Establishment of a Therapeutic Ratio for Gamma Knife Radiosurgery of Trigeminal Neuralgia: The Critical Importance of Biologically Effective Dose Versus Physical Dose.

OBJECTIVE: How variations of treatment time affect the safety and efficacy of Gamma Knife (GK) radiosurgery is a matter of considerable debate. With the relative simplicity of treatment planning for trigeminal neuralgia (TN), this question has been addressed in a group of these patients. Using the concept of the biologically effective dose (BED), the effect of the two key variables, dose and treatment time, were considered. METHODS: A retrospective analysis was performed of 408 TN cases treated from 1997 to 2010. Treatment involved the use of a single 4 mm isocenter. If conditions allowed, the isocenter was placed at a median distance of 7.5 mm from the emergence of the trigeminal nerve from the brain stem. The effects were assessed in terms of the incidence of the complication, hypoesthesia, and in terms of efficacy using the incidence of pain free after 30 days and 1 and 2 years. These responses were evaluated with respect to both the physical dose and the BED, the latter using a bi-exponential repair model. RESULTS: RE-evaluation showed that the prescription doses, at the 100% isodose, varied from 75 to 97.9 Gy, delivered in 25-135 minutes. The relationship between the physical dose and the incidence of hypoesthesia was not significant; the overall incidence was ∼20%. However, a clear relationship was found between the BED and the incidence of hypoesthesia, with the incidence increasing from <5% after a BED of ∼1800 Gy2.47 to 42% after ∼2600 Gy2.47. Efficacy, in terms of freedom from pain, was ∼90%, irrespective of the BED (1550-2600 Gy2.47) at 1 and 2 years. The data suggested that "pain free" status developed more slowly at lower BED values. CONCLUSIONS: These results strongly suggest that safety and efficacy might be better achieved by prescribing a specific BED instead of a physical dose. A dose and time to BED conversion table has been prepared to enable iso-BED prescriptions. This finding could dramatically change dose-planning strategies in the future. However, this concept requires validation for other indications for which more complex dose planning is required.

The role of the concept of biologically effective dose (BED) in treatment planning in radiosurgery.

Radiosurgery (RS) treatment times vary, even for the same prescription dose, due to variations in the collimator size, the number of iso-centres/beams/arcs used and the time gap between each of these exposures. The biologically effective dose (BED) concept, incorporating fast and slow components of repair, was used to show the likely influence of these variables for Gamma Knife patients with Vestibular Schwannomas. Two patients plans were selected, treated with the Model B Gamma Knife, these representing the widest range of treatment variables; iso-centre numbers 3 and 13, overall treatment times 25.4 and 129.6 min, prescription dose 14 Gy. These were compared with 3 cases treated with the Perfexion(®) Gamma Knife. The iso-centre number varied between 11 and 18, treatment time 35.7 - 74.4 min, prescription dose 13 Gy. In the longer Model B Gamma Knife treatment plan the 14 Gy iso-dose was best matched by the 58 Gy2.47 iso-BED line, although higher and lower BED values were associated with regions on the prescription iso-dose. The equivalent value for the shorter treatment was 85 Gy2.47. BED volume histograms showed that a BED of 85 Gy2.47 only covered ∼65% of the target in the plan with the longer overall treatment time. The corresponding BED values for the 3 cases, treated with the Perfexion(®) Gamma Knife, were 59.5, 68.5 and 71.5 Gy2.47. In conclusion BED calculations, taking account of the repair of sublethal damage, may indicate the importance of reporting overall time to reflect the biological effectiveness of the total physical dose applied.

Application of the concept of biologically effective dose (BED) to patients with Vestibular Schwannomas treated by radiosurgery.

In the application of stereotactic radiosurgery, using the Gamma Knife, there are large variations in the overall treatment time for the same prescription dose, given in a single treatment session, for different patients. This is due to not only changes in the activity of the Cobolt-60 sources, but also to variations in the number of iso-centers used, the collimator size for a particular iso-center, and the time gap between the different iso-centers. Although frequently viewed as a single dose treatment the concept of biologically effective dose (BED), incorporating concurrent fast and a slow components of repair of sublethal damage, would imply potential variations in BED because of the influence of these different variables associated with treatment. This was investigated in 26 patients, treated for Vestibular Schwannomas, using the Series B Gamma-Knife, between 1999 and 2005. The iso-center number varied between 2 and 13, and the overall treatment time from 25.4-129.58 min. The prescription doses varied from 10-14 Gy. To obtain physical dose and dose-rates from each iso-center, in a number of locations in the region of interest, a prototype version of the Leksell GammaPlan® was used. For an individual patient, BED values varied by up to 15% for a given physical iso-dose. This was due to variation in the dose prescription at different locations on that iso-dose. Between patients there was a decline in the range of BED values as the overall treatment time increased. This increased treatment time was partly a function of the slow decline in the activity of the sources with time but predominantly due to changes in the number of iso-centers used. Thus, variations in BED values did not correlate with prescription dose but was modified by the overall treatment time.

Radiobiological principles: their application to γ knife therapy.

Gamma Knife treatments are regarded as single dose exposures, however, in reality the total dose delivered is the addition of a variable number of individual smaller doses from the variable number of iso-centres or shots, selected to cover a lesion. The dose prescription, in terms of dose and dose rate, to different points on a given physical iso-surface, will vary according to location. In radiobiological terms this treatment pattern does not represent a single exposure, but a schedule with a variable number of different sized dose fractions given at different dose rates with multiple incompletes repair intervals (the time between shots). Using the concept of biologically effective dose (BED), incorporating a fast and a slow component of repair, the biological effectiveness of a 12-shot protocol was found to vary with the decay in the activity of the (60)Co sources and the time interval between shots. However, the largest effect was found when this standard protocol was compared with one involving only 2 shots. It should be recognised in individual Gamma Knife treatments that there are many variables which have the potential to influence the biological effective of the treatment and thus the importance of a single variable may be difficult to determine in isolation. Reports in the literature support the results of these simulated calculations into the factors likely to change the biologically effective dose with the use of the Gamma Knife.

Toward improving the therapeutic ratio in stereotactic radiosurgery: selective modulation of the radiation responses of both normal tissues and tumor.

A review of the radiobiological factors that influence the response of the brain to radiation is provided in relation to stereotactic radiosurgery (SRS). The prospects for intervention after radiation treatment to selectively modulate the expression of late central nervous system (CNS) injury is considered, as well as an account of recent interest in the use of radiation enhancers to selectively increase the response of tumors to radiation. Brain necrosis in humans, after conventional irradiation, indicates that the risk of necrosis increases rapidly after an equivalent single dose of 12 or 13 Gy. When single-dose treatments are extended due to 60Co decay or planned extension of treatment times, account should be taken of the effects of the repair of sublethal radiation damage to DNA on the efficacy of treatment. Both repair capacity and repair kinetics will also influence tumor control, but parameters to quantify this effect have not yet been established. The volume of CNS tissue that has been irradiated affects the tissue response, but this effect is only significant for volumes less than 0.05 cm3. The gain obtained from irradiation of small volumes is reduced, however, when focal irradiation is given within a wider field of irradiation. Based on a vascular hypothesis explaining the pathogenesis of late CNS damage, approaches designed to selectively modulate the frequency of late CNS damage have been validated. Given the high intrinsic radioresistance of some tumors, as opposed to the presence of hypoxia, an interest has developed in the use of selective radiation enhancers in the treatment of tumors. The compound presently available has proved to be disappointing clinically due to toxicity at effective doses, when repeated administration is required. However, when given at high single doses it is less toxic and may be more effective. Less toxic radiation enhancers need to be developed.