CANCER RISKS AFTER RADIOTHERAPY FOR BENIGN

CONDITIONSHAZEM EL-GAMAL, MDRICHARD BENNETT, MD

MOHS MICROGRAPHIC SURGERY & DERMATOLOGIC SURGERY

SANTA MONICA • PASADENA • UCLA • USC • DREW/KING

WILHELM CONRAD RÖNTGEN(ROENTGEN)

• GERMAN PHYSICIST (1845-1923)

• PHYSICS INSTITUTE (WURZBURG, GERMANY)

• “DISCOVERED” X-RAYS IN NOVEMBER 1895

• WINNER NOBEL PRIZE PHYSICS 1901

HISTORY OF X-RAYS

• 1859 Plueber (Germany)-Vacuum Tube Fluoresced

• 1860 Hittorf (Germany)-Luminous Stream Detected by Magnet

• 1875 Wm. Crookes (English)-High Vacuum Tube; “Cathode Ray” - Apple Green Light

• 1893 Herbert Jackson (English)-Anode to Catch Cathode Stream

HISTORY OF X-RAYS (Cont.)

• 1893 H. Hertz (Germany) - Cathode Rays Through ??

• 1893 R. Leonard (Germany) - Showed Substances Fluoresced With Cathode Rays

• 1895 Roentgen (Germany) - Darkened Room, Put Hand between Chemical & Tube

EARLY X-RAY IMAGE

(Frau Roentgen’s Hand) c. 1895

FORMATION OF THE CATHODE STREAM AND X-RAYS

X-RAY TUBE EASILY OBTAINED

1898 BRITISH ADVERTISEMENT

EARLY X-RAY MACHINE

RADIOSENSITIVITYFrances Williams, MD

The Roentgen Rays in Medicine & SurgeryMacMillan, Co; New York 1901

Fat

Muscle

Bone

THOMAS A. EDISON1896 Fluoroscopic Exhibit

National Electric Light Association, NYC

SIDE EFFECTS OF X-RAY

• DERMATITIS (1896) “SUNBURN”

• “WARTS” (1898)• SQUAMOUS CELL

CARCINOMA →METASTASIS (1907)

• INTERNAL CANCER (1950)

ELECTROMAGNETIC SPECTRUM

PERCY BROWN, MD

AMERICAN MARTYRS TO SCIENCE THROUGH ROENTGEN RAYS

CHARLES C. THOMAS, SPRINGFIELD, 1936

• REPORTS 26 WORKERS IN X-RAY WHO DIED OF SCC, MOSTLY ON LEFT HAND THAT METASTASIZED– 16 MDS (7/16 IN LATE 30 OR 40 YRS OF AGE)

EARLY FLUOROSCOPE USING HAND TO FOCUS

EARLY FLUOROSCOPE USING FOREARM BONES TO FOCUS

SCC AFTER RADIOTHERAPY FOR ECZEMA

X-RAYS IN DERMATOLOGY

• 1898 FIRST REPORTED TO BE USEFUL IN ACNE

• 1899 SCHIFF & FRIEND, ↓ HAIR IN NEVUS

• 1902 DR. PUSEY PUBLISHES TEXTBOOK

• 1907 DR. MACKEE PUBLISHES TEXTBOOK

William A. Pusey, MD (1865-1940)

Professor DermatologyU. of Illinois Medical School

Introduced Radiotherapy to Dermatology

EARLY X-RAY TECHNIQUE

Wm. A. PuseyEarly Textbook by

Dermatologist Featuring Radiology,

1907

George M. MacKee, MD (1878-1955)

PROFESSOR DERMATOLOGY

NEW YORK SKIN & CANCER

MacKee’s Standard Textbook

Radiotherapy in Dermatology

4 Editions(1921, 1927, 1938, 1946)

Rose Hirschler, MD (1875-1940)

Professor DermatologyWomen’s Medical

School, Phil.

Began Radiotherapy Dept.

Died of Leukemia

SKIN PENETRATION BY X-RAYS

1903 BCC INNER CANTHUSTreated with X-ray

Rodent Ulcer

STUDY OVERVIEW

• 17,382 CHARTS REVIEWED FROM 1978-2003

• CASE GROUP– 432 PATIENTS FOUND THAT RECEIVED

RADIOTHERAPY FOR BENIGN CONDITIONS

• CONTROL GROUP– RANDOMLY SELECTED– AGE AND GENDER MATCHED 1:1 TO CASES

INDICATIONS FOR RADIOTHERAPY

Dermatologic Number/(%)Acne 357/(82.8)

Eczema 17/(3.9)

Tinea Capitis 9/(2.1)

Psoriasis 4/(0.9)

Dermatitis/NOS 4/(0.9)

Seborrheic Dermatitis 3/(0.7)

Hair Loss 2/(0.5)

Neurodermatitis 2/(0.5)

INDICATIONS FOR RADIOTHERAPY (Cont.)

Dermatologic (cont.) Number/(%)Yeast 1/(0.2)

Hyperhidrosis 1/(0.2)

Oily Skin 1/(0.2)

Keloid 1/(0.2)

Tinea Pedis 1/(0.2)

Impetigo 1/(0.2)

Hemangioma 1/(0.2)

Tinea Facei 1/(0.2)

INDICATIONS FOR RADIOTHERAPY (Cont.)

Dermatologic (cont.) Number/(%)Pruritis 1/(0.2)

Wart 1/(0.2)

Folliculitis 1/(0.2)

Erythema 1/(0.2)

Actinomycosis 1/(0.2)

INDICATIONS FOR RADIOTHERAPY (Cont.)

ENT Number/(%)Sinus Problems 6/(1.4)

Tonsils 2/(0.5)

Eustachian Tube 1/(0.2)

Asthma 1/(0.2)

Whooping Cough 1/(0.2)

INDICATIONS FOR RADIOTHERAPY (Cont.)

Orthopaedic Number/(%)Tendinitis 1/(0.2)

Ankylosing Spondylitis 1/(0.2)

GOLDSCHMIDT, H.

IONIZING RADIATION THERAPY IN DERMATOLOGY

ARCH DERMATOL 111:1511-1517, 1975

• SURVEY OF U.S. AND CANADIAN DERMATOLOGISTS

• 2,305 RESPONSES TABULATED

89.3

41.834.6

23.9

0102030405060708090

Percent (%)

BCC Acne Eczema PsoriasisIndications for Radiotherapy

DERMATOLOGISTS USING SUPERFICIAL X-RAY THERAPY (1975)

CANCER AND IONIZING RADIATION

CancerX-Rays

DATE INJURY REPORTED BY

1896 Dermatitis hands Grubbe

1896 Epilation Daniel

1902 CA in X-ray Ulcer Frieben

1911 Leukemia in 5 Radiation Jagic

Workers

1912 Anemia in 2 X-ray Workers Belere

1949 BCC in 5 yr old Child Scharnajel/Pack

1950 Thyroid Cancer in X-ray for Thymus Duffy/Fitzgerald

SCHARNAGEL, IM, PACK, GT

MULTIPLE BASAL CELL EPITHELIOMAS IN A 5 Y.O. CHILD

AM. J. DIS CHILD 77:647-651 (1949)

• BCCS DEVELOP IN PORT AREA FOR RADIATION TO THYMUS GLAND

DUFFY, BJ, JR., FITZGERALD, PJ

THYROID CANCER IN CHILDHOOD & ADOLESCENCE

CANCER 1018-1032 (1950)

• 10/28 CASES HAD HAD X-RAY FOR ENLARGED THYMUS GLAND IN INFANCY

Marion Sulzberger, MD (1895-1984)

PROFESSOR & CHAIRMAN

Dept. of DermatologyNYU School of Medicine

SULZBERGER, MB, BAER, RL, BOROTA, A

DO ROENTGEN-RAY TREATMENTS AS GIVEN BY SPECIALISTS PRODUCE CANCERS OR

OTHER SEQUELAE? ARCH DERM SYPH 65:639-655 (1952)

• REEXAMINED 1000 PATIENTS IRRADIATED AND 1000 NON-IRRADIATED PATIENTS

• NO SKIN CANCERS WITH 5-23 YEARS OF FOLLOW-UP

BCCs AFTER RADIOTHERAPY FOR ACNE

INCIDENCE ANGLES FOR X-RAY TREATMENT OF ACNE AND TINEA BARBAE

(MacKee Textbook 1946)

NMSCSTUDY INFORMATION

• 432 PATIENTS IRRADIATED FOR BENIGN MEDICAL CONDITIONS– 148 MEN– 284 WOMEN

• MEAN AGE 65 YEARS FOR CASES & CONTROLS

NMSCMean Number of NMSC in Cases & Controls

7.1

3.5

0.21 0.20

1

2

3

4

5

6

7

8

Number

Mean Number ofBCC (p <0.0001)

Mean Number ofSCC (p=0.22)

CasesControls

NMSCMean Age of First NMSC in Cases & Controls

53.9

60

5051525354555657585960

Age (yrs)

Mean Age at First NMSC(p-value <0.0001)

CasesControls

NMSCMean Number of NMSC in the Central Face

for Cases & Controls

1.63

1.2

00.20.40.60.8

11.21.41.61.8

Number of NMSC

Mean Number of NMSC inCentral Face

(p-value = 0.0001)

CasesControls

NMSCLocation of Presenting NMSC in Cases &

Controls

81.577.3

9.712.88.8 9.9

0102030405060708090

Percent (%)

Mid-face LateralFace

Other

(non-significant)

CasesControls

THYROID DISEASEOdds Ratio of Thyroid Cancer & Non-cancer

Thyroid Problems

17.62

2.3402468

1012141618

Odds Ratio (OR)

Thyroid Cancer (p-value = 0.000125)

Non-cancer Problems(p-value = 0.000075)

BREAST CANCER AND IONIZING RADIATION

Breast Cancer

Ionizing Radiation

MCGREGOR, DH, ET AL

ATOMIC BOMB SURVIVORS - HIROSHIMA, NAGASAKI

J. NATL. CANCER INST. 59:799-811 (1977)

• RELATIVE RISK ≈ AGE AND DOSE

• BUT AGE (10-19) >> DOSE

STUDY DOSE O/E

Atomic Bomb Japan 30 R 1.6

Postpartum Mastitis 380 R 4.5

Multiple Fluoroscopic Exams 70-100 R 0.9-1.7

Skin Hemangiomas 17-52 R 1.15-1.3

Hodgkins Disease

Tinea Capitis

Enlarged Thymus 70 R 3.5

X-RAYS → BREAST CANCER

BREAST CANCERStudy Information

• 244 WOMEN IRRADIATED FOR ACNE• 244 AGE MATCHED WOMEN

CONTROLS• MEAN YEARS F/U: 49 YRS• MEAN AGE:

– CASES: 66.2 YRS– CONTROLS: 65.8 YRS

BREAST CANCERStudy Information (cont.)

• Number of Breast Cancers– Cases: 36– Controls: 16– OR: 2.47 – P-value: 0.0033

36

16

0

5

10

15

20

25

30

35

40

Number

Cases Controls

STANDARD RADIOTHERAPY TECHNIQUE

(Goldschmidt 1994, J. Am. Acad. Derm. 30:173)

BREAST CANCEROdds Ratio of Breast Cancer vs. Age at

XRT

2.472.72

1.75

0

0.5

1

1.5

2

2.5

3

Odds Ratio (OR)

All Women(p=0.0033)

Age <20(p=0.0022)

Age>20(p=0.26)

BREAST CANCEROdds Ratio of Breast Cancer vs.

Number of Treatments

2.47

3.95

1.78

0

0.5

1

1.5

2

2.5

3

3.5

4

Odds Ratio (OR)

All Women(p=0.0033)

Number >=5(p=0.0029)

Number <5(p=0.36)

BREAST CANCEROdds Ratio of Breast Cancer vs. Year

of Treatment

2.47

3.35

0.66

0

0.5

1

1.5

2

2.5

3

3.5

Odds Ratio (OR)

All Women(p=0.0033)

Year of XRT<1950

(p=0.00014)

Year of XRT>=1950(p=0.77)

BREAST CANCEROdds Ratio of Breast Cancer vs.

Anatomic Location of Radiotherapy

2.472.28

3.99

0

0.5

1

1.5

2

2.5

3

3.5

4

Odds Ratio (OR)

All Women(p=0.0033)

Face Only(p=0.016)

Face + OtherSite (p=0.0093)

BREAST CANCEROdds Ratio of Breast Cancer

Multivariate Analysis

2.47

3.34

1.89

0

0.5

1

1.5

2

2.5

3

3.5

Odds Ratio (OR)

All Women(p=0.0033)

Age <20 &Year

XRT<1950(p=0.0004)

Age >20 &Year of XRT

>=1950(p=0.42)

BREAST CANCEROdds Ratio of Breast Cancer

Multivariate Analysis

2.47

4.1

00.5

11.5

22.5

33.5

44.5

Odds Ratio (OR)

All Women (p=0.0033)

Age <20 & YearXRT<1950 &

Treatment Number >=5(p=0.0066)

BREAST CANCERPrevalence of Breast Biopsies in Non-

cancer Cases and Controls

6.28

2.19

0

1

2

3

4

5

6

7

Prevalence (%)

Prevalence of Breast Biopsies in Non-cancer Cases & Controls

(OR = 2.98, p-value = 0.0511)

CasesControls

CONCLUSIONSNMSC

• PATIENTS THAT RECEIVED RADIOTHERAPY FOR BENIGN CONDITIONS:

– NO INCREASED RISK OF DEVELOPING SCC – DEVELOP A GREATER NUMBER OF BCCS– DEVELOP NMSC AT EARLIER AGE – DEVELOP GREATER PROPORTION OF NMSC IN

THE CENTRAL FACE

CONCLUSIONSTHYROID CANCER

• PATIENTS THAT RECEIVED RADIOTHERAPY FOR BENIGN CONDITIONS:

– INCREASED RISK (OR 17.6) FOR DEVELOPING THYROID CANCER

– INCREASED RISK (OR 2.34) FOR DEVELOPING NON-CANCER THYROID PROBLEMS

CONCLUSIONSBREAST CANCER

• WOMEN THAT RECEIVED RADIOTHERAPY FOR ACNE:

– INCREASED RISK (OR 2.47) FOR DEVELOPING BREAST CANCER

– BREAST CANCER RISK CORRELATED TO:• AGE AT RADIOTHERAPY (<20 YEARS)• NUMBER OF TREATMENTS (>=5)• RADIOTHERAPY YEAR (<1950)