Dosimetry perspectives in radiation synovectomy

Physica Medica 47 (2018) 64–72

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Original paper

Dosimetry perspectives in radiation synovectomy a,⁎

Iftikhar Ahmad , Hasan Nisar a b

T

b

Institute of Radiotherapy and Nuclear Medicine (IRNUM), Peshawar, Pakistan Pakistan Institute of Engineering and Applied Sciences (PIEAS), 45650 Islamabad, Pakistan

A R T I C L E I N F O

A B S T R A C T

Keywords: Radiation synovectomy Radionuclide Dosimetry Contamination

Rheumatoid arthritis (RA) is a chronic inflammatory disease that can potentially damage the synovial joints. One of the effective treatment modality for RA is radiation synovectomy (RSV) where properly selected radionuclide is injected into the joint space, enabling controlled destruction of diseased synovial membrane via radiation exposure. Radiation dosimetry in RSV appears challenging due to the heterogeneous nature of synovial membrane, nonuniform distribution and leakage of radionuclide from the synovial cavity. This article reviews the dosimetric perspective pertaining to RSV. Specifically, characteristics of radionuclide for RSV and radiation dose to target and non-target (i.e., articular cartilage, bone, bloodstream, gonads, etc.) tissues of patient have been discussed. The personal dose Hp(0.07) to the hands of medical staff (i.e., radiochemist, therapist physician, nurse) may be considerably high due to handling of high specific activities (∼500 MBq/ml for Y-90); such doses are typically measured using thermoluminescence dosimeters (TLD) ring dosimeters and ranges from 1 to 21.5, 0.1 to 40 and 0.1 to 5 µSv/MBq for the radiochemist, therapist physician and the nurse, respectively. Methods to minimize radiation doses to the patient, medical staff and public are elaborated. Contamination risks and precautionary measures are also reported.

1. Introduction Radiation synovectomy (RSV) refers to the radio-ablation of inflamed synovium by injecting a beta-emitting radionuclide inside the synovial joint cavity. The surface lining of synovium consists of phagocytes that are capable of absorbing the injected radionuclide, where radioactive decay of the radionuclide imparts radiation dose to the synovial tissue. The injected radionuclide is titrated in such a way as to deliver the required therapeutic radiation dose to the synovial tissue, creating a permanently destroyed synovium, enabling improved joint movement and reduced pain, swelling, and effusion. Afterwards, the regenerated tissue is supposed to be asymptomatic [1]. The effectiveness of RSV varies for the given radionuclides used, joint and diseases. However, on the average, RSV has been found effective in up to 80% of patients [2]. RSV was arguably first proposed by Fellinger and Schmid [3] and comprehensively described by Ansell et al. [4]. Specifically, an intraarticular injection of colloidal Au-198 (370 MBq) was used for treating rheumatoid arthritis (RA) of the knees. Although, the symptoms were relieved, the procedure also resulted in significant local and distant side effects, necessitating improved dosimetry techniques for delivering the desired radionuclide dose. However, when performed properly, RSV is safe with very low rate of complications and side effects. Most common

⁎

side effect of RSV is intensification of inflammatory symptoms (radiosynovitis). Leakage of the radionuclide outside the joint cavity is also assumed as a major side effect, which results in increased irradiation of the patient. Rare complications of RSV include temporarily greater pain, allergy, local infection, fever, malaise, ulceration with local skin radiation necrosis, increased oedema and joint effusion, septic arthritis and hemorrhage [2,5,6]. Initial dosimetry investigations were carried using Au-198, injected 24 h prior to the surgical synovectomy; the synovial membrane and fluid were analyzed for radioactivity after surgery. Measurements showed that synovium and fibrin clot were highly radioactive, as opposed to the synovial fluid. More specifically, Au-198 was present in the outer cells (thickness ∼1 mm) of synovium, indicating that Au-198 (mean range < 1 mm) would not deliver the desired/uniform dose to the full thickness of inflamed synovium (often ∼1 cm). Thereafter, Y-90 having a higher beta energy (mean range ∼4 mm) was suggested for RSV [7]. Moreover, the relatively small particle sizes of colloid Au-198 and high energy gamma emissions resulted in excessive loss of the radionuclide into the lymphatic system and doses to remote non-target tissues, respectively. The frequency of damaged circulating lymphocytes was 8.5%, compared with 0.48% for controls [8]. Compared to Au-198, no leakage of Y-90 to the knees, pelvis and abdomen, the groin lymph nodes or liver was observed with scintigraphy study [7,9];

Corresponding author. E-mail address: [email protected] (I. Ahmad).

https://doi.org/10.1016/j.ejmp.2018.02.015 Received 21 August 2017; Received in revised form 11 January 2018; Accepted 16 February 2018 1120-1797/ © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

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activity titration based on the depth and volume of the target tissue. To this end, selection of the radionuclide for RSV would be critical. Specifically, energy characteristics of the emitted beta (β) particle and its linear energy transfer would play a crucial role towards defining the radiation dose profile in the target tissue [33]. That said, a summary of the frequently used radionuclides in RSV procedures along with typically injected activities, particle size, joint of application and primary mode of production is depicted in Table 2. It is important to note that the more relevant clinical index for the selection of a radionuclide is the therapeutic range defined as the depth at which the absorbed dose is equal to 10% of the maximum dose deposited in the synovial surface [33]. In other words, therapeutic range is the distance from the source within which 90% of the energies are absorbed. For RSV purposes, the synovial joints are divided into three groups; small (e.g., fingers, toe), medium (e.g., wrist) and large (e.g., hip, knee) joints. For RSV of the small joints such as the metacarpophalangeal joints, Er-169 citrate colloid may be used with a maximum energy and maximum range in soft tissue of the β particles being 0.34 MeV and 1 mm, respectively, which closely correspond to the thickness of the inflamed synovium [34]. Holmium-166 (Ho-166) ferric hydroxide has also been used for RSV of metacarpophalangeal joints [28]. For bigger joints like the knee, Y-90 colloids are preferred as it offers greater softtissue penetration and a larger particle size resulting in less accumulation in regional lymph nodes [35,36].

however, very small amounts of activity were detected in the blood (< 0.2%), urine (< 0.4%) and faeces (< 0.13%) [4,7,10]. Moreover, the leakage was suspected to occur partially from the injecting needle track and was observed to decrease when it was flushed with normal saline after administration of the radionuclide (before withdrawing the needle from the joint) [11]. Later, absorbed dose profiles for six radionuclides (i.e., Au-198, Dy-165, P-32, Re-186, Y-90, and Ho-166) were analytically calculated. These profiles provided the dose imparted per unit activity of injected radionuclide (Gy/mCi) as a function of penetration distance (mm) and was aimed at estimating the necessary quantity of radionuclide (i.e., activity) and the extent and pattern of absorbed dose in the joint [12]. Moreover, handling of high quantities of unsealed activities are inevitable at each step of the RSV procedure, which pose risk of high local skin doses of beta radiations to the medical staff (i.e., radiochemist, physician, nurses) unless appropriate dosimetry measurements are adopted. Finally, radiation exposure and protective measures for dose reduction of the patient attendants, family members and public are also crucial [13–21]. In this review, we aim at the dosimetry perspective of RSV procedures. Specifically, we start with the properties of an ideal radionuclide for RSV procedures, frequently used radionuclides and their clinical selection for the treatment of small, medium and large joints. Afterwards, various dosimetry aspects of RSV procedures such as the radiation dose to the target (i.e., diseased synovial membrane) and nontarget (i.e., articular cartilage, articular bone, gonads, lymph nodes, whole body, etc.) organs of patient are discussed. Radiation doses to medical staff (i.e., the therapist physician, radiochemist, nursing staff, etc.), relatives of the patient and general public are also discussed. Finally, contamination risks and precautionary measures are highlighted.

3. Dosimetry perspectives in RSV procedures The recommended therapeutic dose to the target tissue for successful RSV depends on the multiple factors such as size, thickness and the type of the disease; thereby, it appears challenging to ascertain the precise absorbed dose in a given treatment [2,34,43,44]. In this context, initial attempts focused on absorbed dose calculations assumed that the synovial joint is a continuous and homogeneous medium of constant density. However, this over-simplified assumption may not be completely consistent with what is practical, as the thickness of inflamed synovium is typically non-uniform and heterogeneous. The backscattered radiation from articular cartilage and bone also confounds the situation [45]. In addition, the emission energy of β particles has been assumed monoenergetic, contrary to the more realistic spectrum of energies [35]. Finally, the distribution pattern of the radionuclide inside the joint, leakage from the joint, transport of energy by bremsstrahlung photons, etc. further inhibit our ability to calculate the absorbed dose in RSV procedures accurately [12]. To this end, adequate dosimetry, where the absorbed doses to the target and to non-target tissues are quantified, provides a valuable tool towards successful RSV procedures [35,46]. Previously, various methodologies to facilitate absorbed dose calculations have been proposed and implemented. For instance, absorbed dose profiles [12,23] and absorbed dose factors [33,34] for frequently used radionuclides (e.g., Y-90, Re-186, P-32, Ho-166, Au-198, Dy-165) in RSV procedures have been previously presented; these profiles/factors can be used to extrapolate the absorbed dose imparted to the synovial joint per unit activity of injected radionuclide as a function of penetration distance. Such factors also help to select the best suited radionuclide towards achieving the proper depth of penetration in target tissue. Importantly, these theoretical models are limited to monoenergetic β-emission; thereby caution may be exercised in extrapolating these algorithms for multiple β-energies or mixed β- and γemissions. In general, the administered activity and type of radionuclide varies from patient to patient and due to the complex geometry of the individual joint with an unknown surface of the inflamed synovial tissue to be treated, it is very difficult to determine the radiation dose to target and non-target tissues accurately. Nonetheless, there has been a growing interest (and requirement) to improve the dosimetric

2. Ideal radionuclide for RSV procedures The basic criteria for an ideal radionuclide for RSV applications, as defined in many studies [1,12,17,22,23], comprise of properties such as the radionuclide being a beta particle emitter with short physical halflife, little or no gamma-ray emission, high chemical purity, no toxicity, rapid and complete biodegradability and cost effectiveness. The most commonly used radionuclides in RSV clinics that qualifies the aforementioned criteria include Yttrium-90 (Y-90), Rhenium-188 (Re-188), Erbium-169 (Er-169), Phosphorous-32 (P-32), Lutetium-177 (Lu-177), Holmium-166 (Ho-166), Samarium-153 (Sm-153) and Dysprosium-165 (Dy-165). Table 1 summarizes the physical properties of these and other typically used radionuclides in RSV applications, respectively [24]. Complete tissue destruction of synovium within the extent of targeted boundaries of the diseased joint (and consequently, RSV success) is primarily determined by the ability to deliver a clinically relevant dose to the diseased synovium. Consequently, it is essential to plan Table 1 Summary of physical properties of typically used radionuclides in RSV applications. Therapeutic range is the distance from the source within which 90% of the energies are absorbed. Radionuclide

Max. Energy (MeV)

Half-life

Max. Range (mm)

Mean Range (mm)

Therapeutic Range (mm)

References

Y-90 Re-186 P-32 Dy-165 Au-198 Ho-166 Sm-153 Re-188 Er-169 Lu-177

2.25 1.07 1.71 1.28 0.962 1.85 0.263 2.12 0.34 0.5

2.7 days 3.7 days 14.4 days 2.3 h 2.7 days 1.13 days 1.93 days 17 h 9.4 days 6.73 days

11 3.6 7.9 5.6 3.9 8.7 3.1 10 1.0 2.0

3.6 1.2 2.6 1.4 0.8 2.2 0.7 3.1 0.3 0.67

2.8 1.0 2.2 1.3 0.9 2.1 0.7 2.1 0.24 0.6

[22] [24] [25] [26] [27] [28,29] [30] [31] [24] [2,32]

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Table 2 Summary for joint of application, injected activities, particle size and primary mood of production of typically used radionuclides in RSV procedures. Radionuclide

Joint of Application (Ref)

Injected Activity, MBq (Ref)

Particle Size, nm (Ref)

Primary mood of productiona

Y-90 (silicate/citrate) Re-186 (sulfide) P-32 (colloid)

Knee [37] Hip, Shoulder & Elbow, Wrist, Ankle [37] Knee, Elbows, Ankles

185 [37] 74–185 & 74 [37] 11–74 [25], 37 [37]

10–100 [37,38] 5–10 [37] 500–2000 [37]

89

Dy-165 (ferric hydroxide) Au-198

Knee, Hip & Ankle Knee

10000–11000 & 7400–9200 [37] 185 [11]

3000–8000 [37] 3000

Ho-166 Sm-153 Re-188 Er-169 (citrate) Lu-177

Knee Knee Knee Small joints of hand & feet [37] Elbow

1110 [39] 555 [40] 555–925 [40] 37 [37] 333 [32]

1200–12000 [39] 1600–2200 [41] 500–1000 [40] 10 [37] 1700 [42]

Y (n, γ) 90Y Re (n, γ) 186Re 31 P(n, γ) 32P 34 Sr (d, α) 32P 32 S (n, p) 32P 164 Dy (n, γ) 165Dy 197 Au (n, γ) 198Au 198 Pt (p, n) 198Au 165 Ho (n, γ) 166Ho 152 Sm (n, γ) 153Sm 188 W(β− decay) 188Re 168 Er (n, γ) 169Er 176 Lu (n, γ) 177Lu 185

a Symbols in parentheses indicate the incident and emergent particles in the given nuclear reaction. n = neutron; γ = gamma radiation; d = deuteron; α = alpha particle; p = proton [12].

β radiation emitted by the injected radionuclide. However, there are several possible manifestations of the biological damage caused by β radiation in RSV. For instance, the highly reactive free radicals produced by β radiation lead to necrosis of synovium that subsequently results in diminishing the synovial folds. Indeed, comparison of MRI scan of knee joints (13 patients) before and after RSV revealed average reduction in synovial thickness of 3.3 mm in one year [49]. As a side effect of RSV, radiation damage to superficial capillaries promotes occlusion (i.e., obstructions in vessels) thereby inducing fibrosis of the synovium and sub-synovial connective tissue of the joint capsule; this is typically followed by a marked decrease in secretory activity and bleeding [50]. The radiation may also cause damage to the articular cartilage and articulating bony surfaces; an unfavorable outcome associated with RSV. The dose to the bone-synovial interface for Y-90, P32, Au-198 and Re-186 have been reported as 25%, 15%, 5% and 4%, respectively [51,52]. It is therefore recommended that the benefit vs. risk of the RSV should be adequately assessed, particularly in younger patients (i.e., age less than 20 years).

procedures in RSV for both the target tissues and organs at risk. For instance, recent reports [47] discuss individualized dose (as opposed to the present fixed dose regimen) and fractional treatment concepts based on the synovial thickening or respective joint effusion. Further, the conventionally applied activities are typically derived from empirical approaches, which are primarily based on the simplified assumptions such as uniform distribution of the administered radionuclide and its complete phagocytosis by the synovial lining cells. Alternatively, a methodology to plan the individualized activity for a given patient, to further enhance the therapeutic index, may presumably prove beneficial. Indeed, such methodology has been recently reported [47]. The method is implemented in two phases. First, the radiological features of interest (i.e., joint effusion, surface area of the synovium, and synovial thickness) are extracted from the MR images of the given joint using semiautomatic software. Second, the radiological features are subsequently used in Monte Carlo simulation to calculate the therapeutic range ST90 and S-values (i.e., absorbed dose factor per unit cumulated activity in the synovium; Gy h-1MBq-1). Finally, the ST90 and S-values are used to select the best suited radionuclide and calculate the administered activity, respectively, which would deliver an absorbed dose of 100 Gy at a determined synovial thickness. Similar tools for accurate quantification of the absorbed dose using diagnostic imaging have been previously reported [1,23]. Such methodologies are capable of providing potential aid to RSV dosimetry in the present clinical practice by more properly delivering the required dose to the target tissue while sparing the organs at risk. It is noteworthy that RSV procedures can be simultaneously implemented in multiple joints, so that the wrist, interphalangeal and metacarpophalangeal joints of one hand can be treated simultaneously [6]. Moreover, the injected activity of the radionuclide depends on the treated joint, with the limit of maximum activity per treatment of 400 MBq for adults [37]; the corresponding activity for children should be smaller (i.e., age-adjusted). Moreover, the total annual activity limit of 750 MBq should also be respected [6]. In addition, the RSV procedure can be repeated many times with reduced activity of the given radionuclide [48]. For example, the recommended activity for initial RSV treatment with Y-90 in knee joint is 185 MBq [44]. However, if necessary, the treatment can be repeated with an activity of 111 MBq [22]. More importantly, an absorbed dose of approximately one Gy to the synovial tissue is recommended for optimal effect which would ultimately reduce the chance for repeating the procedure [40]. Specifically, failure to deliver the required dose to the target tissue may necessitate repeating the RSV treatment.

5. Radiation dose to target and non-target tissues in RSV patients Previously, the dosimetry measurements were based on various approaches such as whole-body scintigraphy [53], histological study of excised tissues [54], Monte Carlo simulation [1,55], MR imaging [56], biological dosimetry (i.e., scoring dicentrics in lymphocytes) [24], etc. A combination of these techniques where pre-treatment imaging of the patient could possibly guide for the activity calculation while subsequent Monte Carlo simulation could provide a map for the distribution of the administered activity and thereby a complete dosimetric analysis of the target and organs at risk. Indeed, studies focused on such combined dosimetric techniques have been recently reported [47]. For instance, MR imaging in tandem with Monte Carlo simulation has been recently used for RSV treatment planning and 3D dose calculation. Despite the use of ionizing radiation, the present practice of RSV is generally safe. The administered radiopharmaceutical directly irradiates the synovial fluid, synovium, articular cartilage and, to a lesser extent, the articulating bones. The short penetration range of emitted β radiations limits the exposure of organs outside synovial cavity. However, the lymphatic circulation may result in leakage of radionuclides to the loco-regional lymph nodes and, afterwards, to non-regional lymph nodes. Although less likely, the radionuclides may eventually enter into the bloodstream. In summary, the injected radionuclide is perhaps capable of exposing the synovium, articular cartilage, articular bone, bloodstream and gonads (particularly in RSV of hip and knee joints) of the patient. A simple schematic of the RSV related anatomy, procedure and mechanism are presented in Fig. 1. The radiation exposure of non-target tissues, particularly articular

4. Radiation induced biological damage in RSV procedures The ultimate goal of RSV is to destroy the inflamed synovium via the 66

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Fig. 1. Simple schematic of the RSV procedure and mechanism. (A) Normal synovial joint, (B) synovial inflammation where the radionuclide (light blue circles) is injected into the joint cavity; the proliferating synoviocytes (irregular round circles) can be differentiated from the normal cells (round circles) as shown in the inset, (C) the injected radionuclide has been phagocytized by the inflamed synovium, and (D) subsequent damage to the inflamed synoviocytes restores the normal synovial membrane. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

completely protected against β-radiation exposure by the articular cartilage. For extra-articular bones, the red marrow is primarily located in the specified marrow cavities of the flat bones of the skull cap, vertebral bodies, pelvic bones and sternum; all these cavities are beyond the penetration range of β-radiation during the RSV of peripheral joints [36]. Consequently, RSV procedure appears to pose minimal risk of bone marrow irradiation. To this end, several studies have quantified radiation doses to articular bones. For example, the dose at a depth of 1.5 mm of cartilage bone from 185 MBq injection of Y-90, determined on the basis of penetration distances of β radiation, was estimated as 1 Gy; the thickness of articular cartilage was considered as 2 mm in this study [58]. Furthermore, the dose to articular bone has been correlated to the energy (range) of emitted β radiation from the given radionuclide. Specifically, the dose to the articular bone surface from Y-90 has been reported to vary from 25% of the lining cells, down to 4% for Re- l86 and essentially 0% for Sm-153 [1]. Radiation doses to different organs of the patient receiving RSV treatment have been summarized in Table 3. The radionuclides used in RSV are typically injected in the form of colloidal, silicate, citrate, sulfide, etc. with optimized particle size. Specifically, the particle is small enough to promote phagocytosis but large enough to hinder leakage from the articular space. In this connection, with minimal leakage from the synovial cavity and short range in tissue, the radiation dose to gonads in RSV from β radiation is negligible [58]. The gamma radiation co-emitted in some radionuclides has the potential to expose more remote non-target tissues; in such cases, radiation dose to gonads is a major concern. Radiation dose to gonads, an exceedingly radiosensitive organ, is particularly important in RSV of large joints located near gonads such as the hip and knee joints; these joints are among the largest in the body and require higher amounts of activity for RSV. The highest radiation dose to gonads results from RSV of the hip joint, as higher amount of activity is injected at a shorter distance. For instance, maximum gamma radiation dose to gonads from 150 MBq of Lu-177 injected to the hip joint was estimated at 23.4 µSv MBq−1 [9,59]. Further, the dose received by ovary and testis in Y-90 based RSV treatment of the knee has been estimated at 1.05 and 1.1 µSv MBq−1, respectively [60]. Moreover, the dose to gonads from gamma rays as determined in phantom studies with 222 MBq of Y-90 injected in knee joint has been reported as 1.1 µGy/MBq, which corresponding to an accumulative dose of 0.244 mGy [22]. Another crucial

bone and cartilage, has been considered as one of the major concerns in the RSV practice. It is noteworthy, however, that radiation dose to these non-target tissues is generally not a limiting factor for the therapy, unless the activity of injected radionuclide is exceptionally large, e.g., 370 MBq (10 mCi) of Y-90; absorbed dose of approximately 2500 mGy to the synovium and articular cartilages has been reported for 10 mCi of Y-90 injected into rheumatoid knees. However, it has been demonstrated that only one-half of the aforementioned activity is sufficient for symptomatic relief [33,34,1]. Moreover, the energy and thereby therapeutic range of the given radionuclide are also crucial towards the exposure of non-target tissues. Nevertheless, radiation effects beyond the synovium are clinically tolerable [22]. The fundamental issue of calculating absorbed dose to articular cartilage in RSV has been also interrogated both in three-dimensional cell culture [57] and animal models [48]. Specifically, bovine articular cartilage was exposed to increasing amount of Y-90 (up to 3 MBq/ml medium). The results indicated a dose dependent suppression of type II collagen synthesis. It was suggested that the observed trend of collagen suppression might account for pre-arthritic breakdown of the structural integrity of articular cartilage. Furthermore, a near-total cell death after five weeks of radionuclide exposure was ascertained by means of light and transmission electron microscopy [57]. However, while translating this in vitro study to clinics, it is important to note that the contact time between the radionuclide and the articular cartilage surface is significantly shorter in the patient’s joint than in the above mentioned in vitro model, presumably due to the phagocytosis of the radionuclide by the synovial macrophages [7]. Furthermore, transient radiation effects have been observed only in young, growing cartilage of rabbit model [48]. Based on these studies, the potential radiation risks vs. benefits should be carefully assessed before treating young patients. The International Commission on Radiation Protection (ICRP) guidelines for medical procedures that involve bone irradiation recommend that the bone surface (10 µm) and the red bone marrow (i.e., blood forming content of bone) have to be considered as two principal radiosensitive targets that requires adequate protection. Consequently, the radiation exposure to articular bone in RSV has also been of significant interest, necessitating the need for a platform that allows accurate absorbed dose determination. Several studies have quantitatively addressed determination of radiation dose to articular bone, as discussed below. The red bone marrow, the radiosensitive part of the bones, is almost 67

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Table 3 Summary of radiation doses to different organs of the patient receiving RSV treatment. Radionuclide

Activity (MBq)

Joint

Procedure of dose finding

Spleen Dose (mGy/MBq)

Liver Dose (mGy/MBq)

Marrow Dose (mGy/MBq)

Dose to Regional lymph node (mGy/ MBq)

Whole body dose (µSv/ MBq)

Ref

Re-186

80 111 77 75 75 74 185 37 40

Elbow Shoulder Ankle Elbow, wrist, hip and ankle Radio-carpal Ankle, Elbow, Wrist Knee Phalangeal Metacarpophalangeal

Scintigraphy

0.33 15.7 32.04 0.93 0.16 2.74 119

0.22 10.65 21.74 1.37

0.04 1.85 3.76

188.3 122.5 –

29 16 32.3 0.102

[61]

37

Knee

Analytic

Y-90 Er-169 Dy-165 Ho-166 Er-169 Re-186 Au-198

1147 1.35 265 2300 75

0

0.72 155 4

[62] [63] [64]

[63] 0.38 4.81 0.03 145 157

[65]

window [1]; radionuclides with particle size below 300 nm exhibit spontaneous leakage while particle size above 10 µm cannot be effectively phagocytosed [22]. Although the actual size of the frequently used radionuclides is much smaller, these are typically attached to larger molecules, the product is usually termed as radiopharmaceutical. For example, the reported average particle size of Y-90 citrate colloid is about 2 µm, with a range of 1–3 µm [22]. It is also desired that the radiopharmaceutical should be biodegradable and easily removed from the joint after radioactive decay [1]. Post-treatment immobilization of the joint for 48 h using appropriate methods such as splint has been found beneficial towards leakage reduction. Specifically, the difference in radionuclide leakage between out-patient and in-patient was not statistically significant (p > 0.05) as long as the joint immobilization was adequate (splint) [68]. In addition, small leakage was observed in RSV treated out-patient (n = 142) with immobilization of the knee for 3 days [22]. Collectively, these studies suggest that immobilization of the treated joint for, at least, 48 h can effectively reduce the leakage of injected radionuclide [59]. Finally, rigorous hygiene such as twice flushing of the toilet is recommended for the RSV treated patients due to higher radioactive urinary excretion, particularly during the first two days following therapy [69]. Bladder catheterization has been suggested in incontinent patients prior to the RSV treatment. Moreover, it is recommended that pregnancy should be avoided for at least for 4 months [44].

mechanism of gonadal exposure is the accumulation of activity in the regional inguinal nodes from the lymphatics draining the hip and knee joints. It may be noted that gonadal doses previously quoted ignore this secondary source of radiation exposure. However, it was calculated that the dose to gonads increases to 0.6 mGy if all the injected activity (i.e., 222 MBq) was taken up by the inguinal lymph nodes [22]. In addition, radiation exposure to gonads from the RSV of knee joints was negligible in the absence of extra-articular or inguinal lymph nodes [59]. In summary, it appears that the radiation dose of gonads in RSV is well tolerated and imposes no serious risk [9]. Specifically, the abovementioned reported doses are substantially less than the dose limit of gonads. For instance, the German radiation protection ordinance defines the dose limit of gonads at the level of 50 mSv per year for radiation workers and 5 mSv per year for public. To minimize extra-articular leakage and enhance the therapeutic effect, it is important for the patient undergoing RSV to ensure that the treated joint remains immobilized for a minimum of 48 h. Avoiding severe exercise and weight bearing is typically instructed. Importantly, studies suggest that bending of the treated joint is more dangerous than physical upright joint load [66]. Complete retention of the injected radionuclide in the joint cavity with no or minimum leakage to any non-target organ is essentially one of the primary requirements for a successful RSV procedure. Alternatively, leakage of injected radionuclide away from the treated joint will not only compromise the RSV outcomes but is also considered to be the primary disadvantage of RSV procedures. Radionuclide leakage to the extra-articular space also poses potential risk for the spread of radionuclide through the physiological pathways of lymph and blood [36]. That said, both theoretical and clinical dosimetry approaches that accommodate leakage of the radionuclide are of particular interest. Specifically, theoretical methods that include Monte Carlo simulation (EGS4) [1], Geant4 [34], GATE [67], etc. have been employed to study the radionuclide leakage in RSV. Because it is difficult to clinically estimate the radiation dose for all tissues due to leakage, the Monte Carlo simulation in which the properties of the simulated tissue and radionuclide are much easier to control present an attractive alternative. Correspondingly, estimates of biological half-life of a given radionuclide have been used to assess leakage of the radionuclides in clinics [1]. Importantly, the particle size of the injected radionuclide and immobilization of the treated joint contribute significantly towards leakage. Typically, the injected radionuclides have an optimal size; these are small enough to enable rapid phagocytosis in the surface layer of synovium, but large enough to inhibit the biological removal of radionuclide, and thereby leakage, from the treated joint. The appropriate size range for the injected radionuclide generally falls in 2–5 µm

6. Radiation induced secondary malignancy in RSV patients RSV appears to be a simple and safe therapeutic option for refractory synovitis in an attempt to avoid surgical synovectomy. Nevertheless, it is suspected that the use of ionizing radiation in RSV may induce long-term risk of malignancy; children and young adults are particularly prone to such concerns. The current literature is limited and inconclusive for assessment of malignancy risk in RSV treated patients. For instance, out of 1228 patients with rheumatoid arthritis, 143 patients underwent RSV using Y-90 while 1075 did not; interestingly, long term follow up (i.e., 30 years) after RSV treatment did not revealed increased rate of cancer incidence in the RSV group [70]. More specifically, the calculated standardized incidence ratio (SIR) for cancer was 0.6 and 1.1 for patients who received Y-90 and who did not, respectively. It may be noted that the SIR was defined as the number of observed cancers in RSV treated group divided by the expected number of cancer cases. Further, the expected numbers of cancer cases were calculated by multiplying the number of person-years (which was calculated for the follow up period) by the corresponding average cancer incidence during the respective calendar period of observation [70]. Recently, identical results were reported in a retrospective study with a 68

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estimated whole body dose to the therapist physician, radiochemist and nursing staff from a patient treated with Y-90 was reported as 0.2–1.8, 0.3–0.6 and 2.9–3.4 µSv, respectively [18]. Interestingly, these reported doses for Y-90 are significantly lower than the doses from Dy-165 despite the former have higher extra-articular leakage and longer physical half-life than the later. Another study revealed whole body dose of 21 μSv for the therapist physician for six treatments using Y-90 [20].

larger cohort (i.e., 2412) of RSV-treated patients [71]. Specifically, no increased risk of cancer was observed in the RSV-treated group compared to the general population. In summary, the hypothesis of increased risk of cancer incidence associated with the radiation exposure in RSV is not supported by available data. Ionizing radiations such as encountered in RSV treatment are capable of inducing chromosomal aberrations, particularly in young children. Recent studies have reported acute lymphoblastic leukemia (ALL) in two children within one year after RSV treatment [37,52]. However, it is important to note that both the aforementioned children had additional autoimmune disorders before receiving RSV treatment [72]. Moreover, an exclusive correlation between the RSV treatment and development of leukemia has been ruled out, due to the significantly short interval between radiation exposure and malignancy [72]. Kampen et al. reviewed 180 published studies that reported on more than 9300 patients treated with RSV (i.e., Y-90); these studies reported only one case each with lymphatic leukemia and chronic myelocytic [22]. Alternatively, micronuclei of peripheral lymphocytes transiently increased soon after Y-90 therapy; however, this increase disappeared after three months [73]. Correspondingly, several studies have consistently shown that genotoxic radiation exposures of the peripheral lymphocytes did not produced statistically significant chromosomal aberrations [74–76].

8. Contamination risk in RSV procedures The risk of contamination is always high when handling unsealed radiation sources such as in case of RSV clinics. In particular, skin contamination in RSV procedures can provoke fairly high personal dose equivalent (Hp (0.07)), presumably due to high specific activities of the radiopharmaceuticals used e.g., about 500 MBq/ml for Y-90; spilling a tiny invisible drop is capable of causing contamination which may result in high local skin doses. It has been suspected that such contamination yielded radiation exposures of the same order of magnitude (i.e., Hp (0,07) = 100–700 mSv per working day at the fingertips) as those caused by direct radiation [14]. Nevertheless, contamination measurements in RSV clinics are carried out often rarely and insufficiently. Implementing simple radiation protection metrics can potentially diminish the risk of contamination, enabling a marked reduction of occupational exposure. First, the awareness of all RSV clinicians regarding high dose levels and high risk of contamination had to be stimulated. In addition, a medical physicist with special expertise in the use of radiopharmaceuticals and decontamination should be part of the RSV clinic. Further, the therapist physician should also be trained in handling unsealed radioactive sources. All medical accessories used to draw up and store the radiopharmaceuticals (e.g., forceps, syringe carriers, shielding gloves, syringe shields, etc.) should be checked for contamination before and after being used. Needle track in the joint of patient may be considered as a source of radiopharmaceutical contamination; flushing this tract before and during the withdrawal with 0.9% saline can reduce the risk of contamination [69]. After radiopharmaceutical injection, the medical physicist must ensure that there is no skin contamination on the injected joint of the patient. In case skin contamination is suspected, small alcohol wipes for swabbing the skin should be applied for removing the contamination. Moreover, the hands of the therapist physician with particular attention to his fingertips are also essential for checking any possible contamination [84]. The injecting syringe should be carefully checked for any residual activity; depending on the amount and type of residual radiopharmaceutical, the syringe can be placed into the radioactive waste store. In RSV clinical practice, the recently RSV treated patient may have serious complaints of growing joint effusion which limits the joint mobility. In such cases, the joint can be punctured, if necessary, for removal of the fluid (water, gelatinous or hemorrhagic) in the nuclear medicine department only, by a physician who has special training in handling unsealed radioactive sources since the joint fluid remains highly radioactive for more than one month after RSV. This would more likely avoid contamination of the patient and the physician himself. Finally, the joint fluid, the contaminated syringe, needle and drapes, are considered as radioactive waste and thereby require appropriate processing [6].

7. Radiation exposure to medical staff It is important to carefully determine the radiation dose of the medical staff such as the therapist physician, radiochemist, nursing staff, etc. involved in RSV treatment, particularly in centers with high load of treated patients. In particular, higher radiation doses are delivered to skin of the medical staff, thereby demanding for special attention. Previously, radiation exposure to the skin of hands of medical staff involved in RSV treatment has been determined [15]. Specifically, 155 joints were treated with three radionuclides (i.e., Er-169, Re-186, Y-90). The maximum cumulative β exposure over all three radionuclides was observed at the left forefinger; 190 mSv for the therapist physician, 120 mSv for the radiochemist and 16 mSV for the attending nurse. The specific β exposure at the left forefinger was 0.56, 1.52, 22.09 µSv/MBq for Er-169, Re-186 and Y-90, respectively. These high doses were primarily delivered during the radiopharmaceutical injection into the joint. Specifically, holding the cannula between thumb and finger during connecting⧹separating the cannula and the syringe for relatively longer duration caused higher doses. Importantly, the specific β exposure was significantly reduced (i.e., from 22.09 to 0.42 µSv/MBq) with the use of holding forceps/tweezers for fixing the injecting needle [15]. These findings are in agreement with the study of Liepe et al.; the β dose was highest at the forefinger which was significantly reduced (i.e., from 22.1 to 0.6 µSv/MBq) by using forceps. Nevertheless, holding the injecting needle/syringe with forceps is not always quite easy for the therapist physicians. To resolve this issue, Barth et al. has proposed and developed a plastic ring for the syringe so that direct contact of the thumb and fingers with syringe can be avoided, potentially reducing the specific skin exposure [14]. Further dose reduction to the level of 0.4 µSv/MBq was achieved by using special radiation resistant gloves, made of elastic, natural rubber latex [16]. Additionally, for Y-90 and Re-186, typically a perspex shielding (thickness ∼2.5 mm) is used in clinics; for Er-169, no such shielding is necessary as the low energy β emission is absorbed by the syringe wall [77]. Table 4 and Table 5 presents a summary of radiation doses to medical staff involved in RSV treatment. In addition to skin doses, whole body radiation doses to the medical staff during RSV treatment are usually very low due to limited range of β radiation; nevertheless, measurement of these doses has been also addressed in several studies. For example, whole body dose equivalent of 103 µSv for the radiochemist and 40 µSv for the therapist physician has been reported in RSV of knee joint with Dy-165 [13]. Moreover, the

9. Radiation exposure to general public from RSV patients The patient receiving RSV treatment should avoid unnecessarily exposing family members and the public to radiation. To this end, hospitalization of the said patients may limit the exposure. Previously, it has been demonstrated that patient hospitalization of 6 h guaranteed the recommended dose limits to both family members and to the general population [19]. Moreover, maximum whole body doses from a 69

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Table 4 Summary of radiation doses to medical staff involved in RSV treatment. Medical staff

Radionuclide

Average left-hand fingers dose (Hp(0.07); µSv/MBq)

Average right-hand fingers dose (Hp(0.07); µSv/MBq)

Thumb

Index

Middle

Ring

Thumb

Index

Middle

Ring

0.34 2.01

0.22 1.54 0.42 1 3 40 21.5 7.8 4.1

0.18 0.43

0.18 0.31

0.10 0.25

0.17 0.14

0.09 0.14

0.07 0.28

Reference

TP MP TP TP RC TP RC TP RC

Y-90

[78]

TP RC TP

Re-186

TP RC

Ho-166

2.89 2.5

[82]

TP

Er-169

0.56

[15]

[15] [79] [21] [80]

1.52

[15] [81]

0.894 0.664

TP = Therapist Physician; MP = Medical Physicist; RC = Radiochemist.

of the treated patient. Immobilization of the treated joint for 48 h is recommended which may significantly reduce the leakage and thereby dose to remote organs. Patient relatives particularly children and pregnant women should keep distance from the treated patient.

Table 5 Maximum exposure of the hands (daily doses) during RSV [83]. Y-90 (MBq)

Maximum dose (Hp(0.07) in mSv/therapy day) RC

TP

N

82 101 16 18 not measured not measured 108 14 7 8 15 4 55 8 8

43 132 16 33 1 1 27 41 62 1 5 11 207 31 83

5 10 2 not not not not not 9 36 1 2 NA NA NA

References 805 1675 620 1480 555 1110 2035 555 460 2005 180 360 888 1332 2442

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measured measured measured measured measured

TP = Therapist Physician; RC = Radiochemist; N = Nurse.

treated patient with Y-90 has been reported to be 55 µSv for people living with the patient [51]. The family members and care givers should be adequately educated about the risk of radiation and preventive measurements. Particular vigilance may be instructed in favor of children and pregnant women, especially distance should be kept in the first hours and days after the therapy. 10. Conclusion Radiation synovectomy (RSV) is a reliable treatment procedure for any form of chronic arthritis with synovitis refractory to conventional treatment, with successful clinical results provided dosimetric concerns are addressed effectively. The RSV clinics should have appropriate radiation safety equipment and expertize for the handling and disposal of contamination and waste. Since RSV is based on unsealed β-emitters, it thereby warrants the proper training of the medical staff involved in the procedure. The personal dose Hp(0.07) to the hands of medical staff typically ranges from 1 to 21.5, 0.1 to 40 and 0.1 to 5 µSv/MBq for the radiochemist, therapist physician and the nurse, respectively. The use of forceps/tweezers for holding the syringe during treatment and radiation protective gloves would markedly reduce the dose to medical staff. The injected radionuclide imposes radiation risk to the articular cartilage and bone, lymph nodes, liver, sleep, gonads and bloodstream 70

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