pISSN: 2093-940X, eISSN: 2233-4718
Journal of Rheumatic Diseases Vol. 24, No. 2, April, 2017
https://doi.org/10.4078/jrd.2017.24.2.74
Review Article
Radiotherapy, a New Treatment Option for Non-malignant
Disorders: Radiobiological Mechanisms, Clinical
Applications, and Radiation Risk
1
2
Shin-Hyung Park , Jeong Eun Lee
1
Department of Radiation Oncology, Kyungpook National University Medical Center, 2Department of Radiation Oncology, Kyungpook National
University School of Medicine, Daegu, Korea
Radiotherapy is used to treat not only malignant tumors but also benign inflammatory and hypertrophic diseases. Because of
concerns about the potential hazards of irradiation, physicians in many countries, especially in North America, ruled radiotherapy out of medical practice for non-malignant diseases. Low-dose radiotherapy modulates the inflammatory response, providing an anti-inflammatory effect. Many researchers have reported low-dose radiotherapy efficacious for degenerative and inflammatory diseases. There are broad potential clinical indications for radiotherapy of non-malignant diseases. The general indications for radiotherapy for non-malignant disorders are acute/chronic painful degenerative diseases, such as chronic or acute
painful osteoarthritic diseases of various joints; hypertrophic (hyperproliferative) disorders of soft tissues, such as early stages
of Morbus Dupuytren and Ledderhose, keloids and pterygium; functional diseases, such as dysthyroid ophthalmopathy and arteriovenous malformations; and others, such as prophylaxis of heterotopic ossification. Radiotherapy for non-malignant disorders may be safely and effectively used, especially in older patients who suffered from these disorders and those who are reluctant to use other treatment options. (J Rheum Dis 2017;24:74-84)
Key Words. Radiotherapy, Osteoarthritis, Tendinitis, Dupuytren contracture
INTRODUCTION
son, in many countries, especially in North America and
Korea, irradiation of non-malignant diseases gradually
became less acceptable as a good medical practice and
most indications disappeared. Nevertheless, Korean
National Health Insurance covers radiotherapy for most
non-malignant disorders.
Worldwide, acceptance of radiotherapy for non-malignant diseases varies widely depending on the geographic
region and type of non-malignant disease [1]. A few treatment indications are generally accepted, e.g., postoperative prophylaxis of keloids and heterotopic ossification and radiotherapy of dysthyroid ophthalmopathy and
desmoids; these indications have a positive approval of
over 50% worldwide. In contrast, other indications revealed a divergent acceptance in different regions, e.g., radiotherapy of painful osteoarthrosis (Eastern Europe,
Ionizing radiation, such as photons (X-rays and gamma
rays), electrons, and charged particles, is used to treat benign inflammatory and hypertrophic diseases, as well as
malignant tumors. For several decades, irradiation of
non-malignant disorders was a common practice. For example, in Leiden in the Netherlands in 1925, 37 patients
had radiotherapy for malignant tumors and 143 patients
had radiotherapy for non-malignant disorders. In the
Rotterdam Radiotherapeutic Institute (Daniel den Hoed
Clinic), 3,348 non-malignant disorders were irradiated in
1948 compared with 857 malignant tumors [1]. However,
many people and physician are concerned about the potential hazards of tumor or leukemia induction and somatic changes after radiation exposure [2-4]. For that reaReceived：March 24, 2017, Accepted：April 10, 2017
Corresponding to：Jeong Eun Lee, Department of Radiation Oncology, Kyungpook National University School of Medicine, 130 Dongduk-ro,
Jung-gu, Daegu 41944, Korea. E-mail：[email protected] Copyright ⓒ 2017 by The Korean College of Rheumatology. All rights reserved.
This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
74
Low-dose Radiotherapy for Non-malignant Disease
85% vs. Western Europe and North America, 23%). Some
diseases are accepted differently because of their different
incidence in the world, e.g., Morbus Dupuytren/Morbus
Ledderhose (60% in Central Europe vs. 5% in Asia and
Africa).
The efficacy of radiotherapy for non-malignant disorders, based on the anti-inflammatory properties of
low-dose ionizing radiation, has long been recognized.
Low-dose of radiation is known to modulate the inflammatory response, providing an anti-inflammatory effect, while high-dose radiotherapy induces the production of pro-inflammatory cytokines. Many researchers
have reported the efficacy of low-dose radiotherapy for
the treatment of degenerative and inflammatory diseases.
Radiation modulates the function of various inflammatory cells including endothelial cells, polymorphonuclear
leukocytes, and macrophages. Even though the current
understanding of this process is incomplete, some of
these mechanisms have been elucidated.
The objective of this review is to summarize currently
proven radiobiological mechanisms in the treatment of
non-malignant diseases and to provide information about
its clinical applications.
production of transforming growth factor β1 (TGF-β1)
and interleukin-6 (IL-6) was increased at 24 hours after
irradiation of murine endothelial cells. In their RNase-protection assays, adhesion of blood mononuclear cells to endothelial cells was at a minimum after exposure to 0.5 Gy
of radiation in the range of 0.3 Gy to 3 Gy. TGF-β1 is
known to be a key endogenous factor with a potent effect
of regulating inflammation. Addition of TGF-β1 to culture medium inhibits leukocyte adhesion in human endothelial cells [8]. In another study regarding the time
course, reduced leukocyte adhesiveness to human endothelial cells was observed as biphasic pattern at 4∼8
hours and 24∼30 hours after irradiation [9]. Another key
molecule involved in the anti-inflammatory process of irradiation is NF-κB. Prasad et al. [10] reported that NFκB showed peak activity at 8 hours and 36 hours following a 0.5 Gy exposure in 244B lymphoblastoid- and B16
melanoma cancer cells. In accordance with an experiment
by Prasad et al. [10], an increased NF-κB DNA-binding
activity was observed in stimulated human endothelial
cells with a maximum at 0.5 Gy. The NF-κB activity was
decreased after irradiation at 0.6∼0.8 Gy and subsequently increased again at doses of 1 and 3 Gy [11].
MAIN SUBJECTS
2) Radiation effects on leukocytes and macrophages
Neutrophils and their products (e.g., proteases and reactive oxygen species) have been reported to have a relationship with the tissue- and organ-damage associated
with inflammation and inflammatory diseases, including
rheumatoid arthritis and vasculitis [12,13]. C-C motif
chemokine ligand 20 (CCL20) is one of the chemotactic
cytokines that neutrophils can produce. After irradiation
of endothelial cells and neutrophils, CCL20 secretion is
induced by direct contact between neutrophil and endothelial cells. Irradiation with doses between 0.5 Gy and 1
Gy results in a significant reduction of CCL20 secretion.
The reduction in CCL20 secretion is correlated with neutrophil adhesion to the endothelial cells [14]. In an experiment by Kern et al. [15], apoptosis of human peripheral blood monocytes was increased dose-dependently. In
their experiment, 80% of donors and 47% of samples
showed a maximum of apoptosis peaking at a radiation
dose between 0.3 and 0.7 Gy. A similar observation was
reported by Gaipl et al. [16], in which apoptosis in polymorphonuclear cells was a maximum at 0.3 Gy and a minimum at 0.5 Gy. More recent data further indicate hampered nuclear translocation of the NF-κB/p65 transcription factor, lowered secretion of proinflammatory cy-
Radiobiological mechanisms
The interrelationship between ionizing radiation and
the immune system displays a dichotomous character
and depends highly on the radiation dose/quality and the
immune cell population investigated. In general, X-ray
treatments with single doses ≥2 Gy exert proinflammatory effects, while low-dose radiation therapy (single
doses＜1 Gy) has been shown to modulate a variety of inflammatory processes and clearly shows anti-inflammatory properties [5]. This implies the involvement of
complex mechanisms operating differentially at different
dose levels.
1) Radiation effects on endothelial cells
The development of an inflammatory response is finely
regulated by sequential leukocyte-endothelial cell interactions and by the action of inflammatory mediator and
adhesion molecules. The adhesion of blood leukocytes to
endothelial cells is an essential process during the development of the inflammation. After low-dose irradiation,
reduced adhesiveness of blood leukocytes to endothelial
cells was observed [6]. Roedel et al. [7] reported that the
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Shin-Hyung Park and Jeong Eun Lee
tokine IL-1, and increased expression of TGF-β1 by inflammation-stimulated macrophages, concomitant with
a significantly reduced migration capability [17]. In conclusion, low-dose X-ray irradiation, most pronounced at a
dose of 0.5 Gy, induces an anti- inflammatory cytokine
microenvironment for macrophages, which might be accompanied by a resolution of inflammation.
3) In vivo animal models
The efficiency of low-dose radiotherapy has also been
proven in several in vivo animal models of inducible
arthritis. Some researchers investigated the radiation effect on arthritis using rat models with a variety of arthritis-inducing methods. Hildebrandt et al. [18] induced arthritis in rats by intra-articular injection of inactivated
Mycobacterium tuberculosis. They compared an irradiation
dose of 1 Gy with 5 fractions and 0.5 Gy with 5 fractions.
Prevention of further joint swelling and a reduction in cartilage and bone destruction were observed, but no differences between dose fractionation schedules were found.
In another study by the same group, these anti-inflammatory effects seemed to be correlated with reduced inducible nitric oxide synthase (iNOS) activity and increased hemoxygenase 1 (HO-1) levels [19]. Schaue et al.
[20] demonstrated that the expression of iNOS was attenuated by radiation concomitant with an increase in the
levels of HO-1 and heat shock protein 70 by using a murine carrageenan air pouch model.
Arenas et al. [21] showed that radiation with doses of
0.1, 0.3, or 0.6 Gy reduced leukocyte adhesion to intestinal venules in mice, and that the maximum effect was
achieved at doses of 0.3 Gy. This study showed that
low-dose radiotherapy has significant anti-inflammatory
effects, inhibiting leukocyte recruitment and increasing
circulating levels of TGF-β1.
The optimal timing of radiotherapy during inflammatory processes was evaluated by the following two
studies, and both studies suggested that irradiation during the early inflammatory phase was more efficient. Frey
et al. [22] used a human tumor necrosis factor (TNF)–
transgenic mouse model that expressed the human cytokine TNF-α and that develop chronic polyarthritis at an
age of 4∼6 weeks. Symptoms of polyarthritis of mice
were significantly improved by irradiation with 2.5 Gy in
5 fractions during the beginning of the disease. In the
study by Liebmann et al. [23], 5 Gy in 5 fractions and 2.5
Gy in 5 fractions with various treatment schedules were
tested on inducible arthritis models in rats. The most pro76
nounced treatment effect was observed after two daily
fractionated series of 2.5 Gy in 5 fractions with an early
treatment onset and repetition interval.
Clinical application of low-dose radiotherapy
The potential clinical indications for radiotherapy of
non-malignant diseases are various, and an interdisciplinary agreement has not always been achieved. According
to the German Working Group on Radiotherapy of Benign
Diseases, the general indications for radiotherapy in
German-speaking countries and in central and Eastern
European region are as follows [24]:
1. Acute/chronic inflammatory disorders, e.g., axillary sweat
gland abscess, furuncula, carbuncula, panaritium, and
other infections not responding to antibiotics
2. Acute/chronic painful degenerative diseases, e.g., insertion
tendinitis and chronic or acute painful osteoarthritic diseases of various joints (e.g., hip and knee)
3. Hypertrophic (hyperproliferative) disorders of soft tissues,
e.g., prophylactic radiotherapy in early stages of Morbus
Dupuytren and Ledderhose, and Morbus Peyronie (induratio
penis plastica), and postoperative prophylaxis of recurrence for keloids and pterygium
4. Functional diseases, such as dysthyroid ophthalmopathy, arteriovenous malformations, age-related macular
degeneration, persisting lymphatic fistula
5. Other indications, such as prophylaxis of heterotopic
ossification at various joints, prophylaxis of neointimal
hyperplasia, e.g., after arterial dilatation or stent implantation, obstruction of hemangiomas and other vascular disorders of various organs
6. Dermatologic diseases, e.g., pruritus due to itching dermatoses and eczemas, inaccessible psoriatic focuses (e.g.,
subungual focuses), basalioma
After a patient and his/her physician decide to receive
radiotherapy, these steps are generally followed (Figure
1A): At first, a consultation with a radiation oncologist
will be conducted to discuss the role and possible side effects of radiotherapy and to determine the type and dose
of radiotherapy to be used. During the simulation process, the patient’s computed tomography (CT) images are
obtained. Sometimes, specific areas of the body need to
be immobilized by a thermoplastic mask and/or an evacuated cushion (Figure 1B) to prevent movement during
radiotherapy. Once the simulation process is completed,
the scanned images are sent to the treatment planning
system. The radiation oncologist contours the target volume and normal organs at risk. A medical physicist genJ Rheum Dis Vol. 24, No. 2, April, 2017
Low-dose Radiotherapy for Non-malignant Disease
Figure 1. (A) The process of radiotherapy planning and delivery. (B, C) Patients undergoing
radiotherapy with an immobilization device in order to reduce
the positioning errors and to
prevent movement during radiation beam delivery. CT: computed tomography, RT: radiotherapy.
erates treatment planning using sophisticated computer
software, a process that can take several days. After the
completion of the treatment planning process, the radiation oncologist then determines the total area that will be
irradiated, the total dose that will be delivered to the target volume, and the radiation dose that will be delivered
to the normal organs around the tumor. After the radiation oncologist approves the radiotherapy plan, the patient can start treatment.
On the first day of the treatment and usually at least
once per week, simple radiography or cone beam CT images are taken to check the accuracy of the patient setup
during radiotherapy. The patient meets with the radiation
oncologist at least once per week to discuss the treatment
progress and any radiation side effects.
1) Painful degenerative disorders including
osteoarthritis and tendinitis
Painful degenerative joint disorders are the most common indications for radiotherapy of non-malignant
diseases. In this category, painful osteoarthritis and tendinitis involving various joints have been successfully
treated with radiotherapy (Table 1). Osteoarthritis is a degenerative disorder of articular cartilage and tendinitis is
a soft tissue disorder involving the attachment site of a
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tendon or ligament to a bone. Although little is known
about the accurate biologic mechanism of the radiation
effect on osteoarthritis, clinical data suggest that low-dose
radiotherapy is effective for the treatment of painful osteoarthritis [25-28].
Trott and Kamprad [29] raised the possibility that the
synovial membrane may be the critical target of radiotherapy for osteoarthritis, on the basis of the results from
previous animal model experiments. They also hypothesized that the effect of radiation in relieving symptoms of
tendinitis may be related to decreased activity of iNOS
pathways and NO production.
Seegenschmiedt and Keilholz [30] reported the results
of 200 patients with epicondylopathia humeri (n=104)
and peritendiniti humeroscapularis (n=96) treated with
radiotherapy. Complete pain relief and partial pain relief
was achieved in 50% and 21% for elbow patients and 48%
and 26% for shoulder patients, respectively. Niewald et
al. [31] reported similar findings in 140 patients with
shoulder periarthritis in which pain relief and improvement of motility was 59% and 89%, respectively, at a median 4.5 months after radiotherapy. Both studies used a
low radiation dose of 6 Gy in 6 fractions, 6 Gy in 12 fractions, or 3 Gy in 6 fractions.
Plantar fasciitis, also known as painful heel spurs, has
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Shin-Hyung Park and Jeong Eun Lee
Table 1. Summary of the studies of radiotherapy for painful degenerative diseases
Study
Daily dose (Gy)
×fraction
Disease
Year
Patient, n
Response rate
Seegenschmiedt
et al. [30]
Epicondylopathia humeri
(EPH)/peritendinitis
humeroscapularis (PHS)
1998
200
Niewald
et al. [31]
Ott et al. [25]*
Periarthritis of the shoulder 2007
141
Painful elbow syndrome
2012
199
Plantar fasciitis
2013
250
Plantar fasciitis
Complete response: EPH 51%,
PHS 48%
Partial response: EPH 20%,
PHS 26%
Pain relief: 69%
Motility improvement: 89%
Early response: 80%
Delayed response: 91%
Complete response: 38%
Partial response: 32%
Pain relief rate: 61.4%
Hermann
et al. [34]
Badakhshi
et al. [33]
Ott et al. [26]*
2014
171
Painful shoulder syndrome 2014
312
Ott et al. [28]*
Achillodynia
2015
112
Micke et al. [27]
Calcaneodynia,
achillodynia, painful
gonarthrosis, painful
bursitis trochanterica
2016
166
Side effect
1.0×6
0.5×12
No side effects
No secondary
malignancy
1.0×6
(mostly)
0.5×6
1×6
0.5×6
1×6
0.5×6
No side effects
0.5×6
Early, delayed, and long-term
1×6
response: 83%, 85%, and
82%, respectively
Early, delayed, and long-term
0.5×6
response: 84%, 88%, and
1×6
95%, respectively
Good response: 37.3%
0.5∼1.0×1
1×6
0.5×12
NA
NA
NA
NA
NA
No side effects
NA: not available. *Prospective trial.
been widely treated with radiotherapy in Germany [32].
Badakhshi and Buadch [33] analyzed 171 patients older
than 65 years with painful plantar fasciitis who were
treated with radiotherapy (3 Gy in 6 fractions) in their
institution. They showed a pain relief rate of 67.3% and
61.4% at 3 months and 54 months after radiotherapy,
respectively. Hermann et al. [34] reported an interesting
result with regard to the factors associated with the response rate of radiation outcome in plantar fasciitis. In
their analysis of 250 patients (285 heels), an age older
than 53 years, length of heel spur ≤6.5 mm, and onset of
pain ＜12 months were associated with a positive radiotherapy response.
An analgesic effect of radiotherapy has been demonstrated in the treatment of painful knee osteoarthritis. In
a German pattern-of-care study performed by Mücke et al.
[35], median pain reduction for at least 3 months was reported in 60% of 5,069 evaluated cases. The median total
dose and daily dose were 6 Gy and 1 Gy, respectively.
Keller et al. [36] also demonstrated that 79.3% of the
1,037 patients experienced relief of their pain with
low-dose radiotherapy.
78
Overall, low-dose radiotherapy has been found to be an
effective treatment option for painful degenerative disorders, with a low toxicity rate. According to the German
Society of Radiation Therapy and Oncology (DEGRO)
guidelines, total doses of 3∼6 Gy with daily doses of 0.5∼
1 Gy in 2∼3 weekly fractions are recommended for painful degenerative disorders [37] (Table 2). Minten et al.
[38] reviewed the effectiveness and safety of low-dose radiotherapy in the treatment of osteoarthritis. They found
that in 25%∼90% and 29%∼71% of cases patients’ pain
and function improved, respectively. However, they concluded that there was still insufficient evidence for a positive effect of low-dose radiotherapy on pain and functioning in patients with osteoarthritis, due to the absence of
high-quality studies.
2) Hyperproliferative disorders
(1) Dupuytren’s contracture
Dupuytren’s contracture, also known as Morbus Dupuytren and Morbus Ledderhose, are hyperproliferative
disorders of the palmar fascia and plantar fascia,
respectively. In the early stages, they usually present with
J Rheum Dis Vol. 24, No. 2, April, 2017
Low-dose Radiotherapy for Non-malignant Disease
Table 2. Specific treatment recommendations regarding radiation doses and indications by the German Working Group on
Radiotherapy of Benign Diseases [24]
Disease
Indication
Single dose (Gy)
Degenerative disease
Insertion tendinitis
Painful periarthropathia humeroscapularis,
epicondylopathia humeri radialis or ulnaris,
calcaneodynia=plantar or dorsal calcaneal spur,
refractory to conventional and drug treatment
Painful osteoarthritis Acute exacerbated painful osteoarthrosis of the hip,
of the knee, the shoulder, the finger joints and of the
thumb joint as well as arthrosis of other joints,
refractory to conventional and drug treatment
Hyperproliferative disease
Morbus Dupuytren, In the early stage (with progressive node or
Morbus Ledderhose strand formation without extension deficit and
symptoms) for the prevention of surgery in more
advanced stages
Keloid
Postoperative prophylaxis of a recurrence
Functional diseases
Heterotopic
ossification
Dysthyroid
ophthalmopathy
Prophylaxis of heterotopic ossifications after trauma
or surgery of large joints (hip, knee, shoulder,
elbow, other joints), after severe polytrauma with
CNS involvement and for prophylaxis of recurrence
after surgical removal of scar bones (thoracic and
abdominal wall)
Progressive ocular symptoms with or without
autoimmune thyropathy or other thyroid disease
Fractionation
Total dose (Gy)
0.5∼1.0
2∼3 fx/wk
3∼12
0.5∼1.0
2∼3 fx/wk
3∼10
2.0∼4.0
2∼5 fx/wk
20∼40
2.0∼3.0
3∼5 fx/wk
12∼20
2.0∼4.0
3∼5 times
after surgery
8.0∼12.0
6.0∼8.0
1 fx before/
after surgery
6.0∼8.0
1.5∼2.0
4∼5 fx/wk
10∼20
fx: fraction. Data from the article of Micke et al. (Int J Radiat Oncol Biol Phys 2002;52:496-513) [24].
a painless single palmar or plantar nodule and may spread
to adjacent limbs. As it progresses further, cords develop
and become predominant. Finally, the cords reach the
periosteum of the bones and may result in palmar or plantar contraction in the advanced stages. Their pathogenesis may be divided into three stages: (1) the early
stage is characterized by an increase of fibroblasts and the
formation of nodules and cords; (2) during the involutional stage, differentiation into myofibroblasts occurs;
and (3) in the advanced stage, collagenous fibers are dominant histologically. Radiotherapy for Dupuytren’s contracture is most effective when patients are in the early
stages of disease, because the target cells of radiation are
proliferating fibroblasts and inflammatory cells (Figure 2).
Previous published studies showed the effectiveness of
radiotherapy for preventing progression and for relieving
symptoms in early-stage Dupuytren’s contracture (Table
3) [39-42]. In the study by Keilholz et al. [39], 96 patients
(142 hands) received two courses of 15 Gy in 5 fractions
(total dose 30 Gy) separated by 6 weeks. The authors reported excellent outcomes with 99% of cases remaining
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Figure 2. The conventional radiotherapy field design in a patient with Morbus Dupuytren.
stable or improved. The overall rate of symptom relief
was 87%. Similarly, Betz et al. [40] analyzed the results of
135 patients (208 hands) with Dupuytren’s contracture
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Shin-Hyung Park and Jeong Eun Lee
Table 3. Summary of the studies of radiotherapy for Dupuytren’s contracture
Study
Disease
Year
Keilholz et al. [39] Morbus Dupuytren 1996
Patient, n
Response rate
96
Stable: 92%
Improved: 7%
Progressed: 1%
Long-term symptom relief:
66%
Complete remission of
cords: 33%
Reduced number: 54%
Pain relief: 68.4%
Progression rate:
3 Gy×10, 19.5%,
3 Gy×7, 24%
No RT: 62%
Betz et al. [40]
Morbus Dupuytren 2010
135
Heyd et al. [41]
Morbus Ledderhose 2010
24
Seegenschmiedt
et al. [42]*
Morbus Dupuytren 2012
489
Daily dose
(Gy) ×fraction
Side effect
3×10
NA
3×10
Minor late skin toxicity: 32%
No secondary malignancy
No RTOG grade ＞2 toxicity
3×10
4×8
3×10
3×7
No RT
CTC grade 1: 26.5%
CTC grade 2: 2.5%
No secondary cancer
NA: not available, RTOG: Radiation Therapy Oncology Group, RT: radiotherapy, CTC: common toxicity criteria. *Randomized
controlled trial.
treated with radiotherapy. With the same dose used by
Keilholz et al.[39], 87% of the patients in the early stage
remained stable or regressed and 66% of all patients achieved long-term relief of symptoms.
A randomized clinical study to identify the optimal radiation dose in the treatment of Dupuytren’s contracture
was conducted by Seegenschmiedt et al. [42]. They compared the results of 489 patients (718 hands) treated with
two courses of 15 Gy in 5 fractions (total dose 30 Gy) separated by 12 weeks, one course of 21 Gy in 7 fractions
within 2 weeks, and no radiotherapy group. After a mean
follow-up of 8.5 years, the progression rates were 19.5%,
24%, and 62% in the 30 Gy group, 21 Gy group, and no radiotherapy group, respectively, and the radiotherapy
groups had a significantly lower progression rate.
Therefore, radiotherapy is effective and well tolerated in
the prevention of Dupuytren’s contracture when applied
in the early nodular stage. Two courses of 15 Gy in 5 fractions (total dose 30 Gy) separated by 6∼12 weeks and a
single course of 21 Gy in 7 fractions are both recommended [43] (Table 2).
(2) Keloids
Keloids are excessive mesenchymal tissue proliferation
in regions of skin injuries that occur as a result of an abnormal wound healing process. Unlike normal scars, they
do not regress spontaneously. Surgical excision alone of
keloids results in a high recurrence rate of 45%∼100%
[44]. Radiotherapy has been shown to be effective for reducing the recurrence rate to 10%∼20% after surgical ex-
80
cision [45,46]. The target cells of radiotherapy are keloid
fibroblasts. In vitro experiments demonstrated that radiation induced apoptosis of fibroblasts and could return tissue to a normal cell population equilibrium [47]. Of note,
radiotherapy is most effective during the early stage of keloids, in which proliferating fibroblasts are abundant
[48]. Generally, it is recommended that radiotherapy be
initiated within 24 hours after surgical excision. Total
doses of 16∼20 Gy with daily doses of 2∼5 Gy in 5 fractions per week are recommended.
3) Symptomatic functional disorders
(1) Heterotopic ossifications
Heterotopic ossifications are abnormal bone formations
in soft tissues. They occur frequently after musculoskeletal
trauma and surgical procedures. Although the etiology is
not completely known, the hypothesis is that an inflammatory stimulus by trauma leads to the release of
growth factors, causing a differentiation from pluripotent
mesenchymal stem cells to osteoblasts. Heterotopic ossifications are mostly asymptomatic. However, it is sometimes painful and may cause decreased range of motion at
the joint. For patients who have symptomatic heterotopic
ossifications, surgical excision may be performed. After
surgery, prophylactic treatment needs to be administered
if patients have a high risk of recurrence. Radiotherapy
and nonsteroidal anti-inflammatory drugs (NSAIDs) are
the two main prophylactic modalities. In a meta-analysis
of randomized trials, both treatments showed effective-
J Rheum Dis Vol. 24, No. 2, April, 2017
Low-dose Radiotherapy for Non-malignant Disease
Figure 3. The 3-dimensional conformal radiotherapy plan in a patient with dysthyroid ophthalmopathy.
ness, although radiotherapy tended to be more effective
than NSAIDs in preventing severe heterotopic ossifications [49]. The rationale for the use of radiotherapy in
heterotopic ossification prophylaxis is that the pluripotent mesenchymal stem cells can be arrested by irradiation before entering the differentiation phase. Thus, the
timing of radiotherapy is important and it is recommended that radiotherapy be delivered either at 4 hours
preoperatively or up to 72 hours postoperatively. A delivery of 7∼8 Gy single fractions has been reported to have
a good prophylaxis rate, both preoperatively and postoperatively [50].
(2) Dysthyroid ophthalmopathy
Dysthyroid ophthalmopathy is an autoimmune disorder
affecting the extraocular muscles and in many cases, it is
associated with hyperthyroidism. In mild cases, supportive managements such as lubricants and sunglasses are
sufficient while awaiting spontaneous recovery. In severe
cases, however, proptosis, periorbital edema, conjunctival
erythema, and visual impairment may occur. Therefore,
the quality of life of patients can decrease and active treatment is necessary.
The etiology of dysthyroid ophthalmopathy is that activated T-lymphocytes lead to inflammatory reactions and
consequent fibrosis. The rationale for the use of radiotherapy for dysthyroid ophthalmopathy is that radiation
could arrest the immune process and could induce a remission of the inflammatory and fibrotic changes. In multiple randomized prospective and retrospective trials, radiotherapy achieved relief of eye symptoms in 65% to
75% of cases [51-55]. According to the DERGO guideline, in the early inflammatory phase, total doses of 2.4∼
16 Gy in 8 fractions and in the advanced inflammatory
phase, total doses of 16∼20 Gy in 8∼10 fractions are recommended [50]. A representative of dose distributions is
shown in Figure 3.
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Radiation risk
Generally, for non-malignant diseases, radiotherapy is
considered when non-radiotherapeutic treatment options fail. The risks of radiation exposure always have to
be weighed against the therapeutic benefit. For patients
with non-malignant disorders who were treated with low
to intermediate radiation dose, most normal tissue side
effects have been reported as rare or minimal as shown in
Tables 1 and 3.
The major reason why clinicians hesitate to apply radiotherapy for their patients, despite its known efficacy, may
be concerns about the potential risk of secondary malignancy [2-4]. However, the evidence of cancer risk comes
from disparate sources and was extracted from data using
outdated radiotherapeutic techniques. The primary sources of data were from Hiroshima and Nagasaki, although
this radiation exposure was evenly distributed throughout the body. Therefore, some authors believe that cancer
risks estimated by the effective dose method may overestimate the true risks of low-dose radiotherapy of small
body parts [56].
In the last two decades, radiotherapy techniques have
substantially improved. The delivery of radiation while
minimizing the dose to the normal tissues is more feasible than before, using various techniques including
three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and charged particle therapy. Also,
there are many methods for radiation protection, including the following: selection of the smallest effective dose;
use of several portals or the smallest effective field size for
a given target volume; orientation of the radiation beam’s
direction of entry away from the body stem or radiosensitive organs (e.g., thyroid, gonads, eye lens); application of shielding (individualized and/or standardized lead
absorbers) in radiation portals; and use of a lead capsule
(for the male gonads), lead collar (in the neck area), or
lead apron (in the pelvic area).
81
Shin-Hyung Park and Jeong Eun Lee
Recently, McKeown et al. [57] reviewed the available
evidence that informs the risk following exposure to low
to intermediate dose radiotherapy. The authors demonstrated that the risk of secondary malignancy was very
small and reduces further with increasing age. In a prospective, randomized study for patients with painful heel
spur, good analgesic effects of radiotherapy was shown
without any acute side effects [58]. There were also concerns about the potential hazards of tumor and leukemia
induction and somatic changes after radiotherapy exposure for non-malignant disorders [3,4]. However,
Broerse et al. [59] found very little increase in the risk of
tumor induction calculated with mathematical models,
but the overall contribution to a patient’s general lifetime
risk remains unclear. They stated that after the fourth
decade of life, the attributable lifetime risk may be lower
than that for the general population. Irradiation of patients younger than 40 years old requires caution and the
balance of risk versus benefit needs to be considered.
There is another group of patients who may be at greater
risk of radiation toxicity. Patients with collagen vascular
diseases (CVD) have shown increased radiation toxicity
and many physicians believe that collagen vascular disease is a relative contraindication to radiotherapy. Some
researchers reported that severe late toxicity increased in
patients with CVD other than rheumatoid arthritis
[60,61]. Other researchers reported that patients with
scleroderma or systemic lupus erythematosus had more
severe radiation toxicity [62,63]. Therefore, a particular
attention is required when we irradiate patients with high
risk CVD (e.g., scleroderma, systemic lupus erythematosus).
CONCLUSION
This review summarizes the radiobiological mechanisms and clinical results from previously published
studies with respect to the use of radiotherapy for
non-malignant disorders. The anti-inflammatory effect of
low-dose radiotherapy has been shown in a variety of in
vitro and in vivo studies. Furthermore, a number of clinical trials have demonstrated the efficacy of radiotherapy
in patients with non-malignant disorders.
Radiotherapy for non-malignant disorders may be safely
and effectively used, especially in older patients who suffered from these disorders and those who are reluctant to
use other non-radiotherapeutic treatment options.
82
CONFLICT OF INTEREST
No potential conflicts of interest relevant to this article
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