Testicular Dose During Prophylaxis of Heterotopic Ossification with Radiation Therapy

Discussion

HO is the pathological process of bone formation in non-osseous tissues following trauma and/or surgical intervention. This misplaced growth occurs between muscle planes and not within the muscle fibers themselves (18). HO was first identified and reported in the literature in 1883 by Riedel (20), a German physician. It was later observed by the French physicians Dejerne and Ceillier (21) in patients suffering traumatic paraplegia in World War I. There are several factors that appear critical to HO formation – a traumatic injury, signals from the site of injury, a supply of mesenchymal cells and the appropriate tissue microenvironment – all appear to be factors that may contribute to the development of HO in injured tissues (1). The most common procedures that result in HO are: ORIF of an acetabular fracture or a total hip arthroplasty (THA) (4, 9). Many clinicians recommend prophylactic RT and/or non-steroidal anti-inflammatory medications (NSAIDs) to prevent HO.

Radiation therapy presumably decreases the risk of HO by inhibiting the proliferation of pluripotential mesenchymal cells that could potentially differentiate into osteoblastic stem cells and is usually given postoperatively, within 72 hours of surgery or preoperatively (3-8). We hypothesized that by utilizing a SBT medially and/or by using higher photon energies (10 and 18 MV), we could minimize the scattered dose to the scrotum/testicles and, consequently, diminish the RT-induced testicular damage. In order to achieve minimal dose divergence at the beam edge, a split beam technique, sometimes called a half-beam block, is often used. In this method, the beam is split along the plane containing the central axis inhibiting geometric divergence of the beams at the split line (22). This technique is often employed in matching one field to another. By applying a half-beam block in the medial edge of the pelvic AP/PA fields in HO prophylaxis, much of the dose that can potentially diverge into the testes, bowel and bladder is diverted laterally.

Most patients who develop HO are males after a TAF. The testes, given their proximity to the pelvis, will be exposed to scattered radiation, which has the potential to alter sperm count and morphology. Radiobiological studies have shown that the testicles are very radiosensitive and very low doses of radiation have been shown to alter sperm production and morphology and cause transient or even total azoospermia/sterilization (11). The largest study (53 patients) evaluating testicular dose and sperm function was conducted by the Southwest Oncology Group (27). The median gonadal dose in this study was 79 cGy. Recovery of fertility occurred approximately 1 year after radiation, which was both dose- and time-dependent. Hall et al. (11) have reported a temporary reduction in the number of spermatozoa with radiation doses as low as 10 cGy and temporary sterility at doses of 15 cGy. Moreover, Freund et al. (29) reported on testicular function dysfunction in 8 seminoma patients treated with radiation, where the absorbed gonadal radiation dose ranged from 15 to 157.5 cGy.

In a prospective study by Patel et al., patients were treated with 800 cGy without direct exposure of the testes/scrotum and while using a testicular shield. Thermoluminescent dosimeters were placed inside and outside the shield. The mean dose inside and outside the shield was 10.2 and 20.2 cGy, respectively. The authors concluded that young males should be counseled of the risks of testicular radiation and treated with a testicular shield (10). Bieri et al. have reported that the daily dose to the testes was 1.86 cGy per fraction without gonadal shielding and 0.65 cGy per fraction with gonadal shielding for males with seminoma treated at 1.8 Gy per fraction to a para-aortic field, suggesting that a scrotal shield should be used to reduce the scatter dose to help avoid impairment of spermatogenesis (27). For male patients presenting for RT prophylaxis of HO, it is standard practice to routinely offer testicular shielding for all patients who want to preserve their fertility or the ability to conceive, since the RT field is in close anatomical proximity to the testes (12, 13).

In a study utilizing dose modeling in phantoms, the estimated total gonadal dose and risk of hereditary effects during therapeutic external irradiation was shown to be ~39 cGy using 6 MV photons without the SBT technique; this was associated with a risk for genetic effects in offspring of 23.4×10⁻⁴. This is 4 times greater than the risk generated from a typical computed tomography scan of the abdomen, which was estimated to be 6×10⁻⁴ in males (14). Generally, most radiation oncologists would agree that side-effects, such as temporary azospermeia and sperm chromosomal abnormalities from scattered dose to the testes, could happen with very low RT doses in the range of 10 to 15 cGy (10). Thus, using a SBT with higher photon energy, as we have reported, has the potential to reduce risk for genetic effects in offspring by two thirds.

Some male patients specifically decline to use the clam shell testicular shield, as did all the patients in this study. Others may be so obese that the standard shell will not fit comfortably between the excess tissues in the thighs of the patient. For such patients then, we must use non-shield techniques to obtain adequate coverage of the targeted area while providing the least integral dose to the testicles. In the current study, we retrospectively evaluated how one could minimize the RT doses to the scrotum/testicles during single-fraction treatment for HO prevention.

We were able to minimize the testicular dose by applying SBT and higher photon energies. There was a significant reduction (>50%) of testicular dose by utilizing these simple-to-use maneuvers. Using SBT and ≥10 MV photon beams led to a smaller scattered RT dose compared to lower energy 6 MV photons. Higher energies lead to a more consistently forward directed beam and decreased side scattering. The major caveat of using high energy 18 MV photons, however, is the neutron contamination that occurs when beams with >10 MV energy are used. The dose contribution to the testicles from neutron contamination in 15 MV or 18 MV photons is difficult to quantify. For this reason, beams of energy 15 MV and higher should also be avoided due to the increased neutron contamination from beam modifying components of high atomic number, such as the target and jaws (30). In conjunction with a “half-beam blocking” technique, one can also employ a physical shield to protect the testes from scattered radiation during treatment as has been demonstrated by Fraass and colleagues (30). They described the use of testicular shielding for testicular dose reduction in 1985. Shields are commercially available and, while considered to be a standard part of therapy when treating young males in the setting of Hodgkin's disease or seminoma, they have not been used as commonly, during HO prophylaxis.

Mourad et al., in 2010, presented the first radiation-induced sarcoma case in the literature after RT prophylaxis of HO. The possibility of second malignancy after RT, especially in younger patients, is an additional concern and should be discussed with the patients. However, it is a rare side-effect and only 2 cases of radiation-induced sarcoma have been reported in the literature to date (23-26). There are two basic approaches to reduce the RT scatter dose effect on the testes. One approach is to improve the treatment delivery so as to decrease the amount of scattering dose, which can be achieved by using CT simulation, SBT and photon energies greater than 6 MV (27, 22). This effect is mainly a result of the decrease in penumbra and lateral scattering when going from lower to higher energy beams.

In summary, our results suggest that the use of field modification and higher beam energies during RT for HO prophylaxis appears to consistently reduce the radiation dose to the scrotum/testicles by about two- to three-fold of the values obtained using standard blocks and lower beam energy. This could translate into a by two- to three-fold reduction of risk for genetic effects in offspring. We also advocate the routine use of a testicular shield for all male patients receiving radiation for HO prophylaxis. Although, a testicular shield is effective in shielding scatter from external (machine head) sources, it does little to prevent in-scatter into the testicular region from within the patient. Hence, in order to further minimize the gonadal dose while maximizing sufficient target volume coverage, we recommend that CT-based simulation, 3-D treatment planning, a SBT and ≥10 MV photon beams be utilized (28, 32-34).