Review

Radiotherapy treatment for

nonmelanoma skin cancer
Expert Rev. Anticancer Ther. Early online, 1–12 (2015)

Yi Rong*1,2, Li Zuo3, Non-melanoma skin cancer is the most common malignancy in the USA, with an estimated
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

Lu Shang4 and 3.5 million cases per year. Treatment options include surgical excision, radiation therapy (RT),
Jose G Bazan*1 photodynamic therapy and topical agents. Although surgical excision remains the mainstay of
1
therapy, RT offers an effective alternative. RT can be used as an adjunct to surgery in high-
Department of Radiation Oncology,
The Ohio State University Wexner
risk situations, or in cases where surgical excision would lead to impaired cosmesis and/or
Medical Center, Columbus, OH 43210, functional outcomes. Radiation treatment modalities for non-melanoma skin cancers are
USA diverse. Studies in the literature have examined the clinical effects of a wide variety of
2
Department of Radiation Oncology, modalities, areas of the body and dosages. The most common modalities include superficial
University of California Davis
Comprehensive Cancer Center, Davis, or orthovoltage RT, electron beam therapy and high dose-rate brachytherapy. This article
CA 95817, USA aims to review the diverse radiotherapy treatment modalities for non-melanoma skin cancers,
3
Radiologic Sciences and Respiratory focusing on tumor control and toxicity.
Therapy Division, School of Health and
Rehabilitation Sciences, College of
KEYWORDS: brachytherapy . cosmesis and toxicity . nonmelanoma skin cancer . orthovoltage radiotherapy . superficial
Medicine, Ohio State University,
radiotherapy
Columbus, OH 43210, USA
For personal use only.

4
Guangxi Institute of Research and
Design, Guangxi, China
*Authors for correspondence:
Skin cancer is the most common type of can- effective and considered the standard of care
Tel.: +1 916 734 8170 cer in the United States. The incidence of skin for most primary NMSCs [4]. These surgical
Fax: +1 916 734 3239 cancer is estimated to be higher than all other options provide cure rates >95% for primary
yrong@ucdavis.edu
jose.bazan2@osumc.edu
types combined, including breast, prostate, and recurrent BCCs and SCCs [13]. However,
lung and colon cancers. Although melanoma RT is indicated when surgery is not an option
represents less than 5% of total skin cancer due to cosmetic or functional reasons, or as an
cases, it is the leading cause of skin cancer adjuvant therapy in high-risk SCCs and BCCs.
death [1]. The most prevalent forms of skin RT offers unique advantages in challenging
cancer are basal cell carcinoma (BCC) and locations for surgery, such as in the head and
squamous cell carcinoma (SCC), both of neck (H/N) region, especially when there is a
which are highly curable. Because these cancers need for good cosmetic outcome. RT is also
develop from epidermal cell types other than favored for treatment of elderly patients
the melanocyte, they are referred to as non- (>60 years old), given concerns about potential
melanoma skin cancers (NMSCs). The total long-term sequelae [4]. Established guidelines
number of NMSCs in the US population is have been provided for the evaluation and
estimated at 3.5 million in 2006 [2]. A recent management of BCCs and SCCs with
geographical review of worldwide incidence of RT [4,15,16], including dose regimen and follow-
NMSCs revealed the locations of high inci- up schedules. However, there is a lack of a
dence rates and highlighted the fact that comprehensive review with a focus on evaluat-
NMSCs are an increasing problem for health ing various radiotherapy modalities. Traditional
care globally [3]. Prior reviews have focused on RT treatment modalities include superficial
the clinical aspects of NMSCs, including x-rays, orthovoltage x-rays, electrons and Co-
tumor characteristics, risk factors, diagnosis, 60 photons. In more recent years, the emerging
assessments and various treatment options [4,5]. new technologies for NMSC treatment include
Treatment options for skin cancers include high dose rate (HDR) brachytherapy using iso-
surgical excision [6–9], Mohs micrographic topes or miniature x-ray sources. The present
surgery [8–14], radiation therapy (RT) [9,15,16], review article aims to include various radiother-
photodynamic therapy [17–21], topical medica- apy modalities for treating nonmelanoma skin
tions [9,22,23], and systemic medical therapy [9]. cancers, with comparing their associated tumor
Surgical excision and Mohs surgery are control and treatment toxicities. An extensive

informahealthcare.com 10.1586/14737140.2015.1042865
2015 Informa UK Ltd ISSN 1473-7140 1

 Review Rong, Zuo, Shang & Bazan

literature search was conducted on the PubMed/Medline data- 48 Gy in 12 fractions, which was adjusted to a uniform dose
base available in English, with no specific publication time prescription of 51 Gy in 17 fractions for small lesions and
restrictions. The search keywords included ‘nonmelanoma skin 60 Gy or more (2–2.5 Gy per fraction) for larger lesions in the
cancer’, ‘BCC’, ‘SCC’, ‘superficial radiotherapy’, ‘orthovoltage following 10 years. The overall local control was 97% at 5 years
radiotherapy’, ‘electron beam’, ‘HDR’, ‘brachytherapy’, and 96% at 10 years, with excellent cosmetic outcomes [34].
‘electronic brachytherapy’, etc. Lovett et al. retrospectively analyzed a total of 339 NMSC
lesions (242 BCCs, 92 SCCs and five variants of SCCs) treated
Superficial & orthovoltage RT with various modalities and reported an overall tumor control
Traditional techniques of treating skin cancer using radiation rate of 86% in all lesions (91% for BCCs and 75% for SCCs)
include superficial and orthovoltage x-ray therapies. [32]. The total dose ranged from 40 Gy to 60 Gy for both
A 1974 survey among dermatologists found that RT was used BCCs and SCCs. It was also noted that the tumor control rate
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

in 55.5% of dermatology clinics in USA and Canada. How- was dependent on the tumor type, tumor size and treatment
ever, the arrival of Mohs surgery offered dermatologists high modality [32]. Specifically, superficial x-ray technique achieved a
cure rates with reduced side effects [24]. In a later survey con- local tumor control of 93–100%, depending on the tumor size.
ducted in 1986, superficial radiation could only be found in This was superior to both electron beam and Cobalt 60 therapy.
12% of dermatology training clinics [25]. Nevertheless, kilovolt- In addition, tumor control rate varies with tumor sizes and dif-
age x-ray therapy can be expected to become even more impor- ferent dose fraction sizes. For BCCs 1 cm or less, all dose frac-
tant in the next few decades, due to the aging population. tion sizes (<2 Gy to >4 Gy) provided >95% tumor control; for
Surgery is often not an option for the rapidly increasing elderly BCCs 1.1–5 cm, 3–6 Gy dose fraction size was recommended
population with skin cancer, as complications with surgery for a 100% local control; data for lesions >5 cm was not con-
are much more likely. Accordingly, superficial and ortho- clusive. Similar results were seen in SCCs, except that the cut-
voltage x-ray therapies are well-tolerated, simple and low-cost off dose fraction size was 5 Gy instead of 6 Gy for tumor size
substitutes. 1.1–5 cm [32]. TABLE 1 summarizes the key series of external
Due to the shallow effective depth, early superficial x-ray beam radiotherapy for the treatment of NMSC.
For personal use only.

therapy used multiple beams from various angles on deep

tumors. This technique reduced high surface doses, while also Electron beam radiotherapy
increasing tumor doses [26]. With the advent of other treatment The ability to deliver a uniform radiation dose to a few centi-
options, both superficial x-rays and orthovoltage x-rays are not meter depth of human tissue with a steep dose fall beyond the
indicated for deep tumors but are still commonly used for therapy range makes the electron beam suitable for superficial
superficial tumors in all areas of the body. In superficial x-ray cancer treatments [39], including skin cancer in the H/N
therapy, the photon energy ranges from 50 to 150 kVp, with an region [40]. The energies used for electron beam radiotherapy
equivalent half-value layer of 1.0–8.0 mm Al. Typical treatment (EBRT) vary from 4 to 20 MeV, resulting in an effective treat-
diameters range from 1.0 to 5.0 cm, at a source-surface distance ment depth of 2–6 cm. Also, a common technique is to use
of 15–20 cm. Due to the limited penetration capability of these 1 cm bolus and 6 MeV beam to treat 1 cm deep lesions. Elec-
low-energy photons, this modality is commonly used for tumors tron beams are available on most commercial linear accelerators.
at very shallow depth, that is, 5 mm. There are several commer- Reported clinical outcomes with EBRT have been controver-
cially available systems for this type of treatment, including sial. Despite the inferior local control rate associated with
SRT-100 (Sensus Healthcare, Boca Raton, FL), Xstrahl EBRT on multivariate analysis reported by Lovett et al. [32],
100 and 150 (Xstrahl Medical Solutions, Suwanee, GA). several other series reported favorable outcomes with local con-
Orthovoltage therapy covers an x-ray energy range of 150– trol rate comparable with superficial x-ray treatments, ranging
300 kV, with an equivalent half-value layer of 1–4 mm Cu. from 81 to 95% [29,40–43]. Furthermore, these studies reported
Treatment diameters range from 4 to 20 cm at a source-surface good cosmetic outcomes in contrast to those reported by
distance of 50 cm. Due to its ability to travel further than Lovett et al. [32]. Griep et al. showed no significant difference
superficial x-ray therapy (2 cm in general), orthovoltage RT is in tumor local control comparing superficial x-rays (97%) and
sometimes called ‘deep’ therapy. The commercially available electrons (94.5%) after a 2-year follow-up, with overall cos-
orthovoltage x-ray systems include Xstrahl 200 & 300 (Xstrahl metic results in favor of EBRT [29]. The dose regimen was
Medical Solutions, Suwanee, GA) and Gulmay Orthovoltage 6–10 fractions of 6–10 Gy for superficial x-rays and 17–18 frac-
Unit (Gulmay Medical Limited, Chertsey, Surrey, UK). tions of 3 Gy four times per week for electron beam. The frac-
Superficial and orthovoltage x-ray RT treatment techniques tion size was adjusted to 2 Gy for a total of 50–60 Gy dose
are effective for BCC and SCC in terms of tumor local control when treating larger volumes. Silva et al. [35] reported 2- and
and cosmetic outcomes [27–38]. A large-scale clinical study by 5-year local control rates of 87% and 79%, respectively, in a
Petrovich et al. reported treatment outcomes from 896 patients population of 334 pinna lesions (201 BCCs, 122 SCCs and
(467 BCCs, 362 SCCs and mixed), mostly treated with super- 11 basosquamous carcinoma) treated with orthovoltage x-ray
ficial and orthovoltage x-rays [34]. The dose regimen in the early (83%) and EBRT (12%), with excellent to good cosmetic out-
years of this series ranged from 30 Gy in three fractions to come. The most common dose prescriptions were 35 Gy/5

doi: 10.1586/14737140.2015.1042865 Expert Rev. Anticancer Ther.

 Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15
For personal use only.

Table 1. Summary of major series for non-melanoma skin cancer using multiple radiation modalities, including superficial x-ray,
orthovoltage x-ray, photon beams and electron beams.
Study Site Mean age (yr) Lesion type Modality Prescription: Mean Local-Control Ref.
(year) dose (Gy)/ Follow-Up
fractionation (yr)
Hunter et al. Pinna BCC: 62 (45–88); BCC (17), SCC Electron, 10 MeV 45–50/8, >2 83.3% [42]

informahealthcare.com
(1982) SCC: 67 (53–89) (26) 52.5–55/15
Petrovich Face, H/N 60 (21–94) BCC (467) SupX 30/3 NS BCC: 99% (5-yr), 98% [34]
et al. (1987) SCC (362) EB 48/12 (10-yr),
BSC (67) Cu HVL 51/17 SCC: 94% (5-yr), 88%
Co-60 60/24–30 (10-yr)
BSC: 95% (5-yr), 96%
(10-yr)
Griep et al. Scalp, Face, 71.5 BCC (295), SupX (99), SupX: 6–10/6–10; 2 SupX: 97% [29]
(1995) H/N, Trunk, Ext. SCC (94) EB (290) Electron: 51–54/ EB: 94.5%
17–18; or 50–60 @
2–3 Gy per fraction
Lovett et al. Scalp, Face, 70–80 BCC (242), SCC SupX (187) 40–60/10–30 Min 2-death BCC: 91% [32]
1990 H/N, Trunk, (30–90) (92), Other (5) EB (57) SCC: 75%
Ext. MV Photon (15)
Combo (80)
Zablow et al. Face, H/N, 70.4 (32–97) BCC (94), SCC Electron, 6 MeV BCC: 50–52/10–13; Min:2; Primary: 88%; Primary [40]
(1992) Trunk, Ext (19), Other (2) SCC: 60/15 Mean: 3.9 +LN: 86%; NED: 93%
de Visscher Lip 68 (41–92) SCC (108): OrthoX. (62) OrthoX: 48–51/12– 6.4 (1.7–12) T1: 99% [37]
et al. (1996) (T189, T2 17, EB (6–8 MeV) (33) 17 T2: 77%
T3 2) Other (13) EB: 55/22
LDR: 60/NS
Silva et al. Pinna 74 (41–104) BCC (201) OrthoX (278), 35/5 3.3 2-yr, 5-yr: [35]
(2000) SCC (122) EB (39) 42.5–45/10 (0.1–13.4) 93%,83% (BCC);
BSC (11) Other (17) 50–65/20–30 82%,79% (SCC)
Locke et al. Scalp, Face, BCC: 73 (11–100) BCC(389) SupX. (317) 40–60/10–30 5.8 (2–24) BCC (92%) [31]
(2001) H/N, Trunk, Ext. SCC: 72 (32–97) SCC(142) EB (100) SCC (80%)
Combo (108)
MV Photon (6)
Tsao et al. Nose 74.5 (42–93) SCC (94) OrthoX. (76) 32.5–35/5 2.9 2-yr: 90% [38]
(2002) EB (13) 42.5–45/10 (0.2–10.4) 5-yr: 85%
Radiotherapy treatment for nonmelanoma skin cancer

Other (5) 20/1

50/15–20
BCC: Basal cell carcinoma; BSC: Basosquamous carcinoma; EB: Electron beam; Ext: Extremities; Gy: Gray; H/N: Head and neck; IMRT: Intensity modulated radiation therapy; NED: No evidence of disease; NS: Not specified
in paper; OrthoX: Orthovoltage x-ray; RT: Radiation therapy; SCC: Squamous cell carcinoma; SupX: Superficial x-ray.
Review

doi: 10.1586/14737140.2015.1042865
 Review Rong, Zuo, Shang & Bazan

[30]

[27]

[33]

[65]

[36]

[44]

[66]
Ref.

BCC: Basal cell carcinoma; BSC: Basosquamous carcinoma; EB: Electron beam; Ext: Extremities; Gy: Gray; H/N: Head and neck; IMRT: Intensity modulated radiation therapy; NED: No evidence of disease; NS: Not specified
fractions for small lesions (field
size = 4.9 cm2), 42.5–45 Gy/10 frac-
tions for median field size (10.5 cm2)

3D conformal (33.3%)
and 50–65 Gy/20–30 fractions for
large field size (81 cm2). The local
Table 1. Summary of major series for non-melanoma skin cancer using multiple radiation modalities, including superficial x-ray,

Local-Control

control rates at 2 and 5 years were

78.3% (overall

BCC: 97–98%
SCC: 94–97%
IMRT (60%)
93% and 83% for BCC, and
86% (BCC)

EB (62.5%)
58% (SCC)

5-yr: 78%

response)
82% and 79% for SCC, respectively.

100%

100%
Support for EBRT has increased as a
4-yr:

3-yr
result of recent publications citing
encouraging clinical outcomes.
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

3.5 (0.1–8.1)

0.3 (0.1–2.3)

3.6 (0.1–7.3)
Locke et al. [31] reported an overall
Follow-Up

3.1 (1–6.4)

1 (0.5–4)
tumor control rate of 89% for
Mean

531 NMSCs (389 BCCs and

(yr)

2.4

1.3

142 SCCs) in 468 patients with a

median 5.8-year follow-up, treated
with superficial x-rays (60%), EBRT

BCC: 56.25–76.5/

SCC: 55.8–79.8/
(19%) or a combination of both
35/5, 40–45/10

54/18 or 44/10
fractionation

59.4–74.25/33
Prescription:

60–70/30–35
45–105/9–21

(20%) [31]. The 5-year local control

dose (Gy)/

50/15–20,

rates were 93% for primary lesions

54–60/15
60/25,

25–36

25–35
and 80% for recurrent lesions; 92%
24/3

for BCCs and 80% for SCCs.

Although the tumor local control was
found inferior with EBRT (94% for
3D conformal RT (3)
Low E photon (101)
For personal use only.

superficial x-rays, 82% for electron

MeV Photons (4)
Half-deep x-ray

MV photon (3)

beams and 82% for combination

Contact x-ray

in paper; OrthoX: Orthovoltage x-ray; RT: Radiation therapy; SCC: Squamous cell carcinoma; SupX: Superficial x-ray.
MV Photons

OrthoX (13)

therapy), a multivariate analysis

Modality

IMRT (10)
Soft x-ray
OrthoX.

Combo

showed that local failure was related

EB (14)

EB (8)
IMRT

to daily fraction size, lesion diameter,

EB

EB

EB

pathologic type and insignificantly

orthovoltage x-ray, photon beams and electron beams (cont.).

with treatment modality [31]. Tumor

local control rates for different sizes
Lesion type

of lesions treated with different dose

BCC (104)

BCC (332)
SCC (121)

SCC (102)

BCC (10)
BCC (61)

BCC (99)
SCC (16)

SCC (26)

SCC (11)

fraction sizes were found to be similar

BCC (2)

BCC (5)
SCC (1)

to Lovett et al’s findings [32]. For the

total dose (at 2.5 Gy per fraction,
4 days a week), Locke et al. recom-
mended 40 Gy for <small BCCs,
78.3 (41.2–96.7)
BCC:74.8 (38.4–
Mean age (yr)

45–60 for median size BCCs or small

75.2 (48–96)
78 (31–103)

91 (80–101)

SCCs and 60 Gy for large BCCs and

95.5); SCC:

63 (48–90)
77 (47–98)

SCCs [31].
Studies by Tsao et al. [38] and
88

Kwan et al. [30] similarly demon-

strated that EBRT provides a similar
control rate compared with orthovolt-
H/N, Trunk, Ext.

Hand, Sternum

age beams. Tsao et al. evaluated

H/N, Thigh,

Trunk, Ext.
Face, H/N,

94 patients with SCCs treated with

EBRT and observed a local relapse-
Pinna

Head

Face

H/N,
Site

Ext.

free rate of 90% and 85% at 2 and

5 years, respectively [38]. Their dose
regimen was 35 Gy/5 fractions for
van Hezewijk
Barnes et al.
et al. (2005)

et al. (2006)

et al. (2010)

et al. (2010)

£2 cm lesions, 45 Gy/10 fractions for

Caccialanza
Kwan et al.

Matthiesen

Matthiesen
et al. 2011
Olschewski

2–5 cm lesions and 50 Gy/20 fractions

Study
(year)

(2004)

(2010)

for >5 cm lesions. Kwan et al. ana-

lyzed a total of 182 patients with

doi: 10.1586/14737140.2015.1042865 Expert Rev. Anticancer Ther.

 Radiotherapy treatment for nonmelanoma skin cancer Review

T2 and more advanced NMSCs (61 BCCs and 121 SCCs) 60–65 Gy in 33 to 36 fractions (1.8 Gy per fraction) for
reported 4-year locoregional control rates of 86% and 58% for lesions £4 cm and 75–80 Gy for lesions >4 cm (with a boost
BCCs and SCCs, respectively [30]. Similar to the of study dose of 18 Gy in 10 fractions, after a 3-week rest period) [47].
Tsao et al., the most common dose fractionation included Local control rates were excellent with only three recurrences
35 Gy/5 fractions, 45 Gy/10 fractions, 50 Gy/15–20 fractions noted, yielding a 5-year actuarial local control rate of 98% [47].
and 60 Gy/25 fractions. The reported inferior tumor control Similar results in terms of excellent local control and func-
rates associated with EBRT may be attributed to patient selec- tional/cosmetic outcome have been reported at sites outside of
tion bias or dosimetric coverage difficulties associated with elec- the H/N region as well [48–50].
tron beams. Careful margin consideration and improved Other studies of HDR brachytherapy in the treatment of
dosimetric coverage may improve locoregional tumor control NMSCs have focused on hypofractionation (daily dose >2 Gy).
with EBRT. A more recent analysis involving 434 cases In 1999, Kohler-Brock et al. reported 10-year results of using
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

(332 BCCs and 102 SCCs), all treated with EBRT, reported 5–10 Gy given twice per week to a total dose of 30–
3-year local relapse-free rates of 97.6% for 54 Gy/18-fraction 40 Gy [51]. A total of 520 patients with NMSCs of the face,
regimen and 96.9% for 44 Gy/10-fraction regimen [44]. mouth, tongue, perianal region and the external genitalia were
When comparing treatment outcomes with superficial or treated using this hypofractionation regimen. Response rates
orthovoltage x-rays versus electron or megavoltage photons, were 97% (91% complete remission and 6% partial remission)
their differences in relative biological effectiveness (RBE) in and only 8% of patients developed a local recurrence. No late
severity of radiation damage need to be considered. Superfical toxicities were reported. More recently, Gauden et al. reviewed
or orthovoltage x-rays have been proven to have a higher rela- 236 patients who were treated with a total dose of 36 Gy given
tive biological effectiveness value compared with electron and over 12 consecutive treatments (3 Gy/fraction) with a Leipzig
megavoltage photons [45]. Silva et al. found no significant applicator [52]. Over 80% of the lesions were located on H/N,
increase in local failure rate with EBRT on multivariate analysis with other sites including extremities and trunk. At a median
using relative biological effectiveness-corrected biological equiv- follow-up of 5.5 years, the local control rate was 98% (232/
alent dose with a multiplying factor of 0.85 [35]. 236). Similarly, Tormo et al. reported a series of 32 NMSC
For personal use only.

patients treated with 42 Gy in 6–7 fractions using the Valencia

HDR brachytherapy applicator [53], with a 98% local control rate at around 4 years.
During the past 25 years, new technologies have emerged for The skin toxicity was all Grade 1, and resolved within 1–2
skin cancer treatment, including HDR brachytherapy using months. TABLE 2 summarizes the key series reporting the use of
radioactive isotopes and electronic brachytherapy (EBT) using HDR brachytherapy for NMSC.
miniature x-ray photon sources. The use of radioactive sources The use of radioisotopes for HDR brachytherapy poses limi-
in brachytherapy treatment for skin cancer dated back to 1899, tations for users. Therefore, only large radiation oncology cen-
but gradually declined due to the popular use of x-ray therapy ters have the capability to support a HDR program. EBT
in the 1940s. Brachytherapy regained its popularity back in the platforms have been developed to use miniature x-ray sources
1960s with the development of remote afterloading systems, that are able to deliver HDR brachytherapy with low-energy
which significantly reduced the exposure to operators from the photons. The main advantages of EBT include the elimination
manual isotope application [46]. Dose fractionation schemes for of radioactive isotopes and minimal shielding requirements,
traditional RT technologies range from 35 to 65 Gy in 5– which makes it possible for small clinics to consider HDR
30 fractions, depending on the treatment site and the tumor treatment option for their patients. The commercially available
size. The use of brachytherapy isotopes such as iridium-192 EBT platforms include Axxent eBx (Xoft Inc., Sunnyvale,
(Ir-192) with skin surface applicators or surface molds can CA) [54], IntraBEAM (Carl Zeiss Meditec, Inc., Dublin, Cali-
reduce treatment fractions to 6–8 for a total dose of 30– fornia) [55], and Esteya (Esteya EBS, Elekta AB-Nucletron,
40 Gy, delivered at a frequency of once or twice per week. Ir- Stockholm, Sweden) [56].
192 is a gamma ray emitter with a half-life of 73.8 days, creat- Early results with this approach appeared promising.
ing gamma particles at a mean energy of 380 keV. Given this Bodner et al. first published a prospective Phase I trial in
level of energy, Ir-192 is effective at treatment depths of 3– 2003 for treatment of superficial NMSCs, using the Photon
5 mm, commonly applied through surface molds or surface Radiosurgery System (Photoelectron Corporation, Lexington,
applicators for HDR brachytherapy skin treatments. The com- MA; an early developer for the miniature 50 kVp x-ray source,
mercially available surface applicators are Leipzig-style applica- which was later combined with IntraBEAM and distributed by
tor cones provided by Nucletron (Elekta, Stockholm, Sweden) Carl Zeiss). With a dose of 30 Gy in 3 weekly fractions for
and Varian (Varian Medical Systems, Palo Alto, CA), or Valen- BCCs and SCCs in 18 patients, the overall response rate was
cia applicators provided by Nucletron. 100% for BCC and 83% for SCC at 12 months [57]. Later in
Long-term results of HDR brachytherapy using surface 2010, Bhatnagar et al. reported the results of 37 patients with
molds for NMSCs have been reported in various series. 44 NMSCs of the H/N (91%) and extremity (9%) [58].
Guix et al. prospectively evaluated 136 patients with NMSC of Patients received 40 Gy in 8 fractions, twice weekly with at
the face treated with HDR brachytherapy to a total dose of least 48 h between treatments. At a median follow-up of only

informahealthcare.com doi: 10.1586/14737140.2015.1042865

 Review Rong, Zuo, Shang & Bazan

Table 2. Summary of major series of non-melanoma skin cancer treatment using HDR or electronic
brachytherapy.
Study Site Mean age Lesion type Modality Prescription: Follow-Up Local- Ref.
(year) (yr) dose (Gy)/ (yr) Control
fractionation
Svoboda Face, H/N, 72 (46–92) BCC (76) HDR 12–50/1–15 0.8 (0.4–1.8) 1-yr: 100% [67]
et al. (1995) Trunk, Ext. SCC (11)
Other (19)
Farrús et al. Lip 67 (42–91) SCC (72) Interstitial LDR 62–67 2.3 (1.1–3.5) 85–98% [68]
(1996)
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Avril et al. Face 66 BCC (173) Interstitial ILDR: 57–76 3.4 4-yr: [69]
(1997) Ear LDR (95) SupX: 34–40 ILDR: 91.2
SupX (57) OrthoX: 33–65 SupX: 95.4%
OrthoX (21) OrthoX: 95%
Guix et al. Face 67 (23–91) BCC (102) HDR 60–80/33–46 Min 1 5-yr: 98% [47]
(2000) SCC (34)
Guinot Lip 73 (38–90) BCC (1) HDR 40.5–45/8–10 1.5 (0.1–3) 3-yr: 88% [70]
et al. (2003) SCC (38)
Lebioda Lip 65 (43–83) SCC (24) Interstitial HDR 35/7 2.7 2-yr: 88% [71]
et al. (2005)
Somanchi Hand 69 (50–87) SCC (25) HDR 40–45/8 5 100% [50]
et al. (2008)
For personal use only.

Bhatnagar Head Ext. 72.5 (49–89) BCC (25) HDR 40/8 0.3 (0.1–0.8) 4-yr: 100% [58]
et al. (2010) SCC (17)
Other (2)
Ayerra et al. Lip 67 SCC (115) HDR (21) HDR: 45–50 2.7 (1.7–15.7) 15-yr: 90% [72]
(2010) Other (6) LDR (100) LDR: 60–70

Maroñas Face 78 (53–91) Facial HDR 48–57/12–19 3.75 5-yr: 89% [60]
et al. (2011) carcinoma (51)
Ghadjar Lip HDR: SCC (103) HDR (33) HDR: 30–44 HDR: 2.7 5-yr: 93% [73]
et al. (2012) 73 (35–95) LDR (70) LDR: 48–66 (0.3–5.6)
LDR: LDR: 3.7
71 (37–90) (0.3–23)
Guinot Lip 75 (36–96) SCC (102) HDR 45/9 3.8 (0.2–11.9) 10-yr: 95% [74]
et al. (2013)
Rio et al. Lip 69 (24–94) SCC (89) LDR 50–62 3 (0.8–10.6) 5-yr: 95% [75]
(2013) Fraction NS
Gauden Face, H/N, 76 (46–98) BCC (121) HDR 36/12 5.5 (2–10) 98% [52]
et al. (2013) Trunk, Ext. SCC (115)
Bhatnagar Face, H/N, 73 (49–97) BCC(91) HDR EBT 40/8 0.8 (0.1–2.3) 100% [59]
2013 Trunk, SCC(70)
Ext. BSC(1)
Other (9)
Arterbery Hand 62 SCC (1) HDR EBT 40/8 1 1-yr: 100% [76]
et al. (2013)
Tormo et al. Hand 78 (43–97) BCC (32) HDR 42/6–7 3.9 (2.6–5) 4-yr: 98% [53]
(2014)
BCC: Basal Cell Carcinoma; BSC: Basosquamous Carcinoma; BT: Brachytherapy; EBT: Electronic brachytherapy; Ext.: Extremities; Gy: Gray; H/N: Head and neck; HDR:
High-Dose-Rate; ILDR: Interstitial LDR; LDR: Low-Dose-Rate; NS: Not specified in paper; OrthoX: Orthovoltage x-ray; RT: Radiation therapy; SCC: Squamous Cell Carci-
noma; SupX: Superficial x-ray.

doi: 10.1586/14737140.2015.1042865 Expert Rev. Anticancer Ther.

 Radiotherapy treatment for nonmelanoma skin cancer Review

4 months, there were no recurrences, no severe toxicities and The rates of poor cosmesis did not differ between the groups
the cosmesis were rated as ‘good’ to ‘excellent’ for 100% of the when assessed by physicians (17% in the 44 Gy group and
patients. The series was subsequently updated to include 13% in the 54 Gy group) [44].
171 lesions treated on 122 patients with the same dose and In terms of brachytherapy, Guix et al. evaluated long-term
fractionation scheme [59]. The mean follow-up was 10 months complication rates and cosmesis in a group of 136 patients
for all patients with no recurrences. At least 1-year follow-up treated with HDR brachytherapy (minimum dose of 60–65 Gy
was available for 46 lesions in 42 patients. The most common in 33–36 fractions) via custom-made molds. Cosmesis was
late effects included Grade 1 hypopigmentation (11%) and excellent or good in 98% of patients 6 months after comple-
rash dermatitis (7%). Cosmesis remained ‘excellent’ to ‘good’ tion of therapy. There were no late toxicities reported [47].
in all of these lesions [59]. With a more hypofractionated approach of 36 Gy in 12 frac-
tions, Gauden et al. found that 88% of the 208 patients in the
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

Toxicity of RT study had excellent or good cosmesis [52]. The rate of late skin
RT side effects are generally divided into acute effects (those hypopigmentation change was 5.5% (n = 13), and no patients
that occur during and up to 3 months after completion of developed telangiectasias. No other late toxicities were reported
therapy) and late effects (those occur >3 months from the end in this study [52]. In a study of hypofractionated HDR brachy-
of treatment). Because radiation is a local therapy, the toxicity therapy (48–57 Gy in 12–19 fractions) for NMSC of the face,
related to RT is highly dependent upon the part of the body Maronas et al. found that no patients developed late toxicity
that is irradiated. The most common acute reactions during a and all patients had good or very good cosmesis [60]. Late toxic-
course of RT for NMSC include skin irritation (including ity with EBT also appeared to be low. Bhatnagar et al. reported
moist desquamation) and fatigue [15]. These side effects occur that cosmesis was rated as ‘excellent’ to ‘good’ in all lesions
nearly universally, regardless of which RT modality is used. with at least 1-year follow-up [59]. TABLE 4 summarizes late toxic-
However, the late toxicity of RT would be expected to vary ity and cosmetic results in the largest HDR or EBT series
based on the RT modality given the wide range in dose distri- reported in the literature.
butions between external beam radiotherapy and brachytherapy
For personal use only.

techniques. Cosmesis is also an important outcome to measure, Expert commentary

and the cosmetic result is often related to the degree of late tis- Currently, there is no clear consensus as to which radiation
sue fibrosis, as well as pigmentation changes and telangiectasias treatment modality is preferred for the treatment of NMSC.
on the skin. A commonly used criterion for scoring cosmesis is Overall, local control and toxicity appear to be quite compara-
based on Lovett scoring [33]. ble among the various modalities. The choice should be
TABLE 3 summarizes toxicity results using external beam radia- patient- and lesion-specific. Factors to consider include patient
tion techniques. In one of the largest series of external beam age, lesion size, lesion location and depth of invasion. Older
RT for NMSC of the face and H/N, Petrovich et al. reported patients with multiple medical comorbidities should be consid-
low rates of late toxicity: 2% rate of mandibular necrosis (for ered for more hypofractionated approaches to limit the number
cancers of the lip); no cases of skin or cartilage necrosis among of visits to the radiotherapy department. In addition, younger
646 patients treated with lesions on the eyelids, nose and exter- patients with lesions not amenable to surgical resection may
nal ear; excellent functional/cosmetic results (though absolute benefit more from brachytherapy treatments to minimize radia-
rates not provided) for patients with smaller lesions and those tion exposure to underlying normal structures. In addition,
treated with <300 cGy/day [34]. In a similar large series of most of skin/surface applicators, that is, Leipzig, Valencia, Xoft
patients with NMSC of the scalp, face, H/N, trunk and and Esteya, are made of metals with a cone shape, which pro-
extremities, Locke et al. reported a higher rate of late complica- vide sufficient protection for surrounding normal tissues near
tions at 5.8%. This included primarily soft tissue necrosis the surface lesions. Lower dose per fraction and lower total
(n = 21), cataracts (n = 6), bone necrosis (n = 3) and cartilagi- dose should also be strongly considered for young patients. In
nous necrosis (n = 1) [31]. Cosmesis was scored by the presence terms of location, EBRT or HDR brachytherapy would be pre-
of skin changes (hypopigmentation, telangiectasias and atrophy) ferred over orthovoltage radiotherapy for lesions of the scalp to
and fibrosis. This series found that 92% of patients with evalu- minimize radiation dose to the brain. Similarly, orthovoltage
able data had good or excellent results. Rates of poor cosmesis therapy should be avoided in NMSCs involving the pinna or
were highest in patients treated with electrons (12%) or combi- nose to minimize dose to the thin, underlying cartilage in these
nation of electrons/superficial therapy (19%) compared with locations. Lesions in areas with poor blood supply, such as the
superficial RT alone (4%) [31]. In a more recent retrospective extremities, should be treated with conventionally fractionated
study of patients with NMSC of the face, H/N treated with RT as opposed to hypofractionated RT to minimize risks of
electron beams, van Hezewijk et al. evaluated two hypofractio- late necrosis. Finally, for patients with lesions that are deeply
nation schedules: 44 Gy in 10 fractions and 54 Gy in 18 frac- invasive and/or require more extensive radiation fields due to
tions. Cosmesis was rated as ‘good’, ‘fair’ or ‘poor’. When perineural invasion or high risk of lymph node metastases,
assessed by the patient, 100% of those treated to 44 Gy had high-energy (megavoltage) photons should be used. SCCs at
good/fair cosmesis compared with 75% in the 54 Gy group. the base of the tongue, for example, are relatively rare and

informahealthcare.com doi: 10.1586/14737140.2015.1042865

 Review Rong, Zuo, Shang & Bazan

Table 3. Summary of major series for nonmelanomatous skin cancer utilizing multiple radiation modalities,
including superficial x-ray, orthovoltage x-ray, photon beams, and electron beams in terms of cosmetic
outcome and late toxicities. Cosmesis outcomes are based on Lovett scoring [33].
Study Treatment Cosmetic outcome Late Toxicities Ref.
(year) modality
Excellent– Fair Poor
(Lesion number)
good
Hunter et al. Electron 70% N/A N/A 4 with late necrosis, 1 with ulceration and [42]
(1982) 10 MeV (43) cartilage involvement; 2 with residual and
6 with recurrent tumor
Petrovich SupX 100% for N/A N/A 5 (2%) lip cancer with necrosis of the [34]
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

et al. (1987) EB Patients with mandible

Cu HVL small lesions
Co-60 and fraction
dose £3 Gy
Griep et al. SupX (99) SupX: 48% SupX: 33% SupX: 19% N/A [29]
(1995) EB (290) EB: 82% EB: 15% EB: 2%
Lovett et al. SupX (187) SupX: 97% 3.1% of 7.3% of Overall complication: 5.5% (17/310), [32]
(1990) EB (57) EB: 78% entire entire including soft tissue necrosis (5%), bone
MV Photon (15) MV Photon: patient patient necrosis (0.3%), and soft tissue and bone
Combo (80) 80% group group necrosis (0.6%)
Combo:
78%
Zablow et al. Electron 91% N/A N/A Necrosis: 1% [40]
For personal use only.

(1992) 6 MeV
Silva et al. OrthoX (278) N/A N/A N/A Grade 4 late toxicity (ulceration/necrosis) [35]
(2000) EB (39) 2 yr: 4.9%; 5 yr: 7.3%
Other (17)
Locke et al. SupX (317) 92% Fair-poor: EB: 12%; Overall complication rate: 5.8% (soft- [31]
(2001) EB (100) Combo: 19%; RT: 4% tissue necrosis 4.1%; cartilaginous
Combo (108) necrosis: 0.1%; bone necrosis: 0.6%;
MV Photon (6) cataracts: 1.1%)
Caccialanza Contact x-ray 75% 14% 2% No late toxicity observed [27]
et al. (2005) Soft x-ray
Half-deep x-ray
Olschewski Low E Photon (101) 94% 6% 0% Pigmentary change (92%); telangiectasia [33]
et al. (2006) MV Photon (3) (10%); fibrosis (43%); skin atrophy (73%)
van Hezewijk EB (54 Gy in 18 fx Patient’s Patient’s Patient’s N/A [44]
et al. (2010) and 44 Gy in 10 fx) 54 Gy: 62% 54 Gy: 13% 54 Gy: 25%
44 Gy: 67% 44 Gy: 33% 44 Gy: 0%
Observer’s Observer’s Observer’s
54 Gy: 38% 54 Gy: 49% 54 Gy: 13%
44 Gy: 33% 44 Gy: 50% 44 Gy: 17%
BCC: Basal cell carcinoma; BSC: Basosquamous carcinoma; EB: Electron beam; Ext: Extremities; Gy: Gray; H/N: Head and neck; IMRT: Intensity modulated radiation ther-
apy; NED: No evidence of disease; NS: Not specified in paper; OrthoX: Orthovoltage x-ray; RT: Radiation therapy; SCC: Squamous cell carcinoma; SupX: Superficial x-ray.

deeply situated in the H/N region. In addition to surgical NMSC, this approach is not suitable in all cases, leading to
resection, external-beam radiotherapy using megavoltage photon an increase in the use of RT. Multiple studies have demon-
beams is one commonly used treatment option and has been strated high local control rates and favorable cosmetic out-
proven to be comparable with surgery in terms of local-regional comes with the various radiation modalities. Superficial and
control rates and survival rates, with less morbidity [61–64]. orthovoltage x-rays are two conventional techniques and are
suitable for shallow skin lesions, due to their limited penetra-
Five-year view tion. EBRT, on the other hand, has higher penetration in tis-
The rising incidence of NMSC is an important global health sue, and therefore, can be used for deeper skin tumors.
problem. While surgical resection is often used to treat However, the high-energy photon and electron beams used in

doi: 10.1586/14737140.2015.1042865 Expert Rev. Anticancer Ther.

 Radiotherapy treatment for nonmelanoma skin cancer Review

Table 4. Summary of major series of nonmelanomatous skin cancer treatment using HDR or electronic
brachytherapy, in terms of cosmetic outcomes and late toxicities. Cosmesis outcomes are based on Lovett
scoring [33].
Study Treatment Cosmetic outcomes Late Toxicity Ref.
(year) modality
Excellent– Fair Poor
good
Avril et al. Interstitial LDR (95) 69% (patients 22% (patients 8% (patients 4 yr. time point [69]
(1997) SupX (57) assessed at assessed at assessed at Dyspigmentation and telangiectasia:
OrthoX (21) 4 years) 4 years) 4 years) 65%
Radiodystrophy: 41%
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Necrosis: 5%
Ophthalmologic complication: 2%
Guix et al. HDR At 6 months: At 6 months: 2% 0% No late toxicity observed [47]
(2000) 98%
Lebioda Interstitial HDR 100% 0% 0% No late toxicity observed [71]
et al. (2005)
Somanchi HDR 80% 20% 0% Mild skin atrophy: 28% [50]
et al. (2008) (patients (patients Mild telangiectasia: 48%
assessed) assessed) Mild alopecia: 28%
Mild scarring: 36%
Bhatnagar HDR 100% 0% 0% No severe late toxicities were observed [58]
et al. (2010)
For personal use only.

Maroñas HDR 100% 0% 0% No late toxicity observed [60]

et al. (2011)
Ghadjar HDR (33) N/A N/A N/A Hyper/hypopigmentation, induration/ [73]
et al. (2012) LDR (70) fibrosis, skin atrophy, telangiectasia
Guinot HDR 100% 0% 0% Grade 1 and 2 fibrosis in all cases; [74]
et al. (2013) telangiectasia found in 2 patients; No
case of bone or soft tissue necrosis
was recorded
Rio et al. LDR 77% 21% 2% No late toxicity observed [75]
(2013)
Gauden HDR 88% 6.5% 5.5% Skin hypopigmentation: 5.5% [52]
et al. (2013)
Bhatnagar HDR EBT 100% 0% 0% Hypopigmentation: 11% [59]
(2013) Dry desquamation: 2%
Alopecia: 2%
Rash dermatitis: 7%
Arterbery HDR EBT 100% 0% 0% No late toxicity observed [76]
et al. (2013)
Tormo et al. HDR 100% 0% 0% No late toxicity reported [53]
(2014)
BCC: Basal cell carcinoma; BSC: Basosquamous carcinoma; BT: Brachytherapy; EBT: Electronic brachytherapy; Ext.: Extremities; Gy: Gray; H/N: Head and neck; HDR: High-
dose rate; ILDR: Interstitial LDR; LDR: Low-dose rate; NS: Not specified in paper; OrthoX: Orthovoltage x-ray; RT: radiation therapy; SCC: Squamous cell carcinoma; SupX:
Superficial x-ray.

EBRT are generated through linear accelerators, which are cosmetic outcomes are superior with HDR techniques. Fur-
generally available only in radiation oncology departments. thermore, EBT is operated through a portable platform, with
More recently, HDR techniques have gained popularity for various skin applicators that directly conform the beam to
the treatment of NMSC. Tumor control rates using HDR patient’s surface. EBT requires less shielding and does not
techniques are comparable with control rates using conven- need to follow isotope regulations. Therefore, EBT is an
tional EBRT. In addition, several studies suggested that attractive option for small clinics with limited access to linear

informahealthcare.com doi: 10.1586/14737140.2015.1042865

 Review Rong, Zuo, Shang & Bazan

accelerators. We expect to see more applications of the EBT Acknowledgement

technique in the near future. In terms of clinical trials, future We would like to thank Mr. Ben Hemmelgarn for his assistance in the
studies should set to more clearly define dose regimens based manuscript preparation.
on tumor size and location, and should also focus on the
ideal choice of radiation treatment modality. The number of Financial & competing interests disclosure
published clinical series using isotope-based HDR and EBT The authors have no relevant affiliations or financial involvement with
techniques is still very limited. More clinical trials involving any organization or entity with a financial interest in or financial conflict
various tumor sizes and locations with well-defined hypofrac- with the subject matter or materials discussed in the manuscript. This
tionated dose regimen are expected for both of these treat- includes employment, consultancies, honoraria, stock ownership or options,
ment modalities. expert testimony, grants or patents received or pending, or royalties.
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15

Key issues
. Overall, local control and toxicities are demonstrated to be comparable among the various modalities. Different modalities have their
own advantages and limitations.
. Superficial and orthovoltage x-ray radiotherapy treatments are effective for basal cell carcinoma and squamous cell carcinoma, with a
more than 90% local control rate in most of clinical series.
. Electron beam radiotherapy provides equivalent local control rates but requires users’ attention to ensure adequate dose coverage and
minimize dosimetric variance.
. High-dose rate provides expedite treatment option for patients, with equivalent tumor local control and cosmetic outcomes.

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