**3. Toxicity and potential risks of LD‐EBRT**

Patients are often sent to the radiotherapist after a long unsuccessful history of diverse conserva‐ tive treatments. The reason for this is a widespread fear among general practitioners that LD‐ EBRT might be associated with severe side effects and risks. These fears are not substantiated, as reactions of the nerves or vessels require much higher doses than used for LD‐EBRT. For exam‐ ple, a dose of 45 Gy in normofractionated oncological therapy is considered to be safe for the spi‐ nal cord and therefore daily clinical practice [44]. Peripheral nerves are even more radioresistant. Acute or chronic side‐effects have never been reported in all contemporary studies on LD‐EBRT.

#### **3.1. Acute reactions of the skin**

Acute side effects are negligible, as very low doses of ionizing radiation (in comparison with oncological treatments) are applied to a distal extremity. The total dose of LD‐EBRT with 3 or 6 Gy is far too low to cause any acute or late reactions on the skin overlaying the calca‐ neus. During normofractionated EBRT (single doses of 1.8–2 Gy, treatment on 5 days a week) erythema and mild edema develop at about 30 Gy [45]. Hyperpigmentation occurs at about 45 Gy, moist epitheliolyses at about 50 Gy. A 50–60 Gy might cause telangiectasias years after the therapy. This is why there is no report on acute treatment side effects in LD‐EBRT until now to the best of our knowledge.

#### **3.2. Initial increase in pain during LD‐EBRT**

About one‐third of the patients might experience a slight increase in pain during LD‐EBRT. In the randomized trial by Heydt et al. this phenomenon was seen in 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) [30]. It does not seem to be correlated with treatment outcome; further detailed information is given in Section 2.3.4.

#### **3.3. Impairment of gonad function**

The dose scattered to the male gonads is somewhat higher than to the ovaries. Jansen et al. calculated for 6 × 0.5 Gy about 1.5 mSv received by the testes and 0.75 mSv to the ovaries [46]. Comparable results have repeatedly been measured in the past [47, 48].

Taken together, the dose received by the gonads is insignificant. As the distal extremity is irra‐ diated, scattered dose to the gonads is comparable to normal diagnostic radiological imaging [49]. The hereditary effects of these doses are very small and very likely negligible [46].

Although spermatogonial cells are very radiosensitive, a single dose of at least 100 mSv is needed to induce a temporary failure of spermatogenesis [50]. A single dose of 1000 mSv (equivalent to 1 Gy photon irradiation) results in an azoospermia for 9–18 months [51]. Interestingly, fractionated doses harm these cells even more. A temporary oligospermia is reported after receiving several fractions up to a cumulative dose of 160 mSv [52]. An azo‐ ospermia lasting for 14–22 months has been reported for fractionated doses of 620–860 mSv [53]. The actually during LD‐EBRT received testicular dose is about 100 times smaller than the lowest dose causing temporary changes in testicular tissues.

The dose to the testicles can be further reduced by utilizing a special testicular shielding. However, clinically meaningful dose reductions have been only measured in MV treatment of subdiaphragmatic/pelvine lymphatic regions or tumors [54, 55].

The mean lethal dose for human oocytes has been estimated at 2 Gy (2000 mSv) [56]. Permanent ovarian failure after radiotherapy is age dependent: in perimenopausal women, a dose of 6 Gy is sufficient [57], while in younger women up to 20 Gy are tolerated. The dose scattered to the ovaries during LD‐EBRT for calcaneodynia cannot cause such sequelae (0.75 mSv).

Naturally, pregnancy has to be excluded in all premenopausal women before beginning with LD‐EBRT, to avoid any risk to the fetus.

#### **3.4. Induction of malignancies**

**3. Toxicity and potential risks of LD‐EBRT**

**3.1. Acute reactions of the skin**

158 Radiotherapy

now to the best of our knowledge.

information is given in Section 2.3.4.

**3.3. Impairment of gonad function**

**3.2. Initial increase in pain during LD‐EBRT**

Patients are often sent to the radiotherapist after a long unsuccessful history of diverse conserva‐ tive treatments. The reason for this is a widespread fear among general practitioners that LD‐ EBRT might be associated with severe side effects and risks. These fears are not substantiated, as reactions of the nerves or vessels require much higher doses than used for LD‐EBRT. For exam‐ ple, a dose of 45 Gy in normofractionated oncological therapy is considered to be safe for the spi‐ nal cord and therefore daily clinical practice [44]. Peripheral nerves are even more radioresistant. Acute or chronic side‐effects have never been reported in all contemporary studies on LD‐EBRT.

Acute side effects are negligible, as very low doses of ionizing radiation (in comparison with oncological treatments) are applied to a distal extremity. The total dose of LD‐EBRT with 3 or 6 Gy is far too low to cause any acute or late reactions on the skin overlaying the calca‐ neus. During normofractionated EBRT (single doses of 1.8–2 Gy, treatment on 5 days a week) erythema and mild edema develop at about 30 Gy [45]. Hyperpigmentation occurs at about 45 Gy, moist epitheliolyses at about 50 Gy. A 50–60 Gy might cause telangiectasias years after the therapy. This is why there is no report on acute treatment side effects in LD‐EBRT until

About one‐third of the patients might experience a slight increase in pain during LD‐EBRT. In the randomized trial by Heydt et al. this phenomenon was seen in 26% (during 6 × 0.5 Gy) vs. 29% (6 × 1 Gy) [30]. It does not seem to be correlated with treatment outcome; further detailed

The dose scattered to the male gonads is somewhat higher than to the ovaries. Jansen et al. calculated for 6 × 0.5 Gy about 1.5 mSv received by the testes and 0.75 mSv to the ovaries [46].

Taken together, the dose received by the gonads is insignificant. As the distal extremity is irra‐ diated, scattered dose to the gonads is comparable to normal diagnostic radiological imaging [49]. The hereditary effects of these doses are very small and very likely negligible [46].

Although spermatogonial cells are very radiosensitive, a single dose of at least 100 mSv is needed to induce a temporary failure of spermatogenesis [50]. A single dose of 1000 mSv (equivalent to 1 Gy photon irradiation) results in an azoospermia for 9–18 months [51]. Interestingly, fractionated doses harm these cells even more. A temporary oligospermia is reported after receiving several fractions up to a cumulative dose of 160 mSv [52]. An azo‐ ospermia lasting for 14–22 months has been reported for fractionated doses of 620–860 mSv [53]. The actually during LD‐EBRT received testicular dose is about 100 times smaller than the

Comparable results have repeatedly been measured in the past [47, 48].

lowest dose causing temporary changes in testicular tissues.

So far, no studies with long‐term observation periods have been published, describing a case of malignancy induced by LD‐EBRT for calcaneodynia. However, induction of malignancies is a stochastic effect of ionizing radiation. This means that there is no threshold dose—in contrast for example to the above‐mentioned reactions of the skin. A photon can accidentally trigger a mutation, which in turn leads to tumor formation many years later. The higher the radiation dose, the higher the probability of such an event occurring.

The best available data on tumor induction of full dose EBRT in oncology has been col‐ lected in patients treated with breast cancer. Almost 11,000 patients have been followed for over 20 years. The risk of a radiation‐induced tumor was approx. 1% per decade after radiotherapy [58].

To estimate the risk associated with much lower doses of LD‐EBRT, mathematical models on the basis of epidemiological long‐term observations of atomic bomb victims have been developed by the ICRP [59].

Jansen et al. applied the ICRP model on LD‐EBRT of a painful heel spur [46]. Assumed was a single field entering at the foot sole with a size of 8 × 10 cm, 200 kV photons, SSD 40 cm. For an LD‐EBRT series with 6 × 1 Gy the average attributable lifetime risk for induction of a fatal tumor was calculated to be about 0.5 in a thousand patients. An important risk factor for radiogenic‐induced cancer is the patient's age by the time the radiation exposure occurs. The risk is already reduced in the 3rd decade of the patient's life, it starts to decrease steadily from the age of 40 [60]. Applying these calculations, the estimated lifetime risk per one thousand patients for a fatal tumor accounts for the age of 25 0.6 (male)/0.8 (female), for the age of 50 0.2/0.3, for the age of 75 0.07/0.1 [46].

However, it must be critically noted that this mathematical model was developed for radia‐ tion protection and relates to the exposure of complete organ systems with approx. 1 Gy. Therefore, other groups argue that a significantly lower risk of radiogenic cancer induction approx. ten times less—should be adopted [49, 61]. Furthermore, taken the new standard scheme with 6 × 0.5 Gy into account, these risks are additionally halved.

This risk (max. 1/1000, very likely much lower) must be seen in relation to the tumor risk of the not additionally radiotherapeutical‐treated population. In 2008, the lifetime risk of a man in Germany to suffer from cancer was 50.7% (25.9% to die from malignancy), in women 42.8% and 20.2% respectively [62].

By limiting the application of LD‐EBRT treatment to patients > 30 years of age, an exposure of the juvenile "relatively higher risk" patient population is avoided.
