The use of brachytherapy in the treatment of nonmelanoma skin cancer: A review

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  • REVIEW

    The use of brachytherapnonmelanoma skin

    Murad Alam, MD, MSCI,a,b,c Shivani Nanda, BS,a

    and Simon Yoo

    Chicago, Il

    varioselecof

    es rratesfunchera

    ntersapy.

    namradibracopti

    TRERAD

    Hsup

    advent of precise surgical treatments, such as MohsinghasSCeryC,ndingerythebyhis

    Abbreviations used:

    BCC: basal cell carcinomaHDR: high-dose rateIr: iridiumLDR: low-dose rateNMSC: nonmelanoma skin cancerSCC: squamous cell carcinoma0190-9622/$36.00

    dermatologists have been understandably con-cerned about the risk of inducing new precancerousand cancer lesions in the radiation field,8 particularly

    2010 by the American Academy of Dermatology, Inc.doi:10.1016/j.jaad.2010.03.027difference could be ascribed to selection bias. Inaddition, ionizing radiation can penetrate deeply,potentially injuring adjacent tissue and organs caus-ing brain and bone necrosis.6,7 Skin changes associ-ated with radiation, such as atrophy, telangiectasia,and pigmentation, may worsen with time.

    Finally, given the abundance of facial NMSCassociated with use of radiation for acne treatment,

    From the Departments of Dermatology,a OtolaryngologyeHead

    and Neck Surgery,b Surgery,c and Radiation Oncology,d

    Feinberg School of Medicine, Northwestern University.

    Northwestern University Department of Dermatology provided

    funding.

    Conflicts of interest: None declared.

    Reprint requests: Murad Alam, MD, MSCI, Department of

    Dermatology, Northwestern University, 676 N St Clair, Suite

    1600, Chicago, IL 60611. E-mail: m-alam@northwestern.edu.

    Published online April 18, 2011.ors may be treated with cryotherapy, photody-ic therapy, or imiquimod.2 In selected patients,ation, including external beam radiation orhytherapy, is an appropriate and effectiveon.

    ATMENT OF NMSC WITHIOTHERAPYistorically, external radiotherapy, consisting oferficial x-rays or electron therapy, has been a

    micrographic surgery, which offers tissue-spartumor removal, the use of radiation for NMSCsdeclined. The reported 5-year control rates for NMtreatment with external beam radiation are vgood, varying from 80% to 92% for SCC and BCrespectively; from 93% to 80% for primary arecurrent NMSC, respectively3; and approximat79% for tumors of the ear.4 However, even these vgood control rates are substantially inferior to98% to 99% 5-year cure rates for primary BCCMohs micrographic surgery,5 although part of tsurgery. Small, well-circumscribed, or superficialtumcurettage, elliptical excision, or Mohs micrographiccommonly used treatment for NMSCs. With theNonmelanoma skin cancers can be treated bycurettage, excisional techniques, and radiation. InWhen radiation is an option, brachytherapy, a formclose to the area to be treated, may have advantagparticular patients. After brachytherapy, recurrencefor small, superficial lesions, with good to excellentindications, efficacy, and adverse effects of brachyt( J Am Acad Dermatol 2011;65:377-88.)

    Key words: basal cell carcinoma; brachytherapy; isquamous cell carcinoma; surface-mold brachyther

    Nonmelanoma skin cancers (NMSCs) are themost common forms of cancer in theCaucasian population, with basal cell carci-

    nomas (BCCs) representing approximately 75% ofNMSCs and cutaneous squamous cell carcinomas(SCCs) comprising 25%.1 The standard of care forBCCs and SCCs is typically local destruction orsurgical removal, including electrodessication andS

    y in the treatment ofcancer: A review

    Bharat B. Mittal, MD,d Natalie A. Kim, BA,a

    , MDa,b,c

    linois

    us modalities, including electrodessication andted cases, radiation may be preferable to surgery.radiation therapy that places the radiation sourceelative to conventional external beam radiation infor nonmelanoma skin cancers are low, especiallytional and cosmetic results. This article reviews thepy in the treatment of nonmelanoma skin cancers.

    titial brachytherapy; nonmelanoma skin cancer;377

  • g-term cosmesis aftered as the quality ofover time, in selectederb cosmetic results as

    diation of skin cancerl beam radiation, in

    brachytherapy declinetreatment of skin lesionby x-rays.18 In more reccome to be used morehead and neck, prostacancers, but use for skiing worldwide.19

    RY

    theurfal) thioth

    radiation source is at a distance from thepatient and aimed at the site to betreated.

    d Although surgery is the first-linetreatment for nonmelanoma skin cancer,radiotherapy can be indicated inselected cases. When radiotherapy ischosen, brachytherapy may be a goodchoice for shallow, widespread lesions, orlesions at anatomic sites (eg, hand, fullscalp) that lie immediately abovestructures vulnerable to irradiation.

    d Brachytherapy provides minimal dosedelivery to surrounding healthy tissue,thus enabling good functional andcosmetic results.

    d Brachytherapy appears to be mosteffective for small, primary, and/orsuperficial squamous cell carcinomasand basal cell carcinomas, which can alsobe treated with surgery or external beamradiotherapy.

    J AM ACAD DERMATOLAUGUST 2011

    378 Alam et alwhich an external source of radiation, commonlycomprising photons or electrons, is aimed at thetarget lesion on the body. Teletherapy has beenimproved or adapted over the years, and is a versatiletechnology that can successfully treat many skincancers.12,13 Indeed, advances in teletherapy dis-placed the popularity of another form of radiationThat being said, there re-main indications for radia-tion treatment of NMSC.Some tumors are truly inop-erable, either because of thepatients inability to physi-cally undergo the removalor the reconstruction, or be-cause of the size and ana-tomic location of the tumor.In addition, elderly or infirmpatients with limited func-tional status but relativelylarge tumors who can theo-retically tolerate surgery maynonetheless prefer a nonin-vasive treatment, such as ra-diation. When surgery hasbeen attempted, but marginclearance is not possible, ad-juvant radiotherapy may alsobe indicated; this may espe-cially be the case for diffuseor neurotropic SCCs, espe-cially those of the scalp, lip,and ear. Finally, although lonsurgery has steadily improvreconstructions has increasedcases, radiotherapy offers supwell.

    In the United States, most rais by teletherapy, or externain younger patients. Radiation for skin cancer hasbeen shown to increase the likelihood of subsequentBCC and SCC by approximately 3-fold9; radiation hasalso been shown to increase the risk of subsequentmelanoma10; and elevated incidence of skin cancerhas been shown to increase the risk of secondprimary nonskin cancers.11 Although there is noclear consensus regardingthe age at which patientsshould receive radiationtherapy for NMSC, late adult-hood, perhaps around age 60years, may be a reasonablethreshold.

    CAPSULE SUMMA

    d In brachytherapy,is applied on (ie, sinto (ie, interstitiaexternal beam radtherapy, brachytherapy, approximately 20 years ago;now brachytherapy is experiencing somewhat ofFrom a technical standpoint, placement of theradioactive sources in modern brachytherapy maybe into a body cavity (intracavity), across a tissueboundary into a contained space (transluminal), intobody tissues (interstitial), or on the body surface(surface-mold technique). In the surface-mold tech-nique, custommolds are created from impressions of

    the tumor surface, fitteand then applied to theand until about 1940, radiumapplication was the favoredmethod.16,17 For the first fewdecades, thin-walled con-tainers plated with RaSO4and inert metals were ap-plied to the skin in directcontact therapy. Startingabout 1930, this approachwas gradually replaced byradium puncture, with 2 to 7radium needles loaded with5 to 10 mg of radium appliedto the surface of the tumor atintervals of 5 mm for 4 to 5hours. Ten-year control rateswith direct contact therapyand radium puncture werereported to be 73.8% and84%, respectively. Radiumbrachytherapy was so popu-lar it was routinely used fornoncancerous dermatologiclesions, such as hemangi-omas.17 By the mid-1940s,d in favor as a modality fors and was gradually replacedent times, brachytherapy hascommonly for treatment of

    te, cervical, and endometrialn cancers is gradually increas-a resurgence, especially in Europe, and even in theUnited States.14

    Brachytherapy for treatment of NMSCBrachytherapy, derived from the Greek brachy,

    or short distance, entails placement of radioactivesources directly onto or into target tissues.15

    Brachytherapy is an ancienttechnique, which has beenused to treat malignanciessince the discovery of radiumby Curie and Becquerel.11

    Treatment of skin cancerwas first attempted in 1899,

    radioactive sourcece mold) or placede body, versus inerapy, in which thed with radioactive isotopes,tumor.20

  • J AM ACAD DERMATOLVOLUME 65, NUMBER 2

    Alam et al 379Since the mid-1960s, radioactive sources are nolonger implanted directly into the patient, as thispractice exposes the radiation oncologist and staff tounacceptable levels of irradiation. Instead, nonra-dioactive tubes, catheters, or other applicators arefirst implanted into the target site, and then sourcesare afterloaded into this apparatus.16 Manual after-loading has now been replaced by remote after-loading, which permits the operator to remain in ashielded site.

    Implants associated with brachytherapy may bepermanent or temporary.21 In either case, the tech-nique minimizes unwanted dose delivery to nearbyhealthy but radiation-sensitive organs, such as thebrain.19 Thus, brachytherapy can be performed on

    Table I. Comparison of dose delivery with commonbrachytherapy techniques

    LDR 192Ir MDR HDR

    Dose rate Low Medium High

    Duration per treatment 2-6 d 1 d MinutesDuration of treatment course 2-6 d 1 d 3-5 wkAvailability (internationally) 11 e eEase of optimization e e 1Dose per treatment, Gy 60 40 0.18-.7*No. of fractions 1 1 7-35Total dose as sole modality, Gy 60 40 35-50*

    HDR, High-dose rate; Ir, iridium; LDR, low-dose rate; MDR, medium-

    dose rate.

    Adapted with permission from Lippincott Williams & Wilkins

    (http://lww.com).35

    *Common regimensmay include20 to 35 fractionsof 180 to 200 cGy

    each in daily or twice-daily treatments; 5 fractions of 700 cGy for

    total dose of 35 Gy; or 10 fractions of 500 cGy for total dose of 50 Gy.the scalp and other areas where traditional externalradiotherapy may be less safe.22,23

    Permanent brachytherapy implants emit radiationat very-low-dose rates (LDR), equivalent to less than0.4 Gy/h for the lifetime of the radioactive isotope.Typically, iodine-125 is used in such implants be-cause of its emission of relatively lowmean energies.In contrast, temporary implants (Table I) are associ-ated with greater variation in dose rates, with LDRimplants delivering 0.4 to 2 Gy/h, over durationsfrom 24 to 144 hours in an inpatient setting; medium-dose-rate devices delivering 2 to 12 Gy/h; and high-dose-rate (HDR) emitters delivering more than 12Gy/h15 (Table I). The most commonly used isotopefor temporary implantation is iridium-192 (192Ir),which has a half-life of 74.2 days and emits g rayswith a mean energy of 380 keV. Other g-emittingisotopes used for temporary implantation, especiallyin the past, include cobalt and cesium.20

    A single treatment of LDR brachytherapy canrequire 3 to 5 days, requiring radiation protectionfor those who are in contact with the patient for theduration. Conversely, an HDR brachytherapy treat-ment can be completed in 1 to 30minutes, usually onan outpatient basis. However, HDR brachytherapy ismore likely to cause damage to surrounding normaltissue than is LDR brachytherapy. To avoid suchcomplications, when HDR brachytherapy is per-formed, the total dose is commonly divided overa few or as many as 30 to 40 sessions, every 1 to28 days.

    Surface-mold brachytherapySurface-mold brachytherapy (Tables II and III) is

    commonly used for the treatment of well-circumscribed, superficial tumors. Molds are con-structed from pliable materials, such as silicone orpolymethyl-methacrylate, and are fitted to the tumorsurface (Figs 1 and 2). Radioactive sources are thenloaded into the mold in such as a manner as todistribute uniform, radioactive dosage throughoutthe tumor volume (Figs 3 and 4). Surface-moldbrachytherapy is often delivered at HDR (\12 Gy/h).

    LDR brachytherapy with surface molds has beenstudied in retrospective studies and case series. Inone retrospective case-control study, the cosmeticoutcome was compared for 15 patients treated forBCC of the face with gold grain Elastoplast molds(Beiersdorf, Birmingham, England) and 15 patientstreated for the same indication with fractionatedsuperficial x-ray.24 The tumors in the brachytherapyarm had received total doses of 60 to 65 Gy during a7-day application, and all of the case and controltumors had been treated more than 10 years ago.Superior long-term cosmesis was observed in thebrachytherapy group. This was ascribed to the rapiddecrease in brachytherapy dose beyond the super-ficial tissues. In addition, it was hypothesized that x-ray treatment may be relatively more prone to inducevery late skin and subcutis adverse effects thanbrachytherapy. A notable case series described thetreatment of several eyelid tumors, including twoneglected BCCs on the cusp of orbital invasion.25 Forthese lesions, LDR brachytherapy with a 15-mmdiameter gold shield was used as an alternative toexenteration and external radiation. In particular, aniodine-125 plaque was applied to the outside of theshield, thus allowing protection of the globe whilepermitting irradiation of the target lesion with 50 Gyto a 5-mm depth. Two-year follow-up indicated norecurrence. Studies on the use of surface-mold HDRbrachytherapy for NMSCs have included prospectiveand retrospective cohort studies along with casereports. Most studies have evaluated the use of

    192g-emitting isotopes such as Ir, whereas at leasttwo studies explored the use of a mixed b-g

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    J AM ACAD DERMATOLAUGUST 2011

    380 Alam et alTable II. Adverse events reported after brachytherap

    Study Adverse eventseacute

    Avril et al31 112/173 Dyspigmentation and te

    Berridge and Morgan24 Unknown

    Conill et al33 24/24 Erythema, edemaConill et al32 54/54 MucositisDebois28 Dyschromia, telangiectasiaGuix et al1 136/136 Erythema

    14/136 UlcerationLee et al27 5/5 Desquamation, erythema, or

    1/5 AlopeciaOzyar and Gurdalli23 None reportedShields et al25 8/8 Mild postoperative discomfor

    edema limits eye movementSedda et al26 53/53 Erythema

    Bleeding (only large lesions)22isotopeeeither rhenium-188 or holmium-166.26,27

    HDR brachytherapy studies have investigated itsuse on NMSCs located in areas such as the nose,eyelid, ear, and back of the hands that may bedifficult to treat surgically or may benefit from thespecial features of brachytherapy, such as the abilityto confine radiation to a superficial treatment area.

    A series of prospective cohort studies evaluatingthe efficacy of NMSC treatment with 192Ir HDRsurface-mold brachytherapy found good posttreat-ment cosmesis and low recurrence rates up to 5 yearslater. Relatively smaller lesions were associated withhigher rates of tumor control and better cosmeticresults compared with l...

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