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

REVIEWS

The use of brachytherapy in the treatment of nonmelanoma skin cancer: A review Murad Alam, MD, MSCI,a,b,c Shivani Nanda, BS,a Bharat B. Mittal, MD,d Natalie A. Kim, BA,a and Simon Yoo, MDa,b,c Chicago, Illinois Nonmelanoma skin cancers can be treated by various modalities, including electrodessication and curettage, excisional techniques, and radiation. In selected cases, radiation may be preferable to surgery. When radiation is an option, brachytherapy, a form of radiation therapy that places the radiation source close to the area to be treated, may have advantages relative to conventional external beam radiation in particular patients. After brachytherapy, recurrence rates for nonmelanoma skin cancers are low, especially for small, superficial lesions, with good to excellent functional and cosmetic results. This article reviews the indications, efficacy, and adverse effects of brachytherapy in the treatment of nonmelanoma skin cancers. ( J Am Acad Dermatol 2011;65:377-88.) Key words: basal cell carcinoma; brachytherapy; interstitial brachytherapy; nonmelanoma skin cancer; squamous cell carcinoma; surface-mold brachytherapy.

N

onmelanoma skin cancers (NMSCs) are the most common forms of cancer in the Caucasian population, with basal cell carcinomas (BCCs) representing approximately 75% of NMSCs and cutaneous squamous cell carcinomas (SCCs) comprising 25%.1 The standard of care for BCCs and SCCs is typically local destruction or surgical removal, including electrodessication and curettage, elliptical excision, or Mohs micrographic surgery. Small, well-circumscribed, or superficial tumors may be treated with cryotherapy, photodynamic therapy, or imiquimod.2 In selected patients, radiation, including external beam radiation or brachytherapy, is an appropriate and effective option.

TREATMENT OF NMSC WITH RADIOTHERAPY Historically, external radiotherapy, consisting of superficial x-rays or electron therapy, has been a 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: [email protected]. Published online April 18, 2011. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.03.027

Abbreviations used: BCC: HDR: Ir: LDR: NMSC: SCC:

basal cell carcinoma high-dose rate iridium low-dose rate nonmelanoma skin cancer squamous cell carcinoma

commonly used treatment for NMSCs. With the advent of precise surgical treatments, such as Mohs micrographic surgery, which offers tissue-sparing tumor removal, the use of radiation for NMSCs has declined. The reported 5-year control rates for NMSC treatment with external beam radiation are very good, varying from 80% to 92% for SCC and BCC, respectively; from 93% to 80% for primary and recurrent NMSC, respectively3; and approximating 79% for tumors of the ear.4 However, even these very good control rates are substantially inferior to the 98% to 99% 5-year cure rates for primary BCC by Mohs micrographic surgery,5 although part of this difference could be ascribed to selection bias. In addition, ionizing radiation can penetrate deeply, potentially injuring adjacent tissue and organs causing brain and bone necrosis.6,7 Skin changes associated with radiation, such as atrophy, telangiectasia, and pigmentation, may worsen with time. Finally, given the abundance of facial NMSC associated with use of radiation for acne treatment, dermatologists have been understandably concerned about the risk of inducing new precancerous and cancer lesions in the radiation field,8 particularly 377

378 Alam et al

J AM ACAD DERMATOL AUGUST 2011

in younger patients. Radiation for skin cancer has a resurgence, especially in Europe, and even in the been shown to increase the likelihood of subsequent United States.14 9 BCC and SCC by approximately 3-fold ; radiation has also been shown to increase the risk of subsequent Brachytherapy for treatment of NMSC melanoma10; and elevated incidence of skin cancer Brachytherapy, derived from the Greek ‘‘brachy,’’ has been shown to increase the risk of second or short distance, entails placement of radioactive primary nonskin cancers.11 Although there is no sources directly onto or into target tissues.15 clear consensus regarding Brachytherapy is an ancient the age at which patients technique, which has been CAPSULE SUMMARY should receive radiation used to treat malignancies therapy for NMSC, late adultsince the discovery of radium In brachytherapy, the radioactive source hood, perhaps around age 60 by Curie and Becquerel.11 is applied on (ie, surface mold) or placed years, may be a reasonable Treatment of skin cancer into (ie, interstitial) the body, versus in threshold. was first attempted in 1899, external beam radiotherapy, in which the That being said, there reand until about 1940, radium radiation source is at a distance from the main indications for radiaapplication was the favored patient and aimed at the site to be tion treatment of NMSC. method.16,17 For the first few treated. Some tumors are truly inopdecades, thin-walled conAlthough surgery is the first-line erable, either because of the tainers plated with RaSO4 treatment for nonmelanoma skin cancer, patient’s inability to physiand inert metals were apradiotherapy can be indicated in cally undergo the removal plied to the skin in direct selected cases. When radiotherapy is or the reconstruction, or becontact therapy. Starting chosen, brachytherapy may be a good cause of the size and anaabout 1930, this approach choice for shallow, widespread lesions, or tomic location of the tumor. was gradually replaced by lesions at anatomic sites (eg, hand, full In addition, elderly or infirm radium puncture, with 2 to 7 scalp) that lie immediately above patients with limited funcradium needles loaded with structures vulnerable to irradiation. tional status but relatively 5 to 10 mg of radium applied large tumors who can theoto the surface of the tumor at Brachytherapy provides minimal dose retically tolerate surgery may intervals of 5 mm for 4 to 5 delivery to surrounding healthy tissue, nonetheless prefer a noninhours. Ten-year control rates thus enabling good functional and vasive treatment, such as rawith direct contact therapy cosmetic results. diation. When surgery has and radium puncture were Brachytherapy appears to be most been attempted, but margin reported to be 73.8% and effective for small, primary, and/or clearance is not possible, ad84%, respectively. Radium superficial squamous cell carcinomas juvant radiotherapy may also brachytherapy was so popuand basal cell carcinomas, which can also be indicated; this may espelar it was routinely used for be treated with surgery or external beam cially be the case for diffuse noncancerous dermatologic radiotherapy. or neurotropic SCCs, espelesions, such as hemangicially those of the scalp, lip, omas.17 By the mid-1940s, and ear. Finally, although long-term cosmesis after brachytherapy declined in favor as a modality for surgery has steadily improved as the quality of treatment of skin lesions and was gradually replaced reconstructions has increased over time, in selected by x-rays.18 In more recent times, brachytherapy has cases, radiotherapy offers superb cosmetic results as come to be used more commonly for treatment of well. head and neck, prostate, cervical, and endometrial In the United States, most radiation of skin cancer cancers, but use for skin cancers is gradually increasis by teletherapy, or external beam radiation, in ing worldwide.19 which an external source of radiation, commonly From a technical standpoint, placement of the comprising photons or electrons, is aimed at the radioactive sources in modern brachytherapy may target lesion on the body. Teletherapy has been be into a body cavity (intracavity), across a tissue improved or adapted over the years, and is a versatile boundary into a contained space (transluminal), into technology that can successfully treat many skin body tissues (interstitial), or on the body surface cancers.12,13 Indeed, advances in teletherapy dis(surface-mold technique). In the surface-mold techplaced the popularity of another form of radiation nique, custom molds are created from impressions of therapy, brachytherapy, approximately 20 years ago; the tumor surface, fitted with radioactive isotopes, now brachytherapy is experiencing somewhat of and then applied to the tumor.20 d

d

d

d

Alam et al 379

J AM ACAD DERMATOL VOLUME 65, NUMBER 2

Table I. Comparison of dose delivery with common brachytherapy techniques LDR Dose rate

Duration per treatment Duration of treatment course Availability (internationally) Ease of optimization Dose per treatment, Gy No. of fractions Total dose as sole modality, Gy

192

MDR

HDR

Low

Ir

Medium

High

2-6 d 2-6 d 11 e 60 1 60

1d 1d e e 40 1 40

Minutes 3-5 wk e 1 0.18-.7* 7-35 35-50*

HDR, High-dose rate; Ir, iridium; LDR, low-dose rate; MDR, mediumdose rate. Adapted with permission from Lippincott Williams & Wilkins (http://lww.com).35 *Common regimens may include 20 to 35 fractions of 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.

Since the mid-1960s, radioactive sources are no longer implanted directly into the patient, as this practice exposes the radiation oncologist and staff to unacceptable levels of irradiation. Instead, nonradioactive tubes, catheters, or other applicators are first implanted into the target site, and then sources are ‘‘afterloaded’’ into this apparatus.16 Manual afterloading has now been replaced by remote afterloading, which permits the operator to remain in a shielded site. Implants associated with brachytherapy may be permanent or temporary.21 In either case, the technique minimizes unwanted dose delivery to nearby healthy but radiation-sensitive organs, such as the brain.19 Thus, brachytherapy can be performed on the scalp and other areas where traditional external radiotherapy may be less safe.22,23 Permanent brachytherapy implants emit radiation at very-low-dose rates (LDR), equivalent to less than 0.4 Gy/h for the lifetime of the radioactive isotope. Typically, iodine-125 is used in such implants because of its emission of relatively low mean energies. In contrast, temporary implants (Table I) are associated with greater variation in dose rates, with LDR implants delivering 0.4 to 2 Gy/h, over durations from 24 to 144 hours in an inpatient setting; mediumdose-rate devices delivering 2 to 12 Gy/h; and highdose-rate (HDR) emitters delivering more than 12 Gy/h15 (Table I). The most commonly used isotope for temporary implantation is iridium-192 (192Ir), which has a half-life of 74.2 days and emits g rays with a mean energy of 380 keV. Other g-emitting isotopes used for temporary implantation, especially in the past, include cobalt and cesium.20 A single treatment of LDR brachytherapy can require 3 to 5 days, requiring radiation protection

for those who are in contact with the patient for the duration. Conversely, an HDR brachytherapy treatment can be completed in 1 to 30 minutes, usually on an outpatient basis. However, HDR brachytherapy is more likely to cause damage to surrounding normal tissue than is LDR brachytherapy. To avoid such complications, when HDR brachytherapy is performed, the total dose is commonly divided over a few or as many as 30 to 40 sessions, every 1 to 28 days. Surface-mold brachytherapy Surface-mold brachytherapy (Tables II and III) is commonly used for the treatment of wellcircumscribed, superficial tumors. Molds are constructed from pliable materials, such as silicone or polymethyl-methacrylate, and are fitted to the tumor surface (Figs 1 and 2). Radioactive sources are then loaded into the mold in such as a manner as to distribute uniform, radioactive dosage throughout the tumor volume (Figs 3 and 4). Surface-mold brachytherapy is often delivered at HDR (\12 Gy/h). LDR brachytherapy with surface molds has been studied in retrospective studies and case series. In one retrospective case-control study, the cosmetic outcome was compared for 15 patients treated for BCC of the face with gold grain Elastoplast molds (Beiersdorf, Birmingham, England) and 15 patients treated for the same indication with fractionated superficial x-ray.24 The tumors in the brachytherapy arm had received total doses of 60 to 65 Gy during a 7-day application, and all of the case and control tumors had been treated more than 10 years ago. Superior long-term cosmesis was observed in the brachytherapy group. This was ascribed to the rapid decrease in brachytherapy dose beyond the superficial tissues. In addition, it was hypothesized that xray treatment may be relatively more prone to induce very late skin and subcutis adverse effects than brachytherapy. A notable case series described the treatment of several eyelid tumors, including two neglected BCCs on the cusp of orbital invasion.25 For these lesions, LDR brachytherapy with a 15-mm diameter gold shield was used as an alternative to exenteration and external radiation. In particular, an iodine-125 plaque was applied to the outside of the shield, thus allowing protection of the globe while permitting irradiation of the target lesion with 50 Gy to a 5-mm depth. Two-year follow-up indicated no recurrence. Studies on the use of surface-mold HDR brachytherapy for NMSCs have included prospective and retrospective cohort studies along with case reports. Most studies have evaluated the use of g-emitting isotopes such as 192Ir, whereas at least two studies explored the use of a mixed b-g

380 Alam et al

J AM ACAD DERMATOL AUGUST 2011

Table II. Adverse events reported after brachytherapy Study

Adverse eventseacute

Adverse eventselong term

Avril et al31

112/173 Dyspigmentation and telangiectasia

Berridge and Morgan24

Unknown

Conill et al33 Conill et al32 Debois28 Guix et al1

24/24 Erythema, edema 54/54 Mucositis Dyschromia, telangiectasia 136/136 Erythema 14/136 Ulceration 5/5 Desquamation, erythema, or ulceration 1/5 Alopecia None reported 8/8 Mild postoperative discomfort and tissue edema limits eye movement 53/53 Erythema Bleeding (only large lesions) 1/1 Erythema, ulceration, bleeding 25/25 Desquamation, crusting, erythema

Lee et al27 Ozyar and Gurdalli23 Shields et al25 Sedda et al26 Semrau et al22 Somanchi et al6 Svoboda et al7 Rio et al30

26/106 Moist reaction 32/106 Erythema, dry desquamation 97/97 Inflammatory exudative desquamation

Rudoltz et al29

1/1 Erythema, moist desquamation

69/173 Scar 9/173 Necrosis 1/173 Cataract 1/173 Lacrimal duct stenosis* 10/15 Slight atrophy, pigmentation change, some hair loss 5/15 Patchy atrophy, moderate telangiectasia, total hair loss None reported 1/54 Achromia and fibrosis None reported 4/136 Radiation necrosis None reported None reported None reported None reported None reported 1/25 Radiation necrosis 17/25 Skin atrophy, telangiectasia, alopecia 6/53 Pigmentation changes, atrophy 4/34 Epiphora 3/34 Pruritus 1/34 Impairment of eyelid aperture None reported

*Adverse events for this study are for all radiotherapy patients, of whom 55% were brachytherapy patients.

isotopeeeither rhenium-188 or holmium-166.26,27 HDR brachytherapy studies have investigated its use on NMSCs located in areas such as the nose, eyelid, ear, and back of the hands that may be difficult to treat surgically or may benefit from the special features of brachytherapy, such as the ability to confine radiation to a superficial treatment area. A series of prospective cohort studies evaluating the efficacy of NMSC treatment with 192Ir HDR surface-mold brachytherapy found good posttreatment cosmesis and low recurrence rates up to 5 years later. Relatively smaller lesions were associated with higher rates of tumor control and better cosmetic results compared with larger lesions. Radiating 136 patients with facial NMSCs, Guix et al1 noted a 5-year remission rate of 99% for primary tumors (n = 73) and 87% for recurrent lesions (n = 63). Notably, serial biopsies and dermatologic examinations were not performed to confirm these remission rates. Cosmesis was assessed by subjective and objective measurements (eg, absence of edema, alopecia, hypopigmentation, hyperpigmentation, fibrosis, scars, telangiectasia, and late effects on normal

tissue) at 6- and 12-month follow-up visits. Reportedly, 133 of 136 patients had favorable cosmesis, defined as minimal to no treatment sequelae at the 6-month follow-up visit. The remaining 2% of patients, all of whom had initial cancer lesions larger than 4 cm, experienced radiation necrosis in normal tissue. However, the report failed to specify the extent to which normal tissue had been damaged.1 Svoboda et al7 treated 96 primary skin neoplasms (9 Bowen disease, 11 SCC, 76 BCC) at various anatomic locations. Results indicated tumor regression and no recurrence in all but 4 cases. All 4 recurrent tumors were BCCs with an initial diameter greater than 2 cm and a depth greater than 3 mm. Based on these results, surface-mold brachytherapy appears to have efficacy for small, primary NMSCs, but larger tumors are likely to recur and injury to normal tissues can occur. HDR surface-mold brachytherapy has also been associated with low risk of recurrence and good cosmesis in studies of NMSC at functionally and cosmetically important sites such as the nose and hand. Debois28 reported the use of cesium-137 surface-mold brachytherapy on 370 primary lesions

Site studied

Avril et al31 Face Berridge and Morgan24 Face Eyelid Conill et al33

Lesion type

5700-9600/1 6000-6500/1 4000

LDR interstitial

86 h

6000-6500/1

HDR surface mold

48 h (total)

2400

SCC (3/5) BCC (1/5) Bowen (1/5) BCC (1/1) SCC (88/97) BCC (9/97) SCC (1/1)

HDR surface patch

30 min-1 h (total)

6000-6500/33-36 (\4 cm) 7500-8000/10 ([4 cm) 5000

HDR surface mold LDR interstitial

Not stated 74-79 h

4050/multiple 5000-6500

HDR surface mold

30 min/session

6000/30

HDR surface resin

15 min-2 h/session

4000-6000/1-3

HDR surface mold LDR plaque

Not stated 96 h

6600/[33 5000/1

HDR surface mold

Not stated

4000-4500/8

HDR surface mold

Up to 5 min/session 1200-5000/1-15

Nose

Guix et al1

Face

Lee et al27

Various

Ozyar and Gurdalli23 Rio et al30

Scalp Face

Rudoltz et al29

Forearm, back of hand Various SCC (37/53) BCC (16/53) Scalp SCC (1/1) Eyelid BCC (2/8) Adenoid cystic carcinoma (4/8) Conjunctival melanoma (1/8) Metastatic carcinoma (1/8) Back of hand, SCC (25/25) fingers Various Metastases (10/106) Bowen (9/106) SCC (11/106) BCC (76/106)

Svoboda et al7

HDR surface mold (117/136) 3-8 min/session HDR Brock applicator (19/136)

BCC, Basal cell carcinoma; HDR, high-dose rate; LDR, low-dose rate; SCC, squamous cell carcinoma.

Follow-up (mo)

Recurrence rate

48 8/95 120 (minimum) Unknown 43 (mean) 2/24

96 (mean)

2/54

[36

11/368

60

3/136

8-20

0/5

72 55 (median)

0 10/97

7

0

51 (mean)

0/53

24 24 (BCC only)

0 0/2

60 (mean)

1/25

9.6 (mean)

4/106

Alam et al 381

165 h 168 h 54-55 h (total)

Debois28

Somanchi et al6

Dosage (cGy)/ fractions

LDR interstitial LDR surface mold LDR interstitial

Lip

Semrau et al22 Shields et al25

Treatment time

BCC (347) BCC (30/30) SCC (4/24) BCC (19/24) Adenocarcinoma (1/24) SCC (52/54) BCC (2/54) Epidermoid (60/370) BCC (300/370) Other (10/370) SCC (34/136) BCC (102/136)

Conill et al32

Sedda et al26

Modality

J AM ACAD DERMATOL

Study

VOLUME 65, NUMBER 2

Table III. Summary of previous studies of brachytherapy for nonmelanoma skin cancer

382 Alam et al

J AM ACAD DERMATOL AUGUST 2011

Fig 1. Polymethyl-methacrylate mold constructed over face mask based on impression of tumor area. Catheters are for transmission of radioactive material, in this case fractionated high-dose-rate brachytherapy. Reproduced with permission from Elsevier from Guix et al.1

Fig 2. Simulation radiograph of applicator in Fig 1. This confirms placement of catheters, which are in parallel and evenly spaced. Reproduced with permission from Elsevier from Guix et al.1

(300 BCC, 60 ‘‘epidermoid,’’ 10 other) of the nose. A reported recurrence rate of 3% (11/368) at a 3-year follow-up may have been an underestimate because of possible ascertainment bias and lack of further follow-up. Unlike most other investigators, Debois28 reported more recurrences in tumors of smaller diameter (\2 cm).1,7 This aberrant outcome in the study of Debois28 may be a result of the absolute preponderance of small tumors (87%) in this study, and not to any proportionately greater risk of recurrence of smaller tumors. As the authors failed to characterize the subtype of the treated BCCs, it is not clear to what extent recurrence may have been associated with tumor subtype rather than size. Another site-specific study treated 25 patients for SCCs on the back of the hand and found one case of recurrence and one of radiation necrosis, the latter

Fig 3. Schematic diagram showing predicted radioactive dose distribution around applicator in Fig 1. Dose falls off rapidly as distance from catheters increases. Reproduced with permission from Elsevier from Guix et al.1

Fig 4. Autoradiograph of applicator in Fig 1 showing dose distribution during administration of 50 cGy. Hot spot (lower left corner) is artifact caused by film being flat and applicator being curved. Reproduced with permission from Elsevier from Guix et al.1

during treatment of a large tumor. Functional measures used to compare treated and nontreated hands included grip strength, joint mobility, fine touch, and 2-point discrimination. The differences across the two groups were not statistically significant.6 As with previously discussed studies, these studies suggest that HDR brachytherapy can induce prolonged remission with few peripheral tissue effects in relatively small, well-demarcated NMSC; long-term cure was not shown, and objective or unbiased measures of postoperative cosmesis remain lacking. Surface-mold brachytherapy has also been used for multiple, recurrent tumors with vast and irregular surface areas. Rudoltz et al29 used HDR surface-mold brachytherapy for multiple recurrent SCCs on the

J AM ACAD DERMATOL

Alam et al 383

VOLUME 65, NUMBER 2

forearm of one patient and two case reports used a surface-mold helmet for SCCs21 and BCCs23 on the scalp. Erythema, ulceration, moist desquamation, or bleeding were reported, but follow-up in all cases revealed no short-term recurrence, providing preliminary evidence for the efficacy of HDR surface molds on extensive, recurrent lesions. At least 2 studies have evaluated HDR brachytherapy using b-emitting isotopes, which may pose less risk to nearby healthy tissue.25 Furthermore, radiation therapy with b-emitting isotopes usually requires 1 to 3 treatments visits, versus many more treatments when g-emitters are used. In a study by Sedda et al,26 43 of 53 patients with recurrent NMSCs required only one treatment with rhenium-188, a b-emitter, whereas the remaining patients with thicker lesions needed up to 3 treatments each. Mean dose declined from 120 Gy to less than 20 Gy at depths greater than 2 mm, and it is unclear why some deeper tumors regressed or whether this regression was merely superficial, with residual deep tumor.26 Indeed, a study of 5 patients with holmium-166, another b-emitting radionuclide, showed that radiation dosage at depths of 2 mm and beyond was inadequate for treatment of NMSCs.27 Because of the small number of studies on b-emitting isotopes, their efficacy in the treatment of NMSC, especially deep and infiltrating lesions, remains unclear. Compilation of these results indicates high local remission rates26,27 after surface-mold brachytherapy of NMSC at various anatomic locations. However, recurrent tumors, tumors of greater depth ([2 mm), and tumors of greater diameter ([2 cm) appear to have a higher failure rate because the dosimetry constraints of brachytherapy result in a sharp decline of radiation dose with increasing depth. Larger, infiltrative lesions also require higher total doses and numbers of treatments, with total doses of up to 8000 cGy fractionated over a large number of treatment sessions. Although use of b-emitting isotopes required fewer sessions, efficacy was compromised for deeper lesions. The most common reported complications of surface-mold brachytherapy included erythema (77%), desquamation (65%), and ulceration (14%). Cosmetic and functional results were evaluated subjectively by blinded6 or unblinded29 raters. Objective measures included the presence of late radiation effects such as alopecia, telangiectasia, skin atrophy, pigmentation disorders, and scarring.1,6,30 Functional measures such as pain,30 or range of motion of joints,6 were also evaluated. Overall, cosmetic and functional results were good, with better results observed for smaller tumors.1

Interstitial brachytherapy Interstitial brachytherapy is an invasive means of internal radiation therapy in which radioactive seeds or wires are placed directly within the tissues at the target site. Unlike external radiotherapy, which requires prolonged treatment times of up to 6 weeks, interstitial brachytherapy requires shorter treatment times of as little as 80 hours. Significantly, interstitial brachytherapy may be used in areas, such as the eyelid, where the creation of the precise surfacemold required for surface-mold brachytherapy may be technically infeasible. The efficacy of interstitial brachytherapy on NMSC has been evaluated primarily through one randomized controlled trial, and additional prospective and retrospective cohort studies focusing on facial lesions. The single randomized controlled trial compared treatment efficacy and cosmetic outcomes by assigning 174 patients with primary BCC to surgery, and another 173 with similar presentation to radiotherapy, mostly (55% these 173) interstitial LDR brachytherapy with 57 to 76 Gy total dose delivered over a mean of 6.9 days. Four-year recurrence rates were 0.7% for surgery (95% confidence interval: 0.1%-3.9%) and 8.8% for brachytherapy (95% confidence interval: 4.3%-17.1%). Good cosmesis was obtained in 87% of patients treated with surgery and 69% of those treated with radiation.31 A controlled retrospective cohort study of 88 BCC and 9 SCC of the nose, periorbital area, and ear compared interstitial LDR for patients previously untreated and those who had earlier received surgery. Total doses were 52 to 55 Gy over 74 to 79 hours, and 5-year disease-free survival was 91% and 80% in the untreated and previously treated patients, respectively.30 A retrospective cohort study of 52 SCCs and 2 BCCs of the lip treated with 192Ir interstitial LDR at a mean total dose of 61.5 Gy over 86.4 hours reported a local control rate of 98% at mean follow-up of 7 years.32 This control rate was significantly higher than that noted by several previous investigations of lip tumors with interstitial LDR brachytherapy. A prospective cohort study examined outcomes of 19 primary BCCs and 4 primary SCC of the eyelids, with a collective mean diameter of 1.3 cm, treated with 192Ir interstitial LDR with mean total dose of 40 Gy over 55 hours. At mean follow-up of 43 months, the local control rate was 91.6%, with good functional results.33 Lower rates of recurrence are seen in NMSC tumors less than 2 cm in diameter and in superficial NMSC tumors not exceeding 2 mm in depth.30,33 Interstitial brachytherapy is generally well tolerated by patients. Acute complications after treatment include inflammatory exudative desquamation

384 Alam et al

J AM ACAD DERMATOL AUGUST 2011

(80%), erythema (20%), and edema (20%). Sequelae are usually more pronounced for larger tumors, and when treatment has entailed a high total dose, a larger fractionated dose, or a higher dose rate.33 In the few studies available, functional and cosmetic results were graded by a single, unblinded examiner for the presence of skin deformity, pigmentation disorders, telangiectasia, and skin atrophy. Good cosmetic and functional results were reported based on this potentially biased assessment, with the most severe complications involving impaired eyelid aperture.30 Overall, interstitial brachytherapy may be advantageous for the treatment of small, superficial lesions of NMSC.

DISCUSSION Indications for external beam radiation and brachytherapy Radiation has a role in the treatment of NMSC in selected cases. In the United States, external beam radiation will likely continue to be the modality of choice when radiation is required, but brachytherapy may be a useful alternative when the need arises. The primary benefit of brachytherapy compared with external beam radiation therapy is its ability to deliver radiation to the target tissue with less injury to surrounding normal-appearing skin. Specifically, brachytherapy may be preferable at certain anatomic sites. Full-scalp irradiation for SCC with brachytherapy may thus have a lower risk of excessive brain irradiation than external beam radiation because the intensity of surface-mold brachytherapy drops off rapidly away from the source (Fig 5). Likewise, treatment of NMSC of the hand with brachytherapy may reduce the risk to underlying tendons and bone, and subcutaneous fibrosis that limits dexterity. Other very large and irregular skin areas that are replete with numerous NMSCs may benefit from custommold or interstitial brachytherapy that conforms to the surface.29 That being said, external beam radiotherapy is a versatile modality that can be adapted to successfully treat most any skin cancer. Moreover, in the United States, expertise in brachytherapy has lagged behind that in external beam radiation, which may thus be the preferred choice at many centers. Because of the rapid drop-off in brachytherapy intensity away from each radioactive source, and the difficulty in designing custom molds and applicators to precisely match various skin surfaces, there are inherent challenges with this therapy in ensuring homogeneous dose application, conformality, and target coverage. Deep and thick lesions of NMSC can be treated by 3-dimensional conformal teletherapy more effectively than with brachytherapy.

Fig 5. Acrylic resin helmet specially constructed for treatment of wide area on scalp. In this case, high-dose-rate brachytherapy with remote afterloading was used. Reproduced with permission from Elsevier from Ozyar and Gurdalli.23

Benefits of low-dose versus high-dose brachytherapy Benefits of high-dose brachytherapy compared with low-dose34,35 include the short duration of treatment, which minimizes the risk that the applicator will move or become misaligned with the target. HDR may be preferred by patients because it is an outpatient treatment, and does not require prolonged bed rest confined in a room; this avoidance of an inpatient stay can also result in significant cost reduction. A technical benefit of HDR is optimization, which means the dwell times of the radioactive source at various locations within the applicator can be precisely modified and managed. However, HDR is biologically more toxic than LDR,34,35 in that the degree of damage to tumor cells relative to the damage to normal tissue cells (ie, the therapeutic ratio) is lower for HDR than LDR. Damage to both tumor and normal cells increases with dose rate, but the increase in injury to healthy cells is proportionately greater. To compensate for this, HDR treatments may be fractionated into 5 or more sessions, whereas LDR usually requires 1 or 2 sessions. Also, because of the complexity and speed of HDR, and the potential for failure in the device that moves the radiation source (eg, source does not retract), errors can occur that result in very high radiation doses to patients. Finally, although HDR may not require a hospital stay, it can require relatively more personnel, and expensive hardware such as various applicators and sophisticated HDR afterloading equipment.

J AM ACAD DERMATOL

Alam et al 385

VOLUME 65, NUMBER 2

Limitations in the efficacy of brachytherapy There are, however, significant limitations in the use of brachytherapy for treatment of even selected NMSCs. Specifically, the tumors that respond best with the lowest recurrence rates are primary, superficial (\2 mm deep), and small (\2 cm in diameter). Common findings indicate a greater recurrence rate for lesions greater than 2 cm in diameter regardless of the mode of brachytherapy used. Moreover, most studies have found that adequate radiation dosage with brachytherapy cannot be delivered at depths much greater than 2 mm, making the treatment of infiltrative tumors impractical. Sufficient dose delivery for deep tumors would require excessive radiation exposure time and dose to the skin. Although a single study1 has reported adequate dose distribution to depths up to 5 mm using surface-mold HDR brachytherapy, these results have not been replicated. In short, the types of tumors brachytherapy has been shown to treat effectively are also the same tumors that are easily removed surgically or could be treated with external beam radiation. It is unclear to what extent large, thick, neglected tumors on elderly or frail patients may be amenable to brachytherapy. Thinner tumors, such as eyelid tumors and widespread shallow areas of skin carcinogenesis, may be better targets for brachytherapy (Figs 6 and 7). Local control, cure, and long-term disease-free survival Secondly, although remission rates after brachytherapy are reported to be high, the reported control rates are not necessarily cures. Published studies7,26,29 evaluating the treatment of NMSC with brachytherapy have usually followed up patients for less than 2 years, with the longest reported follow-up period lasting 6 years in one case study.23 However, studies have reported an increased risk of NMSC recurrence for up to 10 years.36 Consequently, the long-term use of brachytherapy remains to be established. The concern, of course, is that incompletely treated tumors may not only recur, but may also enlarge and threaten structures over time, especially if their deep component eludes eradication. To the extent that radiotherapy for NMSC, including brachytherapy, is usually reserved for older patients, long-term disease-free survival data can be difficult to obtain. On the other hand, it is quite possible that current and future technical improvements in brachytherapy, especially HDR brachytherapy, may lead to higher long-term control rates than previously possible.

Fig 6. Orbital plaque made of lead to shield globe (A) that bears on its outside surface iodine-125 seeds (B) designed to irradiate adjacent orbital tumor. Reproduced with permission from Shields et al.25

Tolerability and adverse events associated with brachytherapy Brachytherapy for NMSCs has been said to be well tolerated by patients. This treatment modality is especially useful for areas, such as the back of the hand or the scalp, where there is concern about radiation dose to the underlying structures, such as tendons or brain. Brachytherapy has the benefit of localizing high radiation dosage to near the site of the implants, so deeper penetrating radiation injury is avoided.1,7,26 In general, good cosmetic functional results are achieved, and local adverse events are mild to moderate. Nonetheless, common reported acute reactions associated with brachytherapy include erythema (79%), ulceration (14%), and desquamation (68%).

386 Alam et al

J AM ACAD DERMATOL AUGUST 2011

surgical excision or Mohs micrographic surgery. Indeed, given the subjectivity of measurements of cosmesis and the dearth of side-by-side comparisons of brachytherapy, external beam radiation, and surgical reconstruction, it is difficult to make a strong assertion as to the relative cosmetic benefits of these treatment modalities. In one study, facial BCCs were randomized to be treated with either surgery or radiotherapy (interstitial brachytherapy, superficial contactherapy involving delivery of low-energy dosages at close proximity to the target site, and conventional radiotherapy). Upon a 4-year followup, blinded, observer-rated cosmetic results were better for lesions treated with surgery for all tumor sites on the face, except the nose, for which the difference in cosmetic results did not reach statistical significance.37 But not much can be concluded from a single study, and further studies with unbiased and ideally objective outcome measures are needed. Similarly, although brachytherapy can be useful for elderly, infirm patients unable to tolerate surgery, a minimal level of functional status is probably necessary before embarking on radiation therapy of any type. Specifically, brachytherapy is best applied only to patients who are able to provide baseline self-care needs. Patients with disorders resulting in periods of confusion or delirium may not be ideal candidates. When selecting patients for brachytherapy, special attention should be given to patients’ ability to follow guidelines regarding radiation exposure. Fig 7. Application of plaque in Fig 6 to eye (A) and after it is affixed with sutures, with patient looking ahead (B). In this case, tumor was adenoid cystic carcinoma of lacrimal gland. Reproduced with permission from Shields et al.25

Operator safety Brachytherapy involves potential risks of radiation exposure to medical personnel involved in treatment. LDR is associated with secondary radiation risk because the duration of treatment is prolonged for days, and HDR, because radiation source is of high intensity. Especially for LDR, remote afterloading techniques, whereby nonradioactive implantation devices are first placed within the tumor and subsequently mechanically loaded with radioactive sources, are often used to enhance operator safety. Patient selection: cosmesis and functional status Although brachytherapy has been shown to be associated with good posttreatment cosmesis, patients seeking optimal cosmesis may still opt for

Conclusions Although brachytherapy is an alternate radiation modality that may be useful for treatment of selected NMSCs that may benefit from radiation, further research is needed to clarify the extent to which this modality can effectively treat the large and deep tumors typically not amenable to surgery (Table IV). Rater-blinded and objective assessments may also better clarify the extent to which cosmesis and functional outcomes with brachytherapy compare favorably or unfavorably with postsurgical outcomes. Longer-term follow-up and prospective controlled studies may similarly yield important information regarding the long-term cure rates associated with the latest techniques of LDR and HDR brachytherapy for NMSC, rather than the short- to medium-term control rates now available. Finally, more data are needed on the differential cure rates of subtypes of BCC, and of B6CC versus SCC. Brachytherapy is not a benign or inexpensive modality. Even in the best hands, local tissue desquamation and ulceration can occur, and typically multiple treatment sessions are required. It is also

Alam et al 387

J AM ACAD DERMATOL VOLUME 65, NUMBER 2

Table IV. Brachytherapy study type and level of evidence Study

Journal

N(subject/lesions)

Avril et al Berridge and Morgan24 Conill et al33 Conill et al32 Debois28 Guix et al1 Lee et al27 Ozyar and Gurdalli23 Rio et al30 Rudoltz et al29 Sedda et al26

Br J Cancer Clin Oncol (R Coll Radiol) Int J Radiat Oncol Biol Phys Clin Transl Oncol J Belge Radiol Int J Radiat Oncol Biol Phys J Nucl Med Int J Radiat Oncol Biol Phys Int J Radiat Oncol Biol Phys J Am Acad Dermatol Clin Exp Dermatol

347/347 30/30 23/24 54/54 370/370 136/136 5/5 1/multiple 97/97 1/multiple 53/53

Semrau et al22 Shields et al25 Somanchi et al6 Svoboda et al7

Br J Dermatol Ophthal Plast Reconstr Surg Clin Oncol (R Coll Radiol) Int J Radiat Oncol Biol Phys

1/multiple 2/2 25/25 76/106

31

certainly worth considering to what extent brachytherapy should be kept in reserve, as a treatment of last resort for lesions that have previously failed dermatologic treatment, including surgery and external beam radiation. That being said, when radiation is considered in the treatment of resistant, recurrent, and inoperable skin tumors, and tumors in patients who cannot tolerate excisional surgery or reconstruction, brachytherapy may have a role. In such circumstances, there is no ideal therapy, and brachytherapy is far from a panacea, but it may be appropriate in selected circumstances, especially when there is widespread tumor or tumor at anatomic sites overlying vulnerable neurovascular or musculoskeletal structures. Further research may improve the use of brachytherapy for NMSC treatment, and provide information that clarifies the precise indications for such treatment. Large-scale randomized controlled trials have yet to be conducted to assess the efficacy and safety of brachytherapy, and to compare it directly with external beam therapy. REFERENCES 1. Guix B, Finestres F, Tello J, Palma C, Martinez A, Guix J, et al. Treatment of skin carcinomas of the face by high-dose-rate brachytherapy and custom-made surface molds. Int J Radiat Oncol Biol Phys 2000;47:95-102. 2. Hansen S, Mathes S, Young D. Skin and subcutaneous tissue. In: Brunicardi FC, Andersen DK, Billiar TR, Dunn DL, Hunter JG, Matthews JB, et al, editors. Schwartz’s principles of surgery. 8th ed. New York: McGraw Hill Companies; 2005. 3. Locke J, Karimpour S, Young G, Lockett MA, Perez CA. Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Biol Phys 2001;51:748-55. 4. Silva JJ, Tsang RW, Panzarella T, Levin W, Wells W. Results of radiotherapy or epithelial skin cancer of the pinna: the

5. 6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Study type

Randomized control trial Case-control study Prospective cohort study Retrospective cohort study Prospective cohort study Prospective cohort study Prospective cohort study Case report Retrospective cohort study Case report Single group pre/post test prospective cohort study Case report Case series Retrospective cohort study Prospective cohort study

Level of evidence29

1 4 5b 5b 5b 5b 5b 5c 5b 5c 5b 5c 5c 5b 5b

Princess Margaret Hospital experience, 1982-1993. Int J Radiat Oncol Biol Phys 2000;47:451-9. Rubin AI, Chen EH, Ratner D. Basal cell carcinoma. N Engl J Med 2005;353:2262-9. Somanchi B, Stanton A, Webb M, Loncaster J, Allan E, Muir L. Hand function after high dose rate brachytherapy for squamous cell carcinoma of the skin of the hand. Clin Oncol (R Coll Radiol) 2008;20:691-7. Svoboda V, Kovarik J, Morris F. High dose-rate microselectron molds in the treatment of skin tumors. Int J Radiat Oncol Biol Phys 1995;31:967-72. Fangman W, Cook J. Postradiation sarcoma: case report and review of the potential complications of therapeutic ionizing radiation. Dermatol Surg 2005;31:966-72. Licher MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. Arch Dermatol 2000;136:1007-11. Guerin S, Duphy A, Anderson H, Shamsaldin A, Svahn-Tapper G, Moller T, et al. Radiation dose as risk factor for malignant melanoma following childhood cancer. Eur J Cancer 2003;39: 2379-86. Cantwell MM, Murray LJ, Catney D, Donnelly D, Autier P, Boniol M, et al. Second primary cancers in patients with skin cancer: a population-based study in Northern Ireland. Br J Cancer 2009;100:174-7. Solan MJ, Brady LW. Skin. In: Halperin EC, Perez CA, Brady LW, editors. Perez and Brady’s principles and practice of radiation oncology. 5th ed. Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp. 690-701. Ang KK, Weber RS. Cutaneous carcinoma. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. 2nd ed. London: Churchill Livingstone; 2006. pp. 853-63. Montemaggi P, Guerrieri P, Federico M, Mortellaro G. Clinical applications of brachytherapy: low-dose-rate and pulse-doserate. In: Halperin EC, Perez CA, Brady LW, editors. Perez and Brady’s principles and practice of radiation oncology. 5th ed. Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp. 476-539. Williamson JF, Brenner DJ. Physics and biology of brachytherapy. In: Halperin EC, Perez CA, Brady LW, editors. Perez and Brady’s principles and practice of radiation oncology. 5th ed.

388 Alam et al

J AM ACAD DERMATOL AUGUST 2011

16. 17. 18.

19.

20. 21.

22.

23.

24.

25.

26.

27.

Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp. 423-75. Hansen PB, Jensen MS. Late results following radiotherapy of skin cancer. Acta Oncol 1968;7:307-20. Furst CJ, Lundell M, Holm L- E. Radiation therapy of hemangiomas, 1909-1959. Acta Oncol 1987;26:33-6. Guadagnolo BA, Ang KK, Ballo MT. The skin. In: Moss WT, Brand WN, Battifora H, editors. Radiation oncology: rationale, technique, results. St Louis (MO): CV Mosby Co; 1979. pp. 52-82. Martinez AA. Brachytherapy. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. 2nd ed. London: Churchill Livingstone; 2006. pp. 255-82. Devlin PM, editor. Brachytherapy applications and techniques. Philadelphia: Lippincott Williams & Wilkins; 2007. Pathi S, Dorigo O. Radiation therapy for gynecologic cancers. In: DeCherney AH, Nathan L, editors. Current diagnosis and treatment obstetrics and gynecology. 10th ed. New York: McGrawHill Co; 2007. Semrau S, Kunz M, Baggesen K, Vogel H, Fietkau R, Gross G, et al. Successful treatment of field cancerization of the scalp by surface mould brachytherapy. Br J Dermatol 2008;159:753-5. Ozyar E, Gurdalli S. Mold brachytherapy can be an optional technique for total scalp irradiation. Int J Radiat Oncol Biol Phys 2002;54:1286. Berridge JK, Morgan DA. A comparison of late cosmetic results following two different radiotherapy techniques for treating basal cell carcinoma. Clin Oncol (R Coll Radiol) 1997;9:400-2. Shields JA, Shields CL, Freire JE, Brady LW, Komarnicky L. Plaque radiotherapy for selected orbital malignancies: preliminary observations; the 2002 Montgomery lecture, part 2. Ophthal Plast Reconstr Surg 2003;19:91-5. Sedda A, Rossi G, Cipriani C, Carrozzo M, Donati P. Dermatological high-dose-rate brachytherapy for the treatment of basal and squamous cell carcinoma. Clin Exp Dermatol 2008; 33:745-9. Lee JD, Park KK, Lee M, Kim E, Rhim KJ, Lee JT, et al. Radionuclide therapy of skin cancers and Bowen’s disease using a specially designed skin patch. J Nucl Med 1997;38:697-702.

28. Debois J. Cesium-137 brachytherapy for epithelioma of the skin of the nose: experience with 370 patients. J Belge Radiol 1994;77:1-4. 29. Rudoltz M, Perkins R, Luthmann R, Fracke T, Green T, Eaglstein F, et al. High-dose-rate brachytherapy with a custom-surface mold to treat recurrent squamous cell carcinomas of the skin of the forearm. J Am Acad Dermatol 1998;38:1003-5. 30. Rio E, Bardet E, Ferron C, Peuvrel P, Supiot S, Campion L, et al. Interstitial brachytherapy of periorificial skin carcinomas of the face: a retrospective study of 97 cases. Int J Radiat Oncol Biol Phys 2005;63:753-7. 31. Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P, Benhamou E, et al. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer 1997; 76:100-6. 32. Conill C, Verger E, Marruecos J, Vargas M, Biete A. Low dose rate brachytherapy in lip carcinoma. Clin Transl Oncol 2004;9: 251-4. 33. Conill C, Sanchez-Reyes A, Molla M, Vilalta A. Brachytherapy with 192Ir as treatment of carcinoma of the tarsal structure of the eyelid. Int J Radiat Oncol Biol Phys 2004;59:1326-9. 34. Thomasden B, Das R. The physics and dosimetry of high-doserate brachytherapy. In: Halperin EC, Perez CA, Brady LW, editors. Perez and Brady’s principles and practice of radiation oncology. 5th ed. Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp. 540-59. 35. Nag S, Scruggs GR. Clinical aspects and applications of highdose-rate brachytherapy. In: Halperin EC, Perez CA, Brady LW, editors. Perez and Brady’s principles and practice of radiation oncology. 5th ed. Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp. 560-82. 36. Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 1996; 49:749-53. 37. Petit JY, Avril MF, Margulis A, Chassagne D, Gerbaulet A, Duvillard P, et al. Evaluation of cosmetic results of a randomized trial comparing surgery and radiotherapy in the treatment of basal cell carcinoma of the face. Plast Reconstr Surg 2000;105:2544-51.