Introduction
The analgesic effect of low-dose radiotherapy (LDRT) in treating painful musculoskeletal disorders (MSDs) is well known. Reference Javadinia, Nazeminezhad and Ghahramani-Asl1,Reference Mitrov and Hargov2 In the last few decades, the mechanism of action as well as the optimal therapeutic dose and fractionation regimen are the main topics under investigation. Reference Niewald, Fleckenstein, Naumann and Ruebe3–Reference Ott, Hertel, Gaipl, Frey, Schmidt and Fietkau5 Germany is considered as one of the leading countries in this field and has a long tradition of treating benign MSDs with LDRT. The German Society of Radiation Oncology published the first treatment guideline in the nineteens of the last century, which was updated lastly in 2018. Reference Mücke, Micke, Seegenschmiedt and Schäfer6 Several studies have investigated LDRT aiming to understand and prove their analgesic effect. Reference Basche, Drescher and Mohr7–Reference Oehler and Hentschel9 The applied doses and the used technique, including target volumes, treated fields, and energy spectrum, differ between these studies and were continuously optimised in the last few decades, keeping up with the rapid progress of the radiotherapy machines and techniques.
This retrospective cohort study tries to declare if there is a correlation between the effectiveness of LDRT in treating painful inflammatory and degenerative MSDs and the used radiotherapy energy.
Patients and Methods
Between September 2019 and January 2020, a total of 91 patients with either painful inflammatory or degenerative MSDs were treated with LDRT. These patients were routinely treated in our department with the Orthovolt unit because of the implementation of a new Orthovolt machine where the patients were treated during the renovation period with Megavoltage Linear accelerator (Linac).
The inclusion criteria were patients older than 40 years with either painful inflammatory disorders such as epicondylitis humeri or plantar fasciitis or degenerative osteoarticular disorders of the wrist or ankle joints. The duration of the symptoms should be 1 month or longer. Patients with a previous history of malignant disease were also included after the exclusion of local or systemic recurrences by clinical and radiological examinations, including MR tomography and bone scintigraphy. Previously irradiated patients or those who were treated with other conservative methods such as ultrasound, local injections, laser therapy and electrotherapy, were also allowed to be included.
The exclusion criteria included patients treated with different energies in the same course. The pain aetiology is regarded as other medical conditions such as rheumatic or vascular diseases. Musculoskeletal proliferative diseases such as Morbus Ledderhose or Morbus Dupuytren and Inflammatory or degenerative disorders affecting small joints such as metacarpophalangeal, interphalangeal and metatarsophalangeal joints, or large joints like shoulder, knee and hip joints were also excluded. Patients desiring to have children in the first 2 years after the treatment or those who did not complete the radiotherapy course or missed follow-up were not allowed to be involved in the study.
The medical history, clinical examination and radiological investigations including an X-ray of the affected region were conducted. All patients were treated with the same fractionation, a single dose of 0·5 Gy, and a total dose of 6·0 Gy (two to three fractions weekly). The pain was evaluated before and on the last day of treatment then 4 to 6 months later using the Numerical Rating Scale, Verbal Rating Scale and modification of von-Pannewitz score as following complete pain relief, partial response and unchanged or worsening the pain conditions.
Patients with eligible criteria were divided into two groups. The first one included those who were treated with the Orthovolt unit (T-200 System, Firma Wolf-Medizintechnik GmbH, St. Gangloff, Thuringia) with the following parameters, 200 Kv, 15 mA, 1 mm copper filtration with different tubes according to the site to treatment using direct fields. The second group included patients treated with Linac machines (TrueBeam generation 2·7, Varian Medical Systems, Palo Alto, CA, USA) with opposing fields using energies between 6 and 18 MV according to the treated area with previous CT simulation. The collected data were statistically analysed using SPSS program version 25 (SPSS Inc., Chicago, IL, USA) with the assumption of the null hypothesis that there is no difference between both groups treated with different energies.
This retrospective analysis was conducted following the ethical standards of clinical research and compatible with the Helsinki Declaration of 1975 and the subsequent revisions. The internal institutional approval and patient agreement in the form of written consent were obtained.
Results
A total of 91 patients with painful inflammatory and degenerative MSDs are compatible with the inclusion criteria. The median age was 60 years, and the median duration of symptoms was 6 months. The male patients represent 46%, and the female patients were 54%. 49% of the patients were treated with the Orthovolt unit, and 51% were treated with a linear accelerator. 98% were previously treated with other methods including local corticosteroid injection, pain killers such as NSAID, physiotherapy and other options. The patient’s characteristics are summarised in Table 1.
Table 1. Patient characteristics
Most of the patients (70%) suffered from an inflammatory heel spur or plantar fasciitis. Patients with epicondylitis humeri represent 17% of the studied patients. The classification of patients according to the treated region is illustrated in Figure 1.
Figure 1. Classification of patients according to the treated region.
At the end of the treatment, 60% of the patients showed subjective improvement of the pain and only 6% had a complete response. The delayed assessment which was conducted 4 to 6 months after the treatment showed 65% of patients a complete response and 8% an improvement. The treatment response is illustrated in Figures 2 and 3.
Figure 2. Evaluation of treatment response at the end of the treatment.
Figure 3. Evaluation of the late treatment response.
The Mann–Whitney U test was used to compare the treatment response between both studied groups, which resulted in retaining the Null hypothesis and proving that the used energy does not affect the response either at the end of the treatment or at the second control.
The same statistical test was used to compare the early and late response according to the disease aetiology, which shows no difference in the early response and better late response of patients suffering from inflammatory diseases with a p-value of 0·015. Figure 4.
Figure 4. Comparison between the early and late response according to disease etiology.
Note: (0 = no response or pain worsening, 1 = partial response, 2 = complete pain relief).
Another statistical analysis with Kruskal–Wallis test was used to compare the response according to the treated location and showed that patients with osteoarthritis of the ankle joint have worse responses otherwise, there was no difference in response between the other treated sites (Figure 5).
Figure 5. Comparison of response according to the treated location.
Note: (0 = no response or pain worsening, 1 = partial response, 2 = complete pain relief).
Comparing the responses at the end of the treatment and 4 to 6 months later using the Wilcoxon signed-rank test resulted in a significant difference with p-value 0·000 favouring the late response.
There were no immediate or delayed side effects associated with the treatment.
Discussion
The analgesic effect of LDRT in treating inflammatory and degenerative MSDs is well known since the beginning of the 20 century. Reference Javadinia, Nazeminezhad and Ghahramani-Asl1 Several studies have been conducted to investigate this effect using different single and total doses, variable techniques and energies. Reference Ott, Jeremias, Gaipl, Frey, Schmidt and Fietkau10–Reference Lindner and Freislederer12 The mechanism of action of LDRT is not yet completely clarified. It is assumed that LDRT stimulates a complex anti-inflammatory process by inhibiting the leucocyte accumulation, transfer and differentiation to macrophages. It also decreases the production of inflammatory-inducing cytokines and nitric oxide, which regulates the vascular permeability after any mechanical and chemical irritation of tissues resulting in the suppression of the inflammatory cycle. Reference Mücke, Micke, Seegenschmiedt and Schäfer6,Reference Roedel, Keilholz and Herrmann13,Reference Rödel, Frey and Gaipl14
The optimal dose and fractionation were also under investigation with a widely accepted single dose of 0·5 to 1·0 Gy and a total dose of 3 to 6 Gy in one or two courses. Reference Mücke, Micke, Seegenschmiedt and Schäfer6,Reference Glatzel, Bäsecke and Krauss15–Reference Ott, Jeremias, Gaipl, Frey, Schmidt and Fietkau18 The Orthovolt machines producing X-ray with low energies (kilovolt) were routinely used in treating benign skin and MSDs until the end of the last century. Reference Zschache19–Reference Seegenschmiedt, Keilholz and Stecken21 The reason for that standard of care was not only to reduce the costs and to spare the expensive Linacs for treating malignant diseases but also because of the assumption that the low energetic spectrum of radiotherapy is more effective in healing superficial soft tissue diseases. Reference Micke and Seegenschmiedt22
The use of linac in the treatment of benign diseases has steadily increased over the past few decades, in parallel with improvements in treatment capacities and reductions in treatment costs. The use of different radiotherapy energies was compared in the multianalysis of the national standard of care in treating plantar fasciitis done by Micke et al. Reference Micke and Seegenschmiedt22 , which showed that there was no difference in response according to the used energy. Another prospective study that evaluated the analgesic effect of LDRT showed the same results. Reference Micke, Ugrak and Bartmann23
Nevertheless, it is important to notice that the investigated samples in these studies were unequal, which can affect the statistical power. In several studies, plays the patient selection also a role in the final results, either by including only one MSD with a specific treatment area, or by broadening the selection criteria to include regions that physically require high energy, such as the large joints which preferably treated with Linac. Reference Micke, Ugrak and Bartmann23
The effectiveness of LDRT in the previously conducted studies varies depending on the aetiology, treated location, severity of the diseases and eventually the duration of symptoms. Reference Micke, Ugrak and Bartmann23–Reference Mucke, Schonekaes, Micke, Seegenschmiedt, Berning and Heyder25 In the case of plantar fasciitis and epicondylitis humeri, a response rate of up to 90% can be achieved. Reference Javadinia, Nazeminezhad and Ghahramani-Asl1,Reference Oehler and Hentschel9,Reference Micke, Ugrak and Bartmann23 The therapeutic effect in the case of osteoarthritic lesions reached up to 75%. Reference Micke, Ugrak and Bartmann23,Reference Keller, Müller and Kortmann26
Conclusion
LDRT is an effective analgesic treatment option for both inflammatory and degenerative MSDs with different success rates according to the site and nature of the pathological condition. There is no difference in response according to used energy, and most of the patients respond lately with a time frame of 4 to 6 months after the end of the treatment.
Acknowledgements
The authors would like to express their sincere gratitude to the study participants, without whose commitment this study would not have been possible.
Conflicts of Interest
All authors declare that they have no conflicts of interest.
