Review
Radiotherapy treatment for nonmelanoma skin cancer Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
Expert Rev. Anticancer Ther. Early online, 1–12 (2015)
Yi Rong*1,2, Li Zuo3, Lu Shang4 and Jose G Bazan*1 1 Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA 2 Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Davis, CA 95817, USA 3 Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, College of Medicine, Ohio State University, Columbus, OH 43210, USA 4 Guangxi Institute of Research and Design, Guangxi, China *Authors for correspondence: Tel.: +1 916 734 8170 Fax: +1 916 734 3239 [email protected] [email protected]
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Non-melanoma skin cancer is the most common malignancy in the USA, with an estimated 3.5 million cases per year. Treatment options include surgical excision, radiation therapy (RT), photodynamic therapy and topical agents. Although surgical excision remains the mainstay of therapy, RT offers an effective alternative. RT can be used as an adjunct to surgery in highrisk situations, or in cases where surgical excision would lead to impaired cosmesis and/or functional outcomes. Radiation treatment modalities for non-melanoma skin cancers are diverse. Studies in the literature have examined the clinical effects of a wide variety of modalities, areas of the body and dosages. The most common modalities include superficial or orthovoltage RT, electron beam therapy and high dose-rate brachytherapy. This article aims to review the diverse radiotherapy treatment modalities for non-melanoma skin cancers, focusing on tumor control and toxicity. KEYWORDS: brachytherapy . cosmesis and toxicity . nonmelanoma skin cancer . orthovoltage radiotherapy . superficial radiotherapy
Skin cancer is the most common type of cancer in the United States. The incidence of skin cancer is estimated to be higher than all other types combined, including breast, prostate, lung and colon cancers. Although melanoma represents less than 5% of total skin cancer cases, it is the leading cause of skin cancer death [1]. The most prevalent forms of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), both of which are highly curable. Because these cancers develop from epidermal cell types other than the melanocyte, they are referred to as nonmelanoma skin cancers (NMSCs). The total number of NMSCs in the US population is estimated at 3.5 million in 2006 [2]. A recent geographical review of worldwide incidence of NMSCs revealed the locations of high incidence rates and highlighted the fact that NMSCs are an increasing problem for health care globally [3]. Prior reviews have focused on the clinical aspects of NMSCs, including tumor characteristics, risk factors, diagnosis, assessments and various treatment options [4,5]. Treatment options for skin cancers include surgical excision [6–9], Mohs micrographic surgery [8–14], radiation therapy (RT) [9,15,16], photodynamic therapy [17–21], topical medications [9,22,23], and systemic medical therapy [9]. Surgical excision and Mohs surgery are 10.1586/14737140.2015.1042865
effective and considered the standard of care for most primary NMSCs [4]. These surgical options provide cure rates >95% for primary and recurrent BCCs and SCCs [13]. However, RT is indicated when surgery is not an option due to cosmetic or functional reasons, or as an adjuvant therapy in high-risk SCCs and BCCs. RT offers unique advantages in challenging locations for surgery, such as in the head and neck (H/N) region, especially when there is a need for good cosmetic outcome. RT is also favored for treatment of elderly patients (>60 years old), given concerns about potential long-term sequelae [4]. Established guidelines have been provided for the evaluation and management of BCCs and SCCs with RT [4,15,16], including dose regimen and followup schedules. However, there is a lack of a comprehensive review with a focus on evaluating various radiotherapy modalities. Traditional RT treatment modalities include superficial x-rays, orthovoltage x-rays, electrons and Co60 photons. In more recent years, the emerging new technologies for NMSC treatment include high dose rate (HDR) brachytherapy using isotopes or miniature x-ray sources. The present review article aims to include various radiotherapy modalities for treating nonmelanoma skin cancers, with comparing their associated tumor control and treatment toxicities. An extensive
2015 Informa UK Ltd
ISSN 1473-7140
1
Review
Rong, Zuo, Shang & Bazan
literature search was conducted on the PubMed/Medline database available in English, with no specific publication time restrictions. The search keywords included ‘nonmelanoma skin cancer’, ‘BCC’, ‘SCC’, ‘superficial radiotherapy’, ‘orthovoltage radiotherapy’, ‘electron beam’, ‘HDR’, ‘brachytherapy’, ‘electronic brachytherapy’, etc.
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Superficial & orthovoltage RT
Traditional techniques of treating skin cancer using radiation include superficial and orthovoltage x-ray therapies. A 1974 survey among dermatologists found that RT was used in 55.5% of dermatology clinics in USA and Canada. However, the arrival of Mohs surgery offered dermatologists high cure rates with reduced side effects [24]. In a later survey conducted in 1986, superficial radiation could only be found in 12% of dermatology training clinics [25]. Nevertheless, kilovoltage x-ray therapy can be expected to become even more important in the next few decades, due to the aging population. Surgery is often not an option for the rapidly increasing elderly population with skin cancer, as complications with surgery are much more likely. Accordingly, superficial and orthovoltage x-ray therapies are well-tolerated, simple and low-cost substitutes. Due to the shallow effective depth, early superficial x-ray therapy used multiple beams from various angles on deep tumors. This technique reduced high surface doses, while also increasing tumor doses [26]. With the advent of other treatment options, both superficial x-rays and orthovoltage x-rays are not indicated for deep tumors but are still commonly used for superficial tumors in all areas of the body. In superficial x-ray therapy, the photon energy ranges from 50 to 150 kVp, with an equivalent half-value layer of 1.0–8.0 mm Al. Typical treatment diameters range from 1.0 to 5.0 cm, at a source-surface distance of 15–20 cm. Due to the limited penetration capability of these low-energy photons, this modality is commonly used for tumors at very shallow depth, that is, 5 mm. There are several commercially available systems for this type of treatment, including SRT-100 (Sensus Healthcare, Boca Raton, FL), Xstrahl 100 and 150 (Xstrahl Medical Solutions, Suwanee, GA). Orthovoltage therapy covers an x-ray energy range of 150– 300 kV, with an equivalent half-value layer of 1–4 mm Cu. Treatment diameters range from 4 to 20 cm at a source-surface distance of 50 cm. Due to its ability to travel further than superficial x-ray therapy (2 cm in general), orthovoltage RT is sometimes called ‘deep’ therapy. The commercially available orthovoltage x-ray systems include Xstrahl 200 & 300 (Xstrahl Medical Solutions, Suwanee, GA) and Gulmay Orthovoltage Unit (Gulmay Medical Limited, Chertsey, Surrey, UK). Superficial and orthovoltage x-ray RT treatment techniques are effective for BCC and SCC in terms of tumor local control and cosmetic outcomes [27–38]. A large-scale clinical study by Petrovich et al. reported treatment outcomes from 896 patients (467 BCCs, 362 SCCs and mixed), mostly treated with superficial and orthovoltage x-rays [34]. The dose regimen in the early years of this series ranged from 30 Gy in three fractions to doi: 10.1586/14737140.2015.1042865
48 Gy in 12 fractions, which was adjusted to a uniform dose prescription of 51 Gy in 17 fractions for small lesions and 60 Gy or more (2–2.5 Gy per fraction) for larger lesions in the following 10 years. The overall local control was 97% at 5 years and 96% at 10 years, with excellent cosmetic outcomes [34]. Lovett et al. retrospectively analyzed a total of 339 NMSC lesions (242 BCCs, 92 SCCs and five variants of SCCs) treated with various modalities and reported an overall tumor control rate of 86% in all lesions (91% for BCCs and 75% for SCCs) [32]. The total dose ranged from 40 Gy to 60 Gy for both BCCs and SCCs. It was also noted that the tumor control rate was dependent on the tumor type, tumor size and treatment modality [32]. Specifically, superficial x-ray technique achieved a local tumor control of 93–100%, depending on the tumor size. This was superior to both electron beam and Cobalt 60 therapy. In addition, tumor control rate varies with tumor sizes and different dose fraction sizes. For BCCs 1 cm or less, all dose fraction sizes (4 Gy) provided >95% tumor control; for BCCs 1.1–5 cm, 3–6 Gy dose fraction size was recommended for a 100% local control; data for lesions >5 cm was not conclusive. Similar results were seen in SCCs, except that the cutoff dose fraction size was 5 Gy instead of 6 Gy for tumor size 1.1–5 cm [32]. TABLE 1 summarizes the key series of external beam radiotherapy for the treatment of NMSC. Electron beam radiotherapy
The ability to deliver a uniform radiation dose to a few centimeter depth of human tissue with a steep dose fall beyond the therapy range makes the electron beam suitable for superficial cancer treatments [39], including skin cancer in the H/N region [40]. The energies used for electron beam radiotherapy (EBRT) vary from 4 to 20 MeV, resulting in an effective treatment depth of 2–6 cm. Also, a common technique is to use 1 cm bolus and 6 MeV beam to treat 1 cm deep lesions. Electron beams are available on most commercial linear accelerators. Reported clinical outcomes with EBRT have been controversial. Despite the inferior local control rate associated with EBRT on multivariate analysis reported by Lovett et al. [32], several other series reported favorable outcomes with local control rate comparable with superficial x-ray treatments, ranging from 81 to 95% [29,40–43]. Furthermore, these studies reported good cosmetic outcomes in contrast to those reported by Lovett et al. [32]. Griep et al. showed no significant difference in tumor local control comparing superficial x-rays (97%) and electrons (94.5%) after a 2-year follow-up, with overall cosmetic results in favor of EBRT [29]. The dose regimen was 6–10 fractions of 6–10 Gy for superficial x-rays and 17–18 fractions of 3 Gy four times per week for electron beam. The fraction size was adjusted to 2 Gy for a total of 50–60 Gy dose when treating larger volumes. Silva et al. [35] reported 2- and 5-year local control rates of 87% and 79%, respectively, in a population of 334 pinna lesions (201 BCCs, 122 SCCs and 11 basosquamous carcinoma) treated with orthovoltage x-ray (83%) and EBRT (12%), with excellent to good cosmetic outcome. The most common dose prescriptions were 35 Gy/5 Expert Rev. Anticancer Ther.
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Pinna
Face, H/N
Scalp, Face, H/N, Trunk, Ext.
Scalp, Face, H/N, Trunk, Ext.
Face, H/N, Trunk, Ext
Lip
Pinna
Scalp, Face, H/N, Trunk, Ext.
Nose
Hunter et al. (1982)
Petrovich et al. (1987)
Griep et al. (1995)
Lovett et al. 1990
Zablow et al. (1992)
de Visscher et al. (1996)
Silva et al. (2000)
Locke et al. (2001)
Tsao et al. (2002)
74.5 (42–93)
BCC: 73 (11–100) SCC: 72 (32–97)
74 (41–104)
68 (41–92)
SCC (94)
BCC(389) SCC(142)
BCC (201) SCC (122) BSC (11)
SCC (108): (T189, T2 17, T3 2)
BCC (94), SCC (19), Other (2)
BCC (242), SCC (92), Other (5)
70–80 (30–90)
70.4 (32–97)
BCC (295), SCC (94)
BCC (467) SCC (362) BSC (67)
BCC (17), SCC (26)
Lesion type
71.5
60 (21–94)
BCC: 62 (45–88); SCC: 67 (53–89)
Mean age (yr)
SupX: 97% EB: 94.5%
2
Min 2-death
SupX: 6–10/6–10; Electron: 51–54/ 17–18; or 50–60 @ 2–3 Gy per fraction 40–60/10–30
2-yr, 5-yr: 93%,83% (BCC); 82%,79% (SCC) BCC (92%) SCC (80%)
2-yr: 90% 5-yr: 85%
3.3 (0.1–13.4) 5.8 (2–24)
2.9 (0.2–10.4)
35/5 42.5–45/10 50–65/20–30 40–60/10–30
OrthoX (278), EB (39) Other (17)
OrthoX. (76) EB (13) Other (5)
32.5–35/5 42.5–45/10 20/1 50/15–20
T1: 99% T2: 77%
6.4 (1.7–12) OrthoX: 48–51/12– 17 EB: 55/22 LDR: 60/NS
OrthoX. (62) EB (6–8 MeV) (33) Other (13)
SupX. (317) EB (100) Combo (108) MV Photon (6)
Primary: 88%; Primary +LN: 86%; NED: 93%
Min:2; Mean: 3.9
BCC: 50–52/10–13; SCC: 60/15
Electron, 6 MeV
SupX (187) EB (57) MV Photon (15) Combo (80)
BCC: 91% SCC: 75%
BCC: 99% (5-yr), 98% (10-yr), SCC: 94% (5-yr), 88% (10-yr) BSC: 95% (5-yr), 96% (10-yr)
NS
30/3 48/12 51/17 60/24–30
SupX EB Cu HVL Co-60
SupX (99), EB (290)
83.3%
Local-Control
>2
Mean Follow-Up (yr)
45–50/8, 52.5–55/15
Prescription: dose (Gy)/ fractionation
Electron, 10 MeV
Modality
[38]
[31]
[35]
[37]
[40]
[32]
[29]
[34]
[42]
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 in paper; OrthoX: Orthovoltage x-ray; RT: Radiation therapy; SCC: Squamous cell carcinoma; SupX: Superficial x-ray.
Site
Study (year)
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.
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Radiotherapy treatment for nonmelanoma skin cancer
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doi: 10.1586/14737140.2015.1042865
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.
[66]
IMRT (60%) EB (62.5%) 3D conformal (33.3%) 1 (0.5–4) H/N, Ext. Matthiesen et al. 2011
63 (48–90)
BCC (10) SCC (11)
IMRT (10) EB (8) 3D conformal RT (3)
BCC: 56.25–76.5/ 25–36 SCC: 55.8–79.8/ 25–35
[44]
3-yr BCC: 97–98% SCC: 94–97% 3.6 (0.1–7.3) EB Face, H/N, Trunk, Ext. van Hezewijk et al. (2010)
BCC:74.8 (38.4– 95.5); SCC: 78.3 (41.2–96.7)
BCC (332) SCC (102)
54/18 or 44/10
[36]
0.3 (0.1–2.3) OrthoX (13) EB (14) MeV Photons (4) H/N, Thigh, Hand, Sternum Barnes et al. (2010)
91 (80–101)
SCC (26) BCC (5)
24/3
78.3% (overall response)
[65]
100% 1.3 59.4–74.25/33 IMRT EB SCC (1) BCC (2) Face Matthiesen et al. (2010)
88
[33]
100% 3.1 (1–6.4) 54–60/15 Low E photon (101) MV photon (3) BCC (104) Head Olschewski et al. (2006)
77 (47–98)
[27]
2.4 45–105/9–21 Pinna Caccialanza et al. (2005)
75.2 (48–96)
BCC (99) SCC (16)
Contact x-ray Soft x-ray Half-deep x-ray
5-yr: 78%
4-yr: 86% (BCC) 58% (SCC) 3.5 (0.1–8.1) 35/5, 40–45/10 50/15–20, 60/25, 60–70/30–35 H/N, Trunk, Ext. Kwan et al. (2004)
78 (31–103)
BCC (61) SCC (121)
OrthoX. EB MV Photons Combo
Local-Control Mean Follow-Up (yr) Site
Mean age (yr)
Lesion type
Modality
Prescription: dose (Gy)/ fractionation
[30]
Rong, Zuo, Shang & Bazan
Study (year)
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 (cont.).
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Ref.
Review
fractions for small lesions (field size = 4.9 cm2), 42.5–45 Gy/10 fractions for median field size (10.5 cm2) and 50–65 Gy/20–30 fractions for large field size (81 cm2). The local control rates at 2 and 5 years were 93% and 83% for BCC, and 82% and 79% for SCC, respectively. Support for EBRT has increased as a result of recent publications citing encouraging clinical outcomes. Locke et al. [31] reported an overall tumor control rate of 89% for 531 NMSCs (389 BCCs and 142 SCCs) in 468 patients with a median 5.8-year follow-up, treated with superficial x-rays (60%), EBRT (19%) or a combination of both (20%) [31]. The 5-year local control rates were 93% for primary lesions and 80% for recurrent lesions; 92% for BCCs and 80% for SCCs. Although the tumor local control was found inferior with EBRT (94% for superficial x-rays, 82% for electron beams and 82% for combination therapy), a multivariate analysis showed that local failure was related to daily fraction size, lesion diameter, pathologic type and insignificantly with treatment modality [31]. Tumor local control rates for different sizes of lesions treated with different dose fraction sizes were found to be similar to Lovett et al’s findings [32]. For the total dose (at 2.5 Gy per fraction, 4 days a week), Locke et al. recommended 40 Gy for 5 cm lesions. Kwan et al. analyzed a total of 182 patients with Expert Rev. Anticancer Ther.
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Radiotherapy treatment for nonmelanoma skin cancer
T2 and more advanced NMSCs (61 BCCs and 121 SCCs) reported 4-year locoregional control rates of 86% and 58% for BCCs and SCCs, respectively [30]. Similar to the of study Tsao et al., the most common dose fractionation included 35 Gy/5 fractions, 45 Gy/10 fractions, 50 Gy/15–20 fractions and 60 Gy/25 fractions. The reported inferior tumor control rates associated with EBRT may be attributed to patient selection bias or dosimetric coverage difficulties associated with electron beams. Careful margin consideration and improved dosimetric coverage may improve locoregional tumor control with EBRT. A more recent analysis involving 434 cases (332 BCCs and 102 SCCs), all treated with EBRT, reported 3-year local relapse-free rates of 97.6% for 54 Gy/18-fraction regimen and 96.9% for 44 Gy/10-fraction regimen [44]. When comparing treatment outcomes with superficial or orthovoltage x-rays versus electron or megavoltage photons, their differences in relative biological effectiveness (RBE) in severity of radiation damage need to be considered. Superfical or orthovoltage x-rays have been proven to have a higher relative biological effectiveness value compared with electron and megavoltage photons [45]. Silva et al. found no significant increase in local failure rate with EBRT on multivariate analysis using relative biological effectiveness-corrected biological equivalent dose with a multiplying factor of 0.85 [35]. HDR brachytherapy
During the past 25 years, new technologies have emerged for skin cancer treatment, including HDR brachytherapy using radioactive isotopes and electronic brachytherapy (EBT) using miniature x-ray photon sources. The use of radioactive sources in brachytherapy treatment for skin cancer dated back to 1899, but gradually declined due to the popular use of x-ray therapy in the 1940s. Brachytherapy regained its popularity back in the 1960s with the development of remote afterloading systems, which significantly reduced the exposure to operators from the manual isotope application [46]. Dose fractionation schemes for traditional RT technologies range from 35 to 65 Gy in 5– 30 fractions, depending on the treatment site and the tumor size. The use of brachytherapy isotopes such as iridium-192 (Ir-192) with skin surface applicators or surface molds can reduce treatment fractions to 6–8 for a total dose of 30– 40 Gy, delivered at a frequency of once or twice per week. Ir192 is a gamma ray emitter with a half-life of 73.8 days, creating gamma particles at a mean energy of 380 keV. Given this level of energy, Ir-192 is effective at treatment depths of 3– 5 mm, commonly applied through surface molds or surface applicators for HDR brachytherapy skin treatments. The commercially available surface applicators are Leipzig-style applicator cones provided by Nucletron (Elekta, Stockholm, Sweden) and Varian (Varian Medical Systems, Palo Alto, CA), or Valencia applicators provided by Nucletron. Long-term results of HDR brachytherapy using surface molds for NMSCs have been reported in various series. Guix et al. prospectively evaluated 136 patients with NMSC of the face treated with HDR brachytherapy to a total dose of informahealthcare.com
Review
60–65 Gy in 33 to 36 fractions (1.8 Gy per fraction) for lesions £4 cm and 75–80 Gy for lesions >4 cm (with a boost dose of 18 Gy in 10 fractions, after a 3-week rest period) [47]. Local control rates were excellent with only three recurrences noted, yielding a 5-year actuarial local control rate of 98% [47]. Similar results in terms of excellent local control and functional/cosmetic outcome have been reported at sites outside of the H/N region as well [48–50]. Other studies of HDR brachytherapy in the treatment of NMSCs have focused on hypofractionation (daily dose >2 Gy). In 1999, Kohler-Brock et al. reported 10-year results of using 5–10 Gy given twice per week to a total dose of 30– 40 Gy [51]. A total of 520 patients with NMSCs of the face, mouth, tongue, perianal region and the external genitalia were treated using this hypofractionation regimen. Response rates were 97% (91% complete remission and 6% partial remission) and only 8% of patients developed a local recurrence. No late toxicities were reported. More recently, Gauden et al. reviewed 236 patients who were treated with a total dose of 36 Gy given over 12 consecutive treatments (3 Gy/fraction) with a Leipzig applicator [52]. Over 80% of the lesions were located on H/N, with other sites including extremities and trunk. At a median follow-up of 5.5 years, the local control rate was 98% (232/ 236). Similarly, Tormo et al. reported a series of 32 NMSC patients treated with 42 Gy in 6–7 fractions using the Valencia applicator [53], with a 98% local control rate at around 4 years. The skin toxicity was all Grade 1, and resolved within 1–2 months. TABLE 2 summarizes the key series reporting the use of HDR brachytherapy for NMSC. The use of radioisotopes for HDR brachytherapy poses limitations for users. Therefore, only large radiation oncology centers have the capability to support a HDR program. EBT platforms have been developed to use miniature x-ray sources that are able to deliver HDR brachytherapy with low-energy photons. The main advantages of EBT include the elimination of radioactive isotopes and minimal shielding requirements, which makes it possible for small clinics to consider HDR treatment option for their patients. The commercially available EBT platforms include Axxent eBx (Xoft Inc., Sunnyvale, CA) [54], IntraBEAM (Carl Zeiss Meditec, Inc., Dublin, California) [55], and Esteya (Esteya EBS, Elekta AB-Nucletron, Stockholm, Sweden) [56]. Early results with this approach appeared promising. Bodner et al. first published a prospective Phase I trial in 2003 for treatment of superficial NMSCs, using the Photon Radiosurgery System (Photoelectron Corporation, Lexington, MA; an early developer for the miniature 50 kVp x-ray source, which was later combined with IntraBEAM and distributed by Carl Zeiss). With a dose of 30 Gy in 3 weekly fractions for BCCs and SCCs in 18 patients, the overall response rate was 100% for BCC and 83% for SCC at 12 months [57]. Later in 2010, Bhatnagar et al. reported the results of 37 patients with 44 NMSCs of the H/N (91%) and extremity (9%) [58]. Patients received 40 Gy in 8 fractions, twice weekly with at least 48 h between treatments. At a median follow-up of only doi: 10.1586/14737140.2015.1042865
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Rong, Zuo, Shang & Bazan
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Table 2. Summary of major series of non-melanoma skin cancer treatment using HDR or electronic brachytherapy. Study (year)
Site
Mean age (yr)
Lesion type
Modality
Prescription: dose (Gy)/ fractionation
Follow-Up (yr)
LocalControl
Ref.
Svoboda et al. (1995)
Face, H/N, Trunk, Ext.
72 (46–92)
BCC (76) SCC (11) Other (19)
HDR
12–50/1–15
0.8 (0.4–1.8)
1-yr: 100%
[67]
Farru´s et al. (1996)
Lip
67 (42–91)
SCC (72)
Interstitial LDR
62–67
2.3 (1.1–3.5)
85–98%
[68]
Avril et al. (1997)
Face Ear
66
BCC (173)
Interstitial LDR (95) SupX (57) OrthoX (21)
ILDR: 57–76 SupX: 34–40 OrthoX: 33–65
3.4
4-yr: ILDR: 91.2 SupX: 95.4% OrthoX: 95%
[69]
Guix et al. (2000)
Face
67 (23–91)
BCC (102) SCC (34)
HDR
60–80/33–46
Min 1
5-yr: 98%
[47]
Guinot et al. (2003)
Lip
73 (38–90)
BCC (1) SCC (38)
HDR
40.5–45/8–10
1.5 (0.1–3)
3-yr: 88%
[70]
Lebioda et al. (2005)
Lip
65 (43–83)
SCC (24)
Interstitial HDR
35/7
2.7
2-yr: 88%
[71]
Somanchi et al. (2008)
Hand
69 (50–87)
SCC (25)
HDR
40–45/8
5
100%
[50]
Bhatnagar et al. (2010)
Head Ext.
72.5 (49–89)
BCC (25) SCC (17) Other (2)
HDR
40/8
0.3 (0.1–0.8)
4-yr: 100%
[58]
Ayerra et al. (2010)
Lip
67
SCC (115) Other (6)
HDR (21) LDR (100)
HDR: 45–50 LDR: 60–70
2.7 (1.7–15.7)
15-yr: 90%
[72]
Maron˜as et al. (2011)
Face
78 (53–91)
Facial carcinoma (51)
HDR
48–57/12–19
3.75
5-yr: 89%
[60]
Ghadjar et al. (2012)
Lip
HDR: 73 (35–95) LDR: 71 (37–90)
SCC (103)
HDR (33) LDR (70)
HDR: 30–44 LDR: 48–66
HDR: 2.7 (0.3–5.6) LDR: 3.7 (0.3–23)
5-yr: 93%
[73]
Guinot et al. (2013)
Lip
75 (36–96)
SCC (102)
HDR
45/9
3.8 (0.2–11.9)
10-yr: 95%
[74]
Rio et al. (2013)
Lip
69 (24–94)
SCC (89)
LDR
50–62 Fraction NS
3 (0.8–10.6)
5-yr: 95%
[75]
Gauden et al. (2013)
Face, H/N, Trunk, Ext.
76 (46–98)
BCC (121) SCC (115)
HDR
36/12
5.5 (2–10)
98%
[52]
Bhatnagar 2013
Face, H/N, Trunk, Ext.
73 (49–97)
BCC(91) SCC(70) BSC(1) Other (9)
HDR EBT
40/8
0.8 (0.1–2.3)
100%
[59]
Arterbery et al. (2013)
Hand
62
SCC (1)
HDR EBT
40/8
1
1-yr: 100%
[76]
Tormo et al. (2014)
Hand
78 (43–97)
BCC (32)
HDR
42/6–7
3.9 (2.6–5)
4-yr: 98%
[53]
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.
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Radiotherapy treatment for nonmelanoma skin cancer
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4 months, there were no recurrences, no severe toxicities and the cosmesis were rated as ‘good’ to ‘excellent’ for 100% of the patients. The series was subsequently updated to include 171 lesions treated on 122 patients with the same dose and fractionation scheme [59]. The mean follow-up was 10 months for all patients with no recurrences. At least 1-year follow-up was available for 46 lesions in 42 patients. The most common late effects included Grade 1 hypopigmentation (11%) and rash dermatitis (7%). Cosmesis remained ‘excellent’ to ‘good’ in all of these lesions [59]. Toxicity of RT
RT side effects are generally divided into acute effects (those that occur during and up to 3 months after completion of therapy) and late effects (those occur >3 months from the end of treatment). Because radiation is a local therapy, the toxicity related to RT is highly dependent upon the part of the body that is irradiated. The most common acute reactions during a course of RT for NMSC include skin irritation (including moist desquamation) and fatigue [15]. These side effects occur nearly universally, regardless of which RT modality is used. However, the late toxicity of RT would be expected to vary based on the RT modality given the wide range in dose distributions between external beam radiotherapy and brachytherapy techniques. Cosmesis is also an important outcome to measure, and the cosmetic result is often related to the degree of late tissue fibrosis, as well as pigmentation changes and telangiectasias on the skin. A commonly used criterion for scoring cosmesis is based on Lovett scoring [33]. TABLE 3 summarizes toxicity results using external beam radiation techniques. In one of the largest series of external beam RT for NMSC of the face and H/N, Petrovich et al. reported low rates of late toxicity: 2% rate of mandibular necrosis (for cancers of the lip); no cases of skin or cartilage necrosis among 646 patients treated with lesions on the eyelids, nose and external ear; excellent functional/cosmetic results (though absolute rates not provided) for patients with smaller lesions and those treated with
Radiotherapy treatment for nonmelanoma skin cancer Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
Expert Rev. Anticancer Ther. Early online, 1–12 (2015)
Yi Rong*1,2, Li Zuo3, Lu Shang4 and Jose G Bazan*1 1 Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA 2 Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Davis, CA 95817, USA 3 Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, College of Medicine, Ohio State University, Columbus, OH 43210, USA 4 Guangxi Institute of Research and Design, Guangxi, China *Authors for correspondence: Tel.: +1 916 734 8170 Fax: +1 916 734 3239 [email protected] [email protected]
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Non-melanoma skin cancer is the most common malignancy in the USA, with an estimated 3.5 million cases per year. Treatment options include surgical excision, radiation therapy (RT), photodynamic therapy and topical agents. Although surgical excision remains the mainstay of therapy, RT offers an effective alternative. RT can be used as an adjunct to surgery in highrisk situations, or in cases where surgical excision would lead to impaired cosmesis and/or functional outcomes. Radiation treatment modalities for non-melanoma skin cancers are diverse. Studies in the literature have examined the clinical effects of a wide variety of modalities, areas of the body and dosages. The most common modalities include superficial or orthovoltage RT, electron beam therapy and high dose-rate brachytherapy. This article aims to review the diverse radiotherapy treatment modalities for non-melanoma skin cancers, focusing on tumor control and toxicity. KEYWORDS: brachytherapy . cosmesis and toxicity . nonmelanoma skin cancer . orthovoltage radiotherapy . superficial radiotherapy
Skin cancer is the most common type of cancer in the United States. The incidence of skin cancer is estimated to be higher than all other types combined, including breast, prostate, lung and colon cancers. Although melanoma represents less than 5% of total skin cancer cases, it is the leading cause of skin cancer death [1]. The most prevalent forms of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), both of which are highly curable. Because these cancers develop from epidermal cell types other than the melanocyte, they are referred to as nonmelanoma skin cancers (NMSCs). The total number of NMSCs in the US population is estimated at 3.5 million in 2006 [2]. A recent geographical review of worldwide incidence of NMSCs revealed the locations of high incidence rates and highlighted the fact that NMSCs are an increasing problem for health care globally [3]. Prior reviews have focused on the clinical aspects of NMSCs, including tumor characteristics, risk factors, diagnosis, assessments and various treatment options [4,5]. Treatment options for skin cancers include surgical excision [6–9], Mohs micrographic surgery [8–14], radiation therapy (RT) [9,15,16], photodynamic therapy [17–21], topical medications [9,22,23], and systemic medical therapy [9]. Surgical excision and Mohs surgery are 10.1586/14737140.2015.1042865
effective and considered the standard of care for most primary NMSCs [4]. These surgical options provide cure rates >95% for primary and recurrent BCCs and SCCs [13]. However, RT is indicated when surgery is not an option due to cosmetic or functional reasons, or as an adjuvant therapy in high-risk SCCs and BCCs. RT offers unique advantages in challenging locations for surgery, such as in the head and neck (H/N) region, especially when there is a need for good cosmetic outcome. RT is also favored for treatment of elderly patients (>60 years old), given concerns about potential long-term sequelae [4]. Established guidelines have been provided for the evaluation and management of BCCs and SCCs with RT [4,15,16], including dose regimen and followup schedules. However, there is a lack of a comprehensive review with a focus on evaluating various radiotherapy modalities. Traditional RT treatment modalities include superficial x-rays, orthovoltage x-rays, electrons and Co60 photons. In more recent years, the emerging new technologies for NMSC treatment include high dose rate (HDR) brachytherapy using isotopes or miniature x-ray sources. The present review article aims to include various radiotherapy modalities for treating nonmelanoma skin cancers, with comparing their associated tumor control and treatment toxicities. An extensive
2015 Informa UK Ltd
ISSN 1473-7140
1
Review
Rong, Zuo, Shang & Bazan
literature search was conducted on the PubMed/Medline database available in English, with no specific publication time restrictions. The search keywords included ‘nonmelanoma skin cancer’, ‘BCC’, ‘SCC’, ‘superficial radiotherapy’, ‘orthovoltage radiotherapy’, ‘electron beam’, ‘HDR’, ‘brachytherapy’, ‘electronic brachytherapy’, etc.
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Superficial & orthovoltage RT
Traditional techniques of treating skin cancer using radiation include superficial and orthovoltage x-ray therapies. A 1974 survey among dermatologists found that RT was used in 55.5% of dermatology clinics in USA and Canada. However, the arrival of Mohs surgery offered dermatologists high cure rates with reduced side effects [24]. In a later survey conducted in 1986, superficial radiation could only be found in 12% of dermatology training clinics [25]. Nevertheless, kilovoltage x-ray therapy can be expected to become even more important in the next few decades, due to the aging population. Surgery is often not an option for the rapidly increasing elderly population with skin cancer, as complications with surgery are much more likely. Accordingly, superficial and orthovoltage x-ray therapies are well-tolerated, simple and low-cost substitutes. Due to the shallow effective depth, early superficial x-ray therapy used multiple beams from various angles on deep tumors. This technique reduced high surface doses, while also increasing tumor doses [26]. With the advent of other treatment options, both superficial x-rays and orthovoltage x-rays are not indicated for deep tumors but are still commonly used for superficial tumors in all areas of the body. In superficial x-ray therapy, the photon energy ranges from 50 to 150 kVp, with an equivalent half-value layer of 1.0–8.0 mm Al. Typical treatment diameters range from 1.0 to 5.0 cm, at a source-surface distance of 15–20 cm. Due to the limited penetration capability of these low-energy photons, this modality is commonly used for tumors at very shallow depth, that is, 5 mm. There are several commercially available systems for this type of treatment, including SRT-100 (Sensus Healthcare, Boca Raton, FL), Xstrahl 100 and 150 (Xstrahl Medical Solutions, Suwanee, GA). Orthovoltage therapy covers an x-ray energy range of 150– 300 kV, with an equivalent half-value layer of 1–4 mm Cu. Treatment diameters range from 4 to 20 cm at a source-surface distance of 50 cm. Due to its ability to travel further than superficial x-ray therapy (2 cm in general), orthovoltage RT is sometimes called ‘deep’ therapy. The commercially available orthovoltage x-ray systems include Xstrahl 200 & 300 (Xstrahl Medical Solutions, Suwanee, GA) and Gulmay Orthovoltage Unit (Gulmay Medical Limited, Chertsey, Surrey, UK). Superficial and orthovoltage x-ray RT treatment techniques are effective for BCC and SCC in terms of tumor local control and cosmetic outcomes [27–38]. A large-scale clinical study by Petrovich et al. reported treatment outcomes from 896 patients (467 BCCs, 362 SCCs and mixed), mostly treated with superficial and orthovoltage x-rays [34]. The dose regimen in the early years of this series ranged from 30 Gy in three fractions to doi: 10.1586/14737140.2015.1042865
48 Gy in 12 fractions, which was adjusted to a uniform dose prescription of 51 Gy in 17 fractions for small lesions and 60 Gy or more (2–2.5 Gy per fraction) for larger lesions in the following 10 years. The overall local control was 97% at 5 years and 96% at 10 years, with excellent cosmetic outcomes [34]. Lovett et al. retrospectively analyzed a total of 339 NMSC lesions (242 BCCs, 92 SCCs and five variants of SCCs) treated with various modalities and reported an overall tumor control rate of 86% in all lesions (91% for BCCs and 75% for SCCs) [32]. The total dose ranged from 40 Gy to 60 Gy for both BCCs and SCCs. It was also noted that the tumor control rate was dependent on the tumor type, tumor size and treatment modality [32]. Specifically, superficial x-ray technique achieved a local tumor control of 93–100%, depending on the tumor size. This was superior to both electron beam and Cobalt 60 therapy. In addition, tumor control rate varies with tumor sizes and different dose fraction sizes. For BCCs 1 cm or less, all dose fraction sizes (4 Gy) provided >95% tumor control; for BCCs 1.1–5 cm, 3–6 Gy dose fraction size was recommended for a 100% local control; data for lesions >5 cm was not conclusive. Similar results were seen in SCCs, except that the cutoff dose fraction size was 5 Gy instead of 6 Gy for tumor size 1.1–5 cm [32]. TABLE 1 summarizes the key series of external beam radiotherapy for the treatment of NMSC. Electron beam radiotherapy
The ability to deliver a uniform radiation dose to a few centimeter depth of human tissue with a steep dose fall beyond the therapy range makes the electron beam suitable for superficial cancer treatments [39], including skin cancer in the H/N region [40]. The energies used for electron beam radiotherapy (EBRT) vary from 4 to 20 MeV, resulting in an effective treatment depth of 2–6 cm. Also, a common technique is to use 1 cm bolus and 6 MeV beam to treat 1 cm deep lesions. Electron beams are available on most commercial linear accelerators. Reported clinical outcomes with EBRT have been controversial. Despite the inferior local control rate associated with EBRT on multivariate analysis reported by Lovett et al. [32], several other series reported favorable outcomes with local control rate comparable with superficial x-ray treatments, ranging from 81 to 95% [29,40–43]. Furthermore, these studies reported good cosmetic outcomes in contrast to those reported by Lovett et al. [32]. Griep et al. showed no significant difference in tumor local control comparing superficial x-rays (97%) and electrons (94.5%) after a 2-year follow-up, with overall cosmetic results in favor of EBRT [29]. The dose regimen was 6–10 fractions of 6–10 Gy for superficial x-rays and 17–18 fractions of 3 Gy four times per week for electron beam. The fraction size was adjusted to 2 Gy for a total of 50–60 Gy dose when treating larger volumes. Silva et al. [35] reported 2- and 5-year local control rates of 87% and 79%, respectively, in a population of 334 pinna lesions (201 BCCs, 122 SCCs and 11 basosquamous carcinoma) treated with orthovoltage x-ray (83%) and EBRT (12%), with excellent to good cosmetic outcome. The most common dose prescriptions were 35 Gy/5 Expert Rev. Anticancer Ther.
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Pinna
Face, H/N
Scalp, Face, H/N, Trunk, Ext.
Scalp, Face, H/N, Trunk, Ext.
Face, H/N, Trunk, Ext
Lip
Pinna
Scalp, Face, H/N, Trunk, Ext.
Nose
Hunter et al. (1982)
Petrovich et al. (1987)
Griep et al. (1995)
Lovett et al. 1990
Zablow et al. (1992)
de Visscher et al. (1996)
Silva et al. (2000)
Locke et al. (2001)
Tsao et al. (2002)
74.5 (42–93)
BCC: 73 (11–100) SCC: 72 (32–97)
74 (41–104)
68 (41–92)
SCC (94)
BCC(389) SCC(142)
BCC (201) SCC (122) BSC (11)
SCC (108): (T189, T2 17, T3 2)
BCC (94), SCC (19), Other (2)
BCC (242), SCC (92), Other (5)
70–80 (30–90)
70.4 (32–97)
BCC (295), SCC (94)
BCC (467) SCC (362) BSC (67)
BCC (17), SCC (26)
Lesion type
71.5
60 (21–94)
BCC: 62 (45–88); SCC: 67 (53–89)
Mean age (yr)
SupX: 97% EB: 94.5%
2
Min 2-death
SupX: 6–10/6–10; Electron: 51–54/ 17–18; or 50–60 @ 2–3 Gy per fraction 40–60/10–30
2-yr, 5-yr: 93%,83% (BCC); 82%,79% (SCC) BCC (92%) SCC (80%)
2-yr: 90% 5-yr: 85%
3.3 (0.1–13.4) 5.8 (2–24)
2.9 (0.2–10.4)
35/5 42.5–45/10 50–65/20–30 40–60/10–30
OrthoX (278), EB (39) Other (17)
OrthoX. (76) EB (13) Other (5)
32.5–35/5 42.5–45/10 20/1 50/15–20
T1: 99% T2: 77%
6.4 (1.7–12) OrthoX: 48–51/12– 17 EB: 55/22 LDR: 60/NS
OrthoX. (62) EB (6–8 MeV) (33) Other (13)
SupX. (317) EB (100) Combo (108) MV Photon (6)
Primary: 88%; Primary +LN: 86%; NED: 93%
Min:2; Mean: 3.9
BCC: 50–52/10–13; SCC: 60/15
Electron, 6 MeV
SupX (187) EB (57) MV Photon (15) Combo (80)
BCC: 91% SCC: 75%
BCC: 99% (5-yr), 98% (10-yr), SCC: 94% (5-yr), 88% (10-yr) BSC: 95% (5-yr), 96% (10-yr)
NS
30/3 48/12 51/17 60/24–30
SupX EB Cu HVL Co-60
SupX (99), EB (290)
83.3%
Local-Control
>2
Mean Follow-Up (yr)
45–50/8, 52.5–55/15
Prescription: dose (Gy)/ fractionation
Electron, 10 MeV
Modality
[38]
[31]
[35]
[37]
[40]
[32]
[29]
[34]
[42]
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 in paper; OrthoX: Orthovoltage x-ray; RT: Radiation therapy; SCC: Squamous cell carcinoma; SupX: Superficial x-ray.
Site
Study (year)
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.
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Radiotherapy treatment for nonmelanoma skin cancer
Review
doi: 10.1586/14737140.2015.1042865
doi: 10.1586/14737140.2015.1042865
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.
[66]
IMRT (60%) EB (62.5%) 3D conformal (33.3%) 1 (0.5–4) H/N, Ext. Matthiesen et al. 2011
63 (48–90)
BCC (10) SCC (11)
IMRT (10) EB (8) 3D conformal RT (3)
BCC: 56.25–76.5/ 25–36 SCC: 55.8–79.8/ 25–35
[44]
3-yr BCC: 97–98% SCC: 94–97% 3.6 (0.1–7.3) EB Face, H/N, Trunk, Ext. van Hezewijk et al. (2010)
BCC:74.8 (38.4– 95.5); SCC: 78.3 (41.2–96.7)
BCC (332) SCC (102)
54/18 or 44/10
[36]
0.3 (0.1–2.3) OrthoX (13) EB (14) MeV Photons (4) H/N, Thigh, Hand, Sternum Barnes et al. (2010)
91 (80–101)
SCC (26) BCC (5)
24/3
78.3% (overall response)
[65]
100% 1.3 59.4–74.25/33 IMRT EB SCC (1) BCC (2) Face Matthiesen et al. (2010)
88
[33]
100% 3.1 (1–6.4) 54–60/15 Low E photon (101) MV photon (3) BCC (104) Head Olschewski et al. (2006)
77 (47–98)
[27]
2.4 45–105/9–21 Pinna Caccialanza et al. (2005)
75.2 (48–96)
BCC (99) SCC (16)
Contact x-ray Soft x-ray Half-deep x-ray
5-yr: 78%
4-yr: 86% (BCC) 58% (SCC) 3.5 (0.1–8.1) 35/5, 40–45/10 50/15–20, 60/25, 60–70/30–35 H/N, Trunk, Ext. Kwan et al. (2004)
78 (31–103)
BCC (61) SCC (121)
OrthoX. EB MV Photons Combo
Local-Control Mean Follow-Up (yr) Site
Mean age (yr)
Lesion type
Modality
Prescription: dose (Gy)/ fractionation
[30]
Rong, Zuo, Shang & Bazan
Study (year)
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 (cont.).
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Ref.
Review
fractions for small lesions (field size = 4.9 cm2), 42.5–45 Gy/10 fractions for median field size (10.5 cm2) and 50–65 Gy/20–30 fractions for large field size (81 cm2). The local control rates at 2 and 5 years were 93% and 83% for BCC, and 82% and 79% for SCC, respectively. Support for EBRT has increased as a result of recent publications citing encouraging clinical outcomes. Locke et al. [31] reported an overall tumor control rate of 89% for 531 NMSCs (389 BCCs and 142 SCCs) in 468 patients with a median 5.8-year follow-up, treated with superficial x-rays (60%), EBRT (19%) or a combination of both (20%) [31]. The 5-year local control rates were 93% for primary lesions and 80% for recurrent lesions; 92% for BCCs and 80% for SCCs. Although the tumor local control was found inferior with EBRT (94% for superficial x-rays, 82% for electron beams and 82% for combination therapy), a multivariate analysis showed that local failure was related to daily fraction size, lesion diameter, pathologic type and insignificantly with treatment modality [31]. Tumor local control rates for different sizes of lesions treated with different dose fraction sizes were found to be similar to Lovett et al’s findings [32]. For the total dose (at 2.5 Gy per fraction, 4 days a week), Locke et al. recommended 40 Gy for 5 cm lesions. Kwan et al. analyzed a total of 182 patients with Expert Rev. Anticancer Ther.
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Radiotherapy treatment for nonmelanoma skin cancer
T2 and more advanced NMSCs (61 BCCs and 121 SCCs) reported 4-year locoregional control rates of 86% and 58% for BCCs and SCCs, respectively [30]. Similar to the of study Tsao et al., the most common dose fractionation included 35 Gy/5 fractions, 45 Gy/10 fractions, 50 Gy/15–20 fractions and 60 Gy/25 fractions. The reported inferior tumor control rates associated with EBRT may be attributed to patient selection bias or dosimetric coverage difficulties associated with electron beams. Careful margin consideration and improved dosimetric coverage may improve locoregional tumor control with EBRT. A more recent analysis involving 434 cases (332 BCCs and 102 SCCs), all treated with EBRT, reported 3-year local relapse-free rates of 97.6% for 54 Gy/18-fraction regimen and 96.9% for 44 Gy/10-fraction regimen [44]. When comparing treatment outcomes with superficial or orthovoltage x-rays versus electron or megavoltage photons, their differences in relative biological effectiveness (RBE) in severity of radiation damage need to be considered. Superfical or orthovoltage x-rays have been proven to have a higher relative biological effectiveness value compared with electron and megavoltage photons [45]. Silva et al. found no significant increase in local failure rate with EBRT on multivariate analysis using relative biological effectiveness-corrected biological equivalent dose with a multiplying factor of 0.85 [35]. HDR brachytherapy
During the past 25 years, new technologies have emerged for skin cancer treatment, including HDR brachytherapy using radioactive isotopes and electronic brachytherapy (EBT) using miniature x-ray photon sources. The use of radioactive sources in brachytherapy treatment for skin cancer dated back to 1899, but gradually declined due to the popular use of x-ray therapy in the 1940s. Brachytherapy regained its popularity back in the 1960s with the development of remote afterloading systems, which significantly reduced the exposure to operators from the manual isotope application [46]. Dose fractionation schemes for traditional RT technologies range from 35 to 65 Gy in 5– 30 fractions, depending on the treatment site and the tumor size. The use of brachytherapy isotopes such as iridium-192 (Ir-192) with skin surface applicators or surface molds can reduce treatment fractions to 6–8 for a total dose of 30– 40 Gy, delivered at a frequency of once or twice per week. Ir192 is a gamma ray emitter with a half-life of 73.8 days, creating gamma particles at a mean energy of 380 keV. Given this level of energy, Ir-192 is effective at treatment depths of 3– 5 mm, commonly applied through surface molds or surface applicators for HDR brachytherapy skin treatments. The commercially available surface applicators are Leipzig-style applicator cones provided by Nucletron (Elekta, Stockholm, Sweden) and Varian (Varian Medical Systems, Palo Alto, CA), or Valencia applicators provided by Nucletron. Long-term results of HDR brachytherapy using surface molds for NMSCs have been reported in various series. Guix et al. prospectively evaluated 136 patients with NMSC of the face treated with HDR brachytherapy to a total dose of informahealthcare.com
Review
60–65 Gy in 33 to 36 fractions (1.8 Gy per fraction) for lesions £4 cm and 75–80 Gy for lesions >4 cm (with a boost dose of 18 Gy in 10 fractions, after a 3-week rest period) [47]. Local control rates were excellent with only three recurrences noted, yielding a 5-year actuarial local control rate of 98% [47]. Similar results in terms of excellent local control and functional/cosmetic outcome have been reported at sites outside of the H/N region as well [48–50]. Other studies of HDR brachytherapy in the treatment of NMSCs have focused on hypofractionation (daily dose >2 Gy). In 1999, Kohler-Brock et al. reported 10-year results of using 5–10 Gy given twice per week to a total dose of 30– 40 Gy [51]. A total of 520 patients with NMSCs of the face, mouth, tongue, perianal region and the external genitalia were treated using this hypofractionation regimen. Response rates were 97% (91% complete remission and 6% partial remission) and only 8% of patients developed a local recurrence. No late toxicities were reported. More recently, Gauden et al. reviewed 236 patients who were treated with a total dose of 36 Gy given over 12 consecutive treatments (3 Gy/fraction) with a Leipzig applicator [52]. Over 80% of the lesions were located on H/N, with other sites including extremities and trunk. At a median follow-up of 5.5 years, the local control rate was 98% (232/ 236). Similarly, Tormo et al. reported a series of 32 NMSC patients treated with 42 Gy in 6–7 fractions using the Valencia applicator [53], with a 98% local control rate at around 4 years. The skin toxicity was all Grade 1, and resolved within 1–2 months. TABLE 2 summarizes the key series reporting the use of HDR brachytherapy for NMSC. The use of radioisotopes for HDR brachytherapy poses limitations for users. Therefore, only large radiation oncology centers have the capability to support a HDR program. EBT platforms have been developed to use miniature x-ray sources that are able to deliver HDR brachytherapy with low-energy photons. The main advantages of EBT include the elimination of radioactive isotopes and minimal shielding requirements, which makes it possible for small clinics to consider HDR treatment option for their patients. The commercially available EBT platforms include Axxent eBx (Xoft Inc., Sunnyvale, CA) [54], IntraBEAM (Carl Zeiss Meditec, Inc., Dublin, California) [55], and Esteya (Esteya EBS, Elekta AB-Nucletron, Stockholm, Sweden) [56]. Early results with this approach appeared promising. Bodner et al. first published a prospective Phase I trial in 2003 for treatment of superficial NMSCs, using the Photon Radiosurgery System (Photoelectron Corporation, Lexington, MA; an early developer for the miniature 50 kVp x-ray source, which was later combined with IntraBEAM and distributed by Carl Zeiss). With a dose of 30 Gy in 3 weekly fractions for BCCs and SCCs in 18 patients, the overall response rate was 100% for BCC and 83% for SCC at 12 months [57]. Later in 2010, Bhatnagar et al. reported the results of 37 patients with 44 NMSCs of the H/N (91%) and extremity (9%) [58]. Patients received 40 Gy in 8 fractions, twice weekly with at least 48 h between treatments. At a median follow-up of only doi: 10.1586/14737140.2015.1042865
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Rong, Zuo, Shang & Bazan
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Table 2. Summary of major series of non-melanoma skin cancer treatment using HDR or electronic brachytherapy. Study (year)
Site
Mean age (yr)
Lesion type
Modality
Prescription: dose (Gy)/ fractionation
Follow-Up (yr)
LocalControl
Ref.
Svoboda et al. (1995)
Face, H/N, Trunk, Ext.
72 (46–92)
BCC (76) SCC (11) Other (19)
HDR
12–50/1–15
0.8 (0.4–1.8)
1-yr: 100%
[67]
Farru´s et al. (1996)
Lip
67 (42–91)
SCC (72)
Interstitial LDR
62–67
2.3 (1.1–3.5)
85–98%
[68]
Avril et al. (1997)
Face Ear
66
BCC (173)
Interstitial LDR (95) SupX (57) OrthoX (21)
ILDR: 57–76 SupX: 34–40 OrthoX: 33–65
3.4
4-yr: ILDR: 91.2 SupX: 95.4% OrthoX: 95%
[69]
Guix et al. (2000)
Face
67 (23–91)
BCC (102) SCC (34)
HDR
60–80/33–46
Min 1
5-yr: 98%
[47]
Guinot et al. (2003)
Lip
73 (38–90)
BCC (1) SCC (38)
HDR
40.5–45/8–10
1.5 (0.1–3)
3-yr: 88%
[70]
Lebioda et al. (2005)
Lip
65 (43–83)
SCC (24)
Interstitial HDR
35/7
2.7
2-yr: 88%
[71]
Somanchi et al. (2008)
Hand
69 (50–87)
SCC (25)
HDR
40–45/8
5
100%
[50]
Bhatnagar et al. (2010)
Head Ext.
72.5 (49–89)
BCC (25) SCC (17) Other (2)
HDR
40/8
0.3 (0.1–0.8)
4-yr: 100%
[58]
Ayerra et al. (2010)
Lip
67
SCC (115) Other (6)
HDR (21) LDR (100)
HDR: 45–50 LDR: 60–70
2.7 (1.7–15.7)
15-yr: 90%
[72]
Maron˜as et al. (2011)
Face
78 (53–91)
Facial carcinoma (51)
HDR
48–57/12–19
3.75
5-yr: 89%
[60]
Ghadjar et al. (2012)
Lip
HDR: 73 (35–95) LDR: 71 (37–90)
SCC (103)
HDR (33) LDR (70)
HDR: 30–44 LDR: 48–66
HDR: 2.7 (0.3–5.6) LDR: 3.7 (0.3–23)
5-yr: 93%
[73]
Guinot et al. (2013)
Lip
75 (36–96)
SCC (102)
HDR
45/9
3.8 (0.2–11.9)
10-yr: 95%
[74]
Rio et al. (2013)
Lip
69 (24–94)
SCC (89)
LDR
50–62 Fraction NS
3 (0.8–10.6)
5-yr: 95%
[75]
Gauden et al. (2013)
Face, H/N, Trunk, Ext.
76 (46–98)
BCC (121) SCC (115)
HDR
36/12
5.5 (2–10)
98%
[52]
Bhatnagar 2013
Face, H/N, Trunk, Ext.
73 (49–97)
BCC(91) SCC(70) BSC(1) Other (9)
HDR EBT
40/8
0.8 (0.1–2.3)
100%
[59]
Arterbery et al. (2013)
Hand
62
SCC (1)
HDR EBT
40/8
1
1-yr: 100%
[76]
Tormo et al. (2014)
Hand
78 (43–97)
BCC (32)
HDR
42/6–7
3.9 (2.6–5)
4-yr: 98%
[53]
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.
doi: 10.1586/14737140.2015.1042865
Expert Rev. Anticancer Ther.
Radiotherapy treatment for nonmelanoma skin cancer
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/09/15 For personal use only.
4 months, there were no recurrences, no severe toxicities and the cosmesis were rated as ‘good’ to ‘excellent’ for 100% of the patients. The series was subsequently updated to include 171 lesions treated on 122 patients with the same dose and fractionation scheme [59]. The mean follow-up was 10 months for all patients with no recurrences. At least 1-year follow-up was available for 46 lesions in 42 patients. The most common late effects included Grade 1 hypopigmentation (11%) and rash dermatitis (7%). Cosmesis remained ‘excellent’ to ‘good’ in all of these lesions [59]. Toxicity of RT
RT side effects are generally divided into acute effects (those that occur during and up to 3 months after completion of therapy) and late effects (those occur >3 months from the end of treatment). Because radiation is a local therapy, the toxicity related to RT is highly dependent upon the part of the body that is irradiated. The most common acute reactions during a course of RT for NMSC include skin irritation (including moist desquamation) and fatigue [15]. These side effects occur nearly universally, regardless of which RT modality is used. However, the late toxicity of RT would be expected to vary based on the RT modality given the wide range in dose distributions between external beam radiotherapy and brachytherapy techniques. Cosmesis is also an important outcome to measure, and the cosmetic result is often related to the degree of late tissue fibrosis, as well as pigmentation changes and telangiectasias on the skin. A commonly used criterion for scoring cosmesis is based on Lovett scoring [33]. TABLE 3 summarizes toxicity results using external beam radiation techniques. In one of the largest series of external beam RT for NMSC of the face and H/N, Petrovich et al. reported low rates of late toxicity: 2% rate of mandibular necrosis (for cancers of the lip); no cases of skin or cartilage necrosis among 646 patients treated with lesions on the eyelids, nose and external ear; excellent functional/cosmetic results (though absolute rates not provided) for patients with smaller lesions and those treated with
