maiche (1991)6
Chamomile cream vs Almond Ointment
RCT/treatment/single-blind
Frequency of G1, G2 or G3 skin reaction
Dressings Hazuka (1997)7 PASS; No treatment
Non-randomized controlled trial/patient/open (historical control)
19/55 treated sites had ≥ G2 desq; treatment; treatment interruptions
1 Liguori V et al, Radiother Oncol 1997; 2 Halperin EC et al, Int J Radiat Oncol Biol Phys 1993; 3 Heggie S et al, Cancer Nurs 2002; 4 Olsen DL et al, Oncol Nurs Forum 2001; 5 Williams MS et al, Int J Radiat Oncol Biol Phys 1996; 6 Maiche AG et al, Acta Oncol 1991; 7 Hazuka MB et al, Proc Am Soc Clin Oncol 1997.
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Study Descriptions and Trial Outcomes on Preventing Acute Radiation Skin Reactions
1 Schreck U et al, Strahlenther Onkol 2002; 2 Potera ME et al, Radiother Oncol 1982; 3 Delaney G et al, Australas Radiol 1997; 4 Shell JA et al, Oncol Nurs Forum 1986; 5 Mak SS et al, Cancer Nurs 2000.
Author (Year) Treatment Arms Study Design Outcomes Assessed
Topical Steroid Cream
Schreck
(2002)1Cream vs powder RCT/patient/open No statistical analysis
Potera
(1982)2
0.2% hydrocortisone valerate cream vs placebo
Nonrandomized controlled trial/ treatment/double-blind
Erythema, dry/moist desq, ulceration, duration/intensity of symptoms
Sucralfate or Derivatives
Delaney
(1997)3
10% sucralfate in sorbolene cream vs sorbolene cream alone
RCT/patient/ quadruple-blind
Mean healing time
Dressings
Shell
(1986)4
Moisture-vapor-permeable dressing; Hydrous lanolin gauze
RCT/patient/open Mean healing time
Mak
(2000)5
Moist hydrocolloid dressing; Topical gentian violet
RCT/patient/open Mean healing time
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Supportive Care Guidelines Group (Ontario)
Prevention of acute skin reaction
1. Gentle washing with water alone or with mild soap and water
2. Insufficient evidence to support or refute specific topical agents◦ Corticosteroids, sucralfate cream, Biafine, ascorbic acid, aloe vera,
chamomile cream, almond cream polymer adhesive skin sealant
3. Insufficient evidence to support or refute specific oral or IV agents◦ Enzymes, sucralfate◦ Amifostine
Management of acute skin reaction
1. Insufficient evidence to support or refute specific topical agents◦ Corticosteroids, sucralfate cream, specific dressings
Bolderston et al. The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline. Support Care Center (2006) 14:802-817.
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Supportive Care Guidelines Group (Ontario)
1. Plain, non-scented, lanolin-free hydrophilic cream◦ Discontinue if skin breakdown occurs
2. Low dose corticosteroid cream may be beneficial in reducing itching and irritation
1. Caution in overusing corticosteroid cream◦ But limited evidence to suggest that average
course of treatment (i.e. 8 weeks) would produce skin thinning
Bolderston et al. The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline. Support Care Center (2006) 14:802-817.
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Acute Dry desquamation, moderate erythemaMoist desquamation and mild bleeding
Chronic
From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.
Radiotherapy Reactions and Complications
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Acute Dry desquamation, moderate erythemaMoist desquamation and mild bleeding
Chronic Hypo- or hyperpigmentationTelangiectasiasEpidermal atrophy and fragilityPermanent epilation/alopecia, sweat gland atrophyNecrosis of soft tissue, cartilage and/or boneSubdermal fibrosisRadiation-induced malignancy
From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.
Radiotherapy Reactions and Complications
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Subdermal fibrosis
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Subdermal fibrosis
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Cheah et al. J Medical Case Reports. (2008) 2:136
9 months 1 year 3.5 years
Postirradiation Morphea
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Fibrosis Morphea
• 1/4 of breast radiation patients
• Little to no inflammatory infiltrate deep subcutaneous tissues
• Gradual over 3 months
• Within radiation port
• Severity correlates with radiation dose
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Fibrosis Morphea
• 1/4 of breast radiation patients
• Little to no inflammatory infiltrate deep subcutaneous tissues
• Gradual over 3 months
• Within radiation port
• Severity correlates with radiation dose
• Rare
• Dermal inflammatory infiltrate dermal fibrosis and SQ fat
• Abrupt onset: erythema, induration
• 1 month-32 years
• 20% can spread beyond radiation port
• Idiosyncratic
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Reports of Postirradiation Morphea
Study (Year)Cases
(n) Cancer TypeInterval Between
Radiation and Skin Disease (yrs)
Cooper & Denham (1990)1 1 Head & Neck 2
Abu-Shakra (1993)2 2 Cervix; Head & Neck <1
Schaffer (2000)3 2 Breast 6.5-32
Ullén & Björkholm (2003)4 1 Breast; Endometrial <1 and 5
Reddy (2005)5 1 Breast <1
Dubner (2006)6 1 Breast 3
Ardern-Jones & Black (2007)7 1 Breast 13
Seale (2008)8 1 Breast 2
Walsh (2008)9 5 Breast 4-12
Herrmann (2009)10 1 Breast 1.5
1 Cooper SG, Denham JW, Br J Radiol 1990; 2 Abu-Shakra M et al, Arthritis Rheum 1993; 3 Schaffer JV et al, Dermatology 2000; 4 Ullén H et al, Int J Gynecol Cancer 2003; 5 Reddy SM et al, Semin Arthritis Rheum 2005; 6 Dubner S et al, Breast J 2006; 7 Ardern-Jones M, Black MM, Clin Exp Dermatol 2003; 8 Seale M et al, Breast J 2008; 9 Walsh N et al, Hum Pathol 2008; 10 Herrmann T et al, Strahlenther Onkol 2009.
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Treatment: Post Irradiation Morphea
• CASE STUDY TREATMENT:◦ Topical clobetasol
• Potent topical steroid• Treatment option for post irradiation morphea • Addressed quickly, so condition improved
• MORE SEVERE CASES:◦ Oral corticosteroids
• Helps with condition• Emphasizes importance of distinguishing post irradiation
morphea and dermal fibrosis
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Schaffer et al. Dermatology. (2000) 200:67-71
Possible Mechanism of Action for Development of Post Irradiation Morphea
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Adverse reactions of radiation
• Considerable inter-individual variability◦ Duration◦ Radiation dose◦ Schedule◦ Age ◦ Acute skin reaction◦ Lifestyle factors◦ Genetic susceptibility
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Radiation Recall Dermatitis (RRD)
• “Recalling” by skin of previous radiation exposure, usually subsequent to cytotoxic drugs or antibiotics
• Median: 39 days• 7 days - 15 years• <2 month separation between radiation therapy and
drug administration• Tumor doses 10 - 61.2 Gy
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Radiation Recall Dermatitis (RRD)
• “Recalling” by skin of previous radiation exposure, usually subsequent to cytotoxic drugs or antibiotics
• Median: 39 days• 7 days - 15 years• <2 month separation between radiation therapy and
drug administration• Tumor doses 10 - 61.2 Gy• Mechanism unknown
◦ Vascularization, DNA repair, radiation-impaired epithelial function of stem cells, increased sensitivity to drugs
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Radiation recall dermatitis-inducing drugs (n = 75)
Drug Frequency (n) (%)
Docetaxel 10 13
Doxorubicin 10 13
Gemcitabine 8 11
Paclitaxel 8 11
Trimetrexate 5 7
Methotrexate 4 5
Hydroxyurea 4 5
Tamoxifen 4 5
Dactinomycin 2 3
Vinblastine 2 3
Others 18 24
Current Oncol. 15(1):53-62, 2008
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Additional RRD Culprits
• Trastuzumab• Sunitinib• Sorafenib• Erlotinib• Cetuximab
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Management of Radiation Dermatitis• Washing, moisturization and low-strength topical steroids• Further research
Postirradiation Morphea vs. Subdermal Fibrosis
Radiation Recall Dermatitis
Management of Radiation Dermatitis• Washing, moisturization and low-strength topical steroids• Further research
Postirradiation Morphea vs. Subdermal Fibrosis
Radiation Recall Dermatitis
Summary
Acute Chronic