radiotherapy-induced dermatologic toxicities jennifer nam choi, md yale university school of...

Radiotherapy-Induced Dermatologic Toxicities

Jennifer Nam Choi, MD

Yale University School of Medicine

Department of Dermatology

Yale Cancer Center

New Haven, CT

Disclosure of Relevant Relationships with Industry

Jennifer N. Choi, MD

Radiotherapy-Induced Dermatologic Toxicities

I do not have any relevant relationships with industry.

Radiotherapy Reactions and Complications

Acute

Chronic

From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.

Radiotherapy Reactions and Complications

Acute Dry desquamation, moderate erythemaMoist desquamation and mild bleeding

Chronic

From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.

Radiotherapy Reactions and Complications

Acute

Chronic

From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.

RadiationDermatitis

Locations Most Associated with Radiation Dermatitis

• Head/Neck • Chest wall

◦ Breast◦ Lung

• Genitourinary◦ Uterine◦ Cervical

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

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

Acute: Radiation Dermatitis

• Erythema• Xerosis

Acute: Radiation Dermatitis

• Erythema• Xerosis• Hyperpigmentation• Dry desquamation• Pruritus• Moist desquamation• Pain

• 2-4 weeks, 20-25 Gy• 80-90%

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

Breast Irradiation

A. Radiation Beam

B. Radiation Beam

C. Breast

D. Ribs

E. Heart

F. Lungs

G. Vertebrae

H. Sternum (breast bone)

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

Radiation Dermatitis Management

• Controversial

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.

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.

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.

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

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.

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.

Acute Dry desquamation, moderate erythemaMoist desquamation and mild bleeding

Chronic

From Bolognia, Jorizzo & Rapini. Dermatology 2e. 2008 Elsevier, Ltd.

Radiotherapy Reactions and Complications

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

Subdermal fibrosis

Subdermal fibrosis

Cheah et al. J Medical Case Reports. (2008) 2:136

9 months 1 year 3.5 years

Postirradiation Morphea

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

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

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.

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

Schaffer et al. Dermatology. (2000) 200:67-71

Possible Mechanism of Action for Development of Post Irradiation Morphea

Adverse reactions of radiation

• Considerable inter-individual variability◦ Duration◦ Radiation dose◦ Schedule◦ Age ◦ Acute skin reaction◦ Lifestyle factors◦ Genetic susceptibility

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

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

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

Additional RRD Culprits

• Trastuzumab• Sunitinib• Sorafenib• Erlotinib• Cetuximab

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