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Radiation therapy

Radiation therapy is a well-known cause of fibrosis

Many people with knee arthrofibrosis have tried radiation therapy. But, how wise is radiotherapy for treating fibrotic diseases? We'll aim to explain the effects of therapeutic ionising radiation. Our conclusion is that we would not advice radiotherapy for arthrofibrosis with the current knowledge, and explain why. This is a big topic with a lot to think about, but it’s worth coming to grips with if you’re considering radiotherapy.

Understanding radiotherapy is complicated, there are many different approaches, including the type of radiation, the dose, the way it is administered, and how many times it’s administered, which you can read about here [1]. There are different sources and types of ionising radiation, and the absorbed dose affects the severity of side effects [2]. There are two main differences in application we need to know about - external beam therapy (e.g. X-rays), and internal radiation therapy, which is also called brachytherapy. In brachytherapy, short-lived radioactive material is placed inside the tissue (inside the joint capsule). Although the radioactivity only lasts a short time, the metal “seeds” that carry the radioactivity remain long-term. This is the therapy I had, but most reports of radiotherapy for arthrofibrosis use external beam radiation, presumably the conventional type applying single beam X-rays – these details usually aren’t published in arthrofibrosis papers.

 

By definition, ionising radiation has enough energy to displace electrons and break chemical bonds, and any cell or molecule can be damaged [3]. Ionising radiation is toxic, with adverse side-effects including DNA damage and inflammation [4] that can cause long-term health problems, such as cancer [3]. The effects may be acute (early), or late, sometimes emerging many years down the track. Late side-effects are more likely to occur in slowly dividing cells, including those in muscle and bone [1]. Cells that are rapidly dividing, like cancer cells, are more susceptible to acute radiation-induced damage. This cytotoxic (cell killing) effect is used to advantage when tumours need to be destroyed, and this type of radiation therapy is widely used to save lives. Cancer radiotherapy is clearly justifiable, and care is taken by a team of professionals to optimise and target the radiation dose to reduce side-effects [3]. The aim is to kill cancer cells while reducing damage to healthy cells and minimising undesirable side-effects [5].

 

Unfortunately, other well-known side-effects of radiotherapy are inflammation and fibrosis [5]. When ionising radiation strips electrons away from the atoms in water molecules, highly damaging free radicals and reactive oxygen species (ROS) are created, resulting in a large increase in oxidative stress [5]. This sets of a range of effects in the body, including more ROS, inflammation and cell damage, as well as significant increases in TGF-β production [4,5], This is bad, TGF-β is the key molecule responsible for fibrosis pathology. A range of epigenetic changes (modifications to DNA) also occur which transform cells into myofibroblasts [5], the cells that make fibrosis.

Figure from Shrishrima et. al. 2019

Figure from Shrishrima et. al. 2019 [5]

It doesn’t sound good - this therapy that should help to treat fibrosis is instead a well-known cause of fibrosis. To make matters worse, we don’t know how ionising radiation affects soft tissues, including the synovial membrane and tendons [6]. Plus, there are considerable differences between individuals in terms of radiation efficacy and adverse reactions to radiotherapy as a result of genetic differences in cytokine and fibrosis genes [4].

 

Perhaps, like surgery, the outcome depends on how many myofibroblasts are killed by the radiation and how many are created by it. In the absence of any way to measure the numbers of myofibroblasts in a knee, this remains an unknown, with the therapy not having any “clinically relevant” effects in the longer term.

You might have heard that radiotherapy reduces inflammation. This idea appears to come from the death of some types of immune cells and the production of anti-inflammatory cytokines in response to radiotherapy. But these so-called anti-inflammatory cytokines have powerful pro-fibrosis actions, including TGF-β, IL-4 and IL-13 [4]. In addition, macrophages, the immune cells that are heavily implicated in inflammation and fibrosis, are more resistant to radiation [7]. Not only that, but cell death from radioactivity recruits large numbers of immune cells to the site [8], so the end result is an increase in immune cells in the treated area, with many of these becoming macrophages. The fact is, radiotherapy directly stimulates the immune system [4].

Figure from De Maggio 2015

Figure from De Maggio 2015 [4]

So, what does the science tell us about outcomes of radiotherapy for arthrofibrosis? As usual, it seems there aren’t any quality studies investigating this. The few papers published on this topic are usually old studies with small numbers and a high risk of bias (no “blinding”) (for example, see [9]). A larger study of radiotherapy for shoulder arthrofibrosis had no control group to compare outcomes to, no blinding and a short follow-up period [10]. Shoulder arthrofibrosis spontaneously resolves in many cases, so randomised controls are essential for determining the efficacy of treatments.

 

With a lack of evidence for radiotherapy in arthrofibrosis, we can look at the evidence for other forms of fibrosis. This treatment is widely used for treating forms of skin fibrosis, known as hypertrophic and keloid scars, and being visible, the results are easier to assess. Keloid scars have a recurrence rate of 50 to 100% after surgery and medications [11], and this rate can be reduced with radiotherapy within 48 hours after surgery. However, even with radiotherapy complete recovery is not possible, and high quality research indicates the scar recurs in around half of treated people [12].

 

There are important lessons from this research on skin fibrosis though. It suggests that the key for successful radiotherapy appears to be applying it early after surgery, as well as using relatively high doses of radiation of 9 to 20 Gy in a number of sessions (fractions) [12, 13], One paper suggests that a minimum dose of 20 Gy in 5 fractions is needed to effectively control skin fibrosis [11]. We know that ionising radiation affects rapidly dividing cells more than resting cells, so it makes sense to perform radiotherapy soon after surgery when there is rapid cellular proliferation to heal the wound. The early post-operative period is when cells called fibroblasts transform into myofibroblasts. Killing these off in the proto-myofibroblast period when they’re vulnerable makes sense, because later they stop dividing and will be much less sensitive to the effects of radiation. There is a risk of over-doing this, resulting in a wound that doesn’t heal.

 

Radiation doses of around 20 Gy appear to be necessary, but this dose is high enough to create more fibrosis and even cancer. We know that the adverse side-effects of ionising radiation increases with the dose of radiation, with inflammation [4] and the risk of cancer increasing with doses above 0.1 to 0.2 Gy [2]. In skin fibrosis the myofibroblasts are in the surface layers of tissue, so the beam of radiation can be very accurately targeted and healthy cells surrounding the scar are protected. Radiotherapy is also used for treating early Dupuytren's disease, a fibrotic condition of the hand, but again the superficial nature of the fibrosis permits careful targeting of the radiation and limits damage to healthy tissue.

 

Reducing the effects of radiation on healthy cells is a real problem if you want to treat a large area like a joint. The risk of radiation-induced inflammation and fibrosis extending beyond the fibrotic region into healthy tissue and actually increasing the extent of fibrosis seems unavoidable in the major joints. There might be a higher level of risk using radiotherapy for hips where internal organs could be impacted, and it’s interesting to note that radiotherapy does not appear to be used for treating organ fibrosis. As mentioned, risks can be reduced by reducing the dose of radiation, but this also reduces the efficacy. One recent study compared the outcomes for early post-op knee radiotherapy in 15 people with arthrofibrosis undergoing revision total knee replacement, compared to 11 people who had revision TKR without radiotherapy. There was no statistical difference in the outcomes at 1 year [14].

 

Each person needs to weigh up the pros and cons of radiotherapy and make their own informed decision, and we hope that the information on this page helps. To summarize, the known side-effect of increasing inflammation, together with the risk of increasing fibrosis rather than reducing it, means that we would not advice to try radiotherapy in a fibrotic joint. 

References

  1. Majeed H & V., G. in StatPearls [Internet] (2022).

  2. Kamiya, K. et al. Long-term effects of radiation exposure on health. Lancet 386, 469-478, doi:10.1016/S0140-6736(15)61167-9 (2015).

  3. Hill, K. D. & Einstein, A. J. New approaches to reduce radiation exposure. Trends Cardiovasc Med 26, 55-65, doi:10.1016/j.tcm.2015.04.005 (2016).

  4. Di Maggio, F. M. et al. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm (Lond) 12, 14, doi:10.1186/s12950-015-0058-3 (2015).

  5. Shrishrimal, S., Kosmacek, E. A. & Oberley-Deegan, R. E. Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis. Oxid Med Cell Longev 2019, 4278658, doi:10.1155/2019/4278658 (2019).

  6. Baier, C. et al. Irradiation in the treatment of arthrofibrosis after total knee arthroplasty: a preliminary trial. Cent. Eur. J. Med. 7, 553-556, doi:10.2478/s11536-012-0009-9 (2012).

  7. Ruckert, M., Flohr, A. S., Hecht, M. & Gaipl, U. S. Radiotherapy and the immune system: More than just immune suppression. Stem Cells 39, 1155-1165, doi:10.1002/stem.3391 (2021).

  8. McLaughlin, M. et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer 20, 203-217, doi:10.1038/s41568-020-0246-1 (2020).

  9. Farid, Y. R., Thakral, R. & Finn, H. A. Low-dose irradiation and constrained revision for severe, idiopathic, arthrofibrosis following total knee arthroplasty. J Arthroplasty 28, 1314-1320, doi:10.1016/j.arth.2012.11.009 (2013).

  10. Ott, O. J. et al. Benign painful shoulder syndrome: initial results of a single-center prospective randomized radiotherapy dose-optimization trial. Strahlenther Onkol 188, 1108-1113, doi:10.1007/s00066-012-0237-6 (2012).

  11. Renz, P. et al. Dose Effect in Adjuvant Radiation Therapy for the Treatment of Resected Keloids. Int J Radiat Oncol Biol Phys 102, 149-154, doi:10.1016/j.ijrobp.2018.05.027 (2018).

  12. Deng, K. et al. Strontium-90 brachytherapy following intralesional triamcinolone and 5-fluorouracil injections for keloid treatment: A randomized controlled trial. PLoS One 16, e0248799, doi:10.1371/journal.pone.0248799 (2021).

  13. Knowles, A. & Glass, D. A., 2nd. Keloids and Hypertrophic Scars. Dermatol Clin 41, 509-517, doi:10.1016/j.det.2023.02.010 (2023).

  14. Smith, E. B., Franco, M., Foltz, C., DiNome, J. & Chen, A. F. Can adjunctive perioperative radiation improve range of motion after total knee revision for arthrofibrosis? Knee 27, 1426-1432, doi:10.1016/j.knee.2020.06.007 (2020).

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