- Email: [email protected]
Tolerance of normal human brain to boron neutron capture therapy
ARTICLE IN PRESS
Applied Radiation and Isotopes 61 (2004) 1083–1087
Tolerance of normal human brain to boron neutron capture therapy J.A. Coderrea,*, J.W. Hopewellb, J.C. Turcottea, K.J. Rileyc, P.J. Binnsc, W.S. Kiger IIId, O.K. Harlinga a
Nuclear Engineering Department, Massachusetts Institute of Technology, 150 Albany Street, Cambridge, MA 02139, USA b Department of Clinical Oncology, The Churchill Hospital, Oxford OX3 7LJ, UK c Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA d Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Abstract Data from the Harvard–MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1 cm3) dose and average whole-brain dose show a steep dose–response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED507SE) were 6.271.0 Gy(w) for average wholebrain dose and 14.171.8 Gy(w) for peak brain dose. r 2004 Elsevier Ltd. All rights reserved. Keywords: BNCT; Brain; Tolerance; Somnolence syndrome
1. Introduction The initial boron neutron capture therapy (BNCT) clinical studies, using epithermal neutrons, were primarily for dose-escalation and safety. In these studies, a dose for BNCT was prescribed to a specific volume or critical region of the normal brain. In the clinical studies of BNCT conducted between 1994 and 1999, for patients with glioblastoma multiforme (GBM) at Brookhaven National Laboratory (BNL) and by the group at Harvard and the Massachusetts Institute of Technology (Harvard–MIT), the peak dose to a 1 cm3 volume of normal brain was escalated in a systematic way. As the dose escalation studies progressed, the treatments changed from a single-field irradiation or parallelopposed fields, to multiple non-coplanar irradiation fields arranged so as to maximize the dose to the tumor. *Corresponding author. Tel.: +1-617-452-3383. E-mail address: [email protected] (J.A. Coderre).
A consequence of this approach is a concomitant increase in the average dose to the normal brain. The initial BNCT clinical studies at BNL and Harvard–MIT, which have now been completed, involved the use of the amino acid analog p-boronophenylalanine (BPA) as the boron delivery agent and epithermal neutron beams (Busse et al., 2003; Diaz, 2003). In the first 37 patients treated at BNL, the incidence of side effects was minimal and the patterns of local control and the time to progression were similar to those of conventional radiotherapy (Chanana et al., 1999). In the subsequent higher dose groups, where patients were treated with three fields, the incidence of side effects, in particular CNS side effects, increased; some patients developed a subacute toxicity known as the somnolence syndrome. The somnolence syndrome is a poorly understood complication in patients receiving cranial irradiation (Faithfull and Brada, 1998). The clinical signs include a tiredness, drowsiness and fatigue that shows onset B1–3 weeks after the irradiation. The syndrome
0969-8043/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.apradiso.2004.05.009
ARTICLE IN PRESS J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
lasts for a period of weeks and generally resolves. In patients with GBM, somnolence may be hard to distinguish from the symptoms of tumor re-growth. The diagnosis can be subjective and is often made retrospectively after it becomes apparent that the cause was the radiation and not recurrent tumor. Somnolence is not a well-defined endpoint and is not generally considered to be a major complication after conventional radiation therapy and is considered to be acceptable in patients undergoing conventional radiation therapy to the brain. Somnolence is observed in >50% of pediatric patients undergoing craniospinal irradiation as part of a bone marrow ablation protocol for treatment of lymphoma or leukemia (Ryan, 2000). A recent physical dosimetry inter-comparison of the Brookhaven Medical Research Reactor and the MIT reactor-based epithermal neutron beams now provides a basis for combining the clinical data from the two studies for further analysis. Systematic differences between the methodology for photon dosimetry used at BNL (thermoluminescent dosimeters) and at Harvard–MIT (ionization chambers) have been identified and quantified (Riley et al., 2002). The photon component of the calculated peak brain doses and average whole-brain doses in the BNL patients have now been normalized to measurements made using the MIT methodology. In this report, the combined BNL and Harvard–MIT series of patients are analyzed, providing the most complete data set yet reported for the estimation of brain tolerance to the complex mixture of radiation components produced during BNCT.
2. Materials and methods Published data for peak and average whole-brain doses to patients receiving BNCT at BNL and Harvard– MIT have been combined and analyzed. The gamma-ray component of the BNL doses to brain have been lowered by 20%, based on the analysis of a dosimetry interchange described by (Riley et al., 2002). All brain doses are expressed in weighted (Gy(w)) units using RBE and CBE factors reported previously (Coderre and Morris, 1999; Coderre et al., 2003). Briefly, the CBE factor for BPA in normal brain is 1.3; the RBE used for the fast neutron and thermal neutron dose components is 3.2. At Harvard–MIT, a dose reduction factor (DRF) of 0.5 was applied to the gamma-ray dose component to brain due to the low dose-rate of gamma-rays in this beam (Palmer et al., 2002). No DRF was applied for the low dose rate gamma-rays in the BNL beam. A total of 53 patients were entered into a series of dose-escalation protocols at BNL between 1994 and 1999 (Chanana et al., 1999; Diaz, 2003). All but one of these patients had gross or subtotal tumor resection, 3–5 weeks prior to BNCT. The patients all received BPA,
solubilized with fructose (BPA-F), as a 2-h i.v. infusion. The radiation dose was escalated in several ways: (1) by increasing the peak dose (maximum dose to 1 cm3 of brain) from 8.4 to 14.8 Gy(w), (2) by increasing the number of radiation fields from 1 to 3 (Fig. 1), and (3) by increasing the amount of BPA infused, from 250, to 290, to 330 mg/kg body weight. This increased the 10B concentrations in blood from 12 to 16 mg/g at the time of irradiation. The increased number of radiation fields proved to be the major reason for the increases in the average whole-brain dose, which ranged from as low as 1.8 Gy(w) with one-field technique to as high as 8.5 Gy(w) using 3 fields (Fig. 1). In the period between 1994 and 1999, researchers at Harvard–MIT carried out similar clinical studies for patients with glioblastoma, melanoma metastatic to the brain, or subcutaneous melanoma of the extremities (Palmer et al., 2002; Busse et al., 2003). Twenty-four patients were treated with escalating doses: 18 glioblastomas, 2 intracranial melanomas, and 4 subcutaneous melanomas. A significant difference from the BNL study was the use of two fractions on consecutive days; this required a second BPA infusion for the second dose. Their rationale for the two-fraction approach was: (1) the second BPA administration could lead to a redistribution of boron into tumor cells missed on the first fraction, i.e. an attempt to improve the uniformity of tumor cell kill, (2) to provide some sparing of normal brain by fractionation of the photon component of the dose and (3) as the doses were escalated, the irradiation times in the MITR-II M67 beam became excessively long (2–3 h per field compared to 20–40 min per field at BNL): splitting the treatment into two fractions was a major practical consideration for the patients. BPA was delivered at escalating doses of 250, 300 and 350 mg/kg, administered i.v., over 60, 90 and 90 min, respectively,
100
80
% Brain Volume
1084
2 fields
60
3 fields
40
20 1 field 0 0
2
4
6
8
10
12
14
16
Dose (Gy(w))
Fig. 1. Representative dose volume histograms for patients treated at BNL with either 1, 2 or 3 fields. Reproduced from Coderre et al. (2003), with permission from Adenine Press.
ARTICLE IN PRESS J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
3. Results The reports from both the Harvard-MIT and the BNL studies indicate that the use of BNCT on residual tumor volumes of X60 cm3 leads to a greater incidence of neurological toxicity associated with increased intracranial pressure (Chanana et al., 1999; Busse et al., 2003), but this is an acute effect related to tumor cell killing and the associated edema. Other than side effects related to the residual tumor volume, the most commonly observed neurological side effect was a somnolence syndrome. Somnolence was observed in patients treated with BNCT in both the BNL and the Harvard–MIT studies. The median age of the patients treated at Harvard–MIT and at BNL was the same: 56 years (Busse et al., 2003; Diaz, 2003). There was no apparent correlation between age and the incidence of the somnolence syndrome. The combined data for 68 evaluable patients from the Harvard–MIT and BNL BNCT clinical studies are shown in Fig. 2. The data are plotted as peak dose versus average whole-brain dose. Dose escalations in both studies involved incremental increases in the peak dose as well as a progression from a 1-field to a 3-field treatment. The solid symbols represent patients who were diagnosed as having the somnolence syndrome. It is clear that neither the peak dose nor the average whole-brain dose is totally
100
somnolence probability (%)
producing 10B concentrations in blood during irradiation of 10–15 mg/g (Kiger III et al., 2001). In the GBM patients treated in the Harvard–MIT study, the peak brain doses ranged from 8.7 to 16.4 Gy(w), and the average whole-brain doses from 2.7 to 7.4 Gy(w) (Palmer et al., 2002).
1085
80
60
40
Average Brain Dose
20 ........
Peak Brain Dose 95% confidence
0 0
5
10
15
20
25
Dose (Gy(w))
Fig. 3. Dose-related changes in the probability of developing a somnolence syndrome. Dose is expressed as either the average brain or peak brain dose. The doses associated with a 50% incidence of the effect (ED507SE) were 6.271.0 Gy(w) and 14.171.8 Gy(w) for the average brain dose and peak brain dose, respectively. These data represent the combined results from 68 patients in both the BNL and the Harvard–MIT clinical studies.
predictive for the development of somnolence. However, average whole-brain doses in the range of 5–7 Gy(w) do seem to mark the threshold for the development of somnolence. When the data are re-plotted to indicate the variation in the incidence of patients developing the somnolence syndrome as a function of either the peak or the average whole-brain dose (Fig. 3) a clear dose effect relationship is seen. When these data are fitted by probit analysis the doses associated with a 50% incidence of the effect (ED507SE) were calculated. These were 6.271.0 and 14.171.8 Gy(w) for the average whole-brain doses and peak brain doses, respectively.
18 BNL BNL with somnolence MIT MIT with somnolence
Peak Dose (Gy(w))
16
4. Discussion
14
12
10
8
6 1
2
3
4
5
6
7
8
9
Average Whole-Brain Dose (Gy(w))
Fig. 2. Average whole-brain dose versus peak dose for the patients treated in the BNL and Harvard–MIT BNCT studies. Solid symbols denote those patients that developed a somnolence syndrome. Reproduced from Coderre et al. (2003), with permission from Adenine Press.
The frequently adopted endpoint for brain tolerance in humans to conventional photon radiation therapy is the development of necrosis. It is well accepted in the radiotherapy literature that brain tolerance depends critically on the dose, the fractionated irradiation schedule and the volume of the brain receiving that dose. In a widely quoted survey of literature on normal tissue tolerance, Emami lists brain tolerance doses to conventional fractionated therapy (2 Gy per fraction) as total doses (TD) producing e.g. 5% or 50% incidence of necrosis within 5 years (TD5/5, TD50/5) as follows (Emami et al., 1991): 1=3 brain volume irradiated : TD5=5 ¼ 60 Gy; TD50=5 ¼ 75 Gy; 2=3 brain volume irradiated : TD5=5 ¼ 50 Gy; TD50=5 ¼ 65 Gy; 3=3 brain volume irradiated : TD5=5 ¼ 45 Gy; TD50=5 ¼ 60 Gy:
ARTICLE IN PRESS 1086
J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
Different photon radiotherapy dose fractionation schemes can be compared by converting them to a biologically effective dose (BED) according to the rearranged linear quadratic formalism, BED ¼ nd½1 þ d=ða=bÞ; where ‘n’ is the number of fractions, ‘d’ is the dose per fraction, and the a=b ratio is a tissue-specific parameter (Thames and Hendry, 1987). For normal CNS tissue, a value of 2 Gy is frequently accepted for the a=b ratio (van der Kogel, 1991). The above formula allows the singledose equivalent of various fractionated photon irradiation dose schedules to be calculated for comparison with BNCT doses. Assuming that the fractionated doses are delivered in 30 fractions, and using an a=b ratio of 2 Gy (van der Kogel, 1991) in the calculation, the TD5/5 dose of 60 Gy to 1/3 of the brain volume is equivalent to a single dose of 14.5 Gy of photons and the TD5/5 dose of 45 Gy to 3/3 of the brain volume is equivalent to a single dose of 11.6 Gy of photons. Patients undergoing total-body irradiation as part of the conditioning regimen prior to bone marrow transplantation receive doses between 9 and 15 Gy in various fractionation schedules. For instance, six fractions of 2 Gy to the whole brain, delivered over 3 days, or twelve fractions of 1.2 Gy given over 4 days, are well tolerated and correspond to single, uniform wholebrain doses of 6 and 5.8 Gy of photons, respectively (Wenz et al., 2000; Wheldon and Barrett, 2001). The proportion of brain tissue irradiated has been shown to be a determining factor in the development of late side effects (Emami et al., 1991; Flickinger et al., 2000). Flickinger et al. analyzed the risks of brain necrosis following stereotactic radiosurgery for arteriovenous malformations (Flickinger et al., 2000). In this multivariate analysis, the two most important predictive factors were tumor location and the volume of normal brain receiving a single dose greater than 12 Gy. For lesions with parietal and temporal locations in the brain, when brain volumes of 20–30 cm3 are irradiated with doses of X12 Gy, there is approximately a 5% incidence of brain necrosis. There are not sufficient data from BNCT patients that developed somnolence to attempt this type of analysis, and though similar, in that both treatments are delivered in a single dose, the overall dose/volume relationships are very different between stereotactic radiosurgery and BNCT. In addition, these authors cautioned, ‘‘Extrapolating these findings to treatment of other targets and/or with other techniques (especially more homogeneous dose distributions with doses near 12 Gy) is likely to be unreliable.’’ However, there does appear to be a case to suggest that the incidence of somnolence in the patients treated with BNCT at BNL and Harvard–MIT is in some way related to the irradiated volume. In the BNL study, average whole-brain doses were higher than those in the Harvard–MIT trial (Fig. 2). In the highest dose group in
the BNL study, those treated with 3 fields, the incidence of somnolence was 7/7. In the Harvard–MIT series, of the three patients that developed the somnolence syndrome, one patient received the highest average whole-brain dose of the entire series, but the other two patients who developed somnolence received lower doses than a number of patients that did not develop somnolence, so the issue is not as clear-cut as it appears to be in the BNL data and could be related to the extent of the follow-up data for each particular patient. Peak dose does not appear to be the critical factor in the development of somnolence (Fig. 2). On the other hand, average wholebrain doses above about 5.5 Gy(w) are associated with somnolence in the BNL patients, but not in all cases in the Harvard–MIT patients. However, peak and average whole-brain doses do appear to be related to the incidence of the neurological side effect somnolence, but both, and in particular averaged whole-brain doses in BNCT mask much important information. All of the published photon data related to brain tolerance cited above are for a relatively uniformly delivered dose to the specified brain volume. Whole-brain doses in BNCT are not uniform (see Fig. 1) and calculation of average whole-brain doses are misleading, these averaged doses should be used with caution in comparison to more uniformly delivered photon data. It is necessary to examine the dose volume histograms (DVHs) for normal brain in BNCT treatments using 1, 2, or 3 fields and in particular for those associated with a somnolence syndrome. Representative dose volume histograms shown in Fig. 1 illustrate how the number of treatment fields is the major factor in determining the average whole-brain dose. However, even the most uniformly delivered BNCT treatment (three fields) still represents a wide range of doses. The three-field DVH shown in Fig. 1 represents an average whole brain dose of approximately 7 Gy(w) but the doses delivered to this brain range from 2 to 13.5 Gy(w). In such a situation, a value of 7 Gy(w) for the average dose is of little biological relevance. The neurological side effect (somnolence) in such a patient will most likely be determined by the dose received by a smaller volume of brain, analogous to the stereotactic radiosurgery data for brain necrosis (Flickinger et al., 2000). In all of the BNCT patients that developed a somnolence syndrome, a significant volume of brain received a dose in excess of 10 Gy(w), indeed, in some of these patients as much as 10% of the brain volume received a dose greater than 12 Gy(w). The relationship between the risk of developing somnolence and volume (or region) of brain irradiated is not certain in the literature relating to conventional photon irradiation.
5. Conclusions The two completed clinical studies described have demonstrated that BNCT can be delivered safely to
ARTICLE IN PRESS J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
patients with brain tumors. Normal brain tolerance, defined as the development of somnolence, has been defined. The average brain doses are relatively low, which opens the possibility of future studies with combination therapies. Other results from ongoing clinical studies of BNCT should eventually be included in the combined analysis described here for the patients treated at BNL and Harvard–MIT.
Acknowledgements Supported, in part, by the Norman C. Rasmussen Career Development Award, Department of Nuclear Engineering, Massachusetts Institute of Technology to JAC.
References Busse, P.M., Harling, O.K., Palmer, M.R., Kiger III, W.S., Kaplan, J., Kaplan, I., Chuang, C.F., Goorley, J.T., Riley, K.J., Newton, T.H., Santa Cruz, G.A., Lu, X.Q., Zamenhof, R.G., 2003. A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease. J. Neurooncol. 62, 111–121. Chanana, A.D., Capala, J., Chadha, M., Coderre, J.A., Diaz, A.Z., Elowitz, E.H., Iwai, J., Joel, D.D., Liu, H.B., Ma, R., Pendzick, N., Peress, N.S., Shady, M.S., Slatkin, D.N., Tyson, G.W., Wielopolski, L., 1999. Boron neutron capture therapy for glioblastoma multiforme: Interim results from the phase I/II dose-escalation studies. Neurosurgery 44, 1182–1193. Coderre, J.A., Morris, G.M., 1999. The radiation biology of boron neutron capture therapy. Radiat. Res. 151, 1–18. Coderre, J.A., Turcotte, J.C., Riley, K.J., Binns, P.J., Harling, O.K., Kiger III, W.S., 2003. Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation. Technol. Cancer Res. Treatment 2, 355–375. Diaz, A.Z., 2003. Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven
1087
National Laboratory from a clinician’s point of view. J. Neurooncol. 62, 101–109. Emami, B., Lyman, J., Brown, A., Coia, L., Goitein, M., Munzenrider, J.E., Shank, B., Solin, L.J., Wesson, M., 1991. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21, 109–122. Faithfull, S., Brada, M., 1998. Somnolence syndrome in adults following cranial irradiation for primary brain tumors. Clin. Oncol. 10, 250–254. Flickinger, J.C., Kondziolka, D., Lunsford, L.D., Kassam, A., Phuong, L.K., Liscak, R., Pollock, B., 2000. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous malformation radiosurgery study group. Int. J. Radiat. Oncol. Biol. Phys. 46, 1143–1148. Kiger III, W.S., Palmer, M.R., Riley, K.J., Zamenhof, R.G., Busse, P.M., 2001. A pharmacokinetic model for the concentration of 10B in blood after boronophenylalaninefructose administration in humans. Radiat. Res. 155, 611–618. Palmer, M.R., Goorley, J.T., Kiger III, W.S., Busse, P.M., Riley, K.J., Harling, O.K., Zamenhof, R.G., 2002. Treatment planning and dosimetry for the Harvard–MIT Phase I clinical trial of cranial neutron capture therapy. Int. J. Radiat. Oncol. Biol. Phys. 53, 1361–1379. Riley, K.J., Binns, P.J., Greenberg, D.D., Harling, O.K., 2002. A physical dosimetry intercomparison for BNCT. Med. Phys. 29, 898–904. Ryan, J., 2000. Radiation somnolence syndrome. J. Pediatr. Oncol. Nurs. 17, 50–53. Thames, H.D., Hendry, J.H., 1987. Radiobiological guide for radiotherapists. Fractionation in Radiotherapy. Taylor & Francis, Philadelphia, pp. 229–230. van der Kogel, A.J., 1991. Central nervous system radiation injury in small animal models. In: Gutin, P.H., Leibel, S.A., Sheline, G.E. (Eds.), Radiation Injury to the Nervous System. Raven Press, New York, pp. 91–111. Wenz, F., Steinvorth, S., Lohr, F., Fruehauf, S., Wildermuth, S., van Kampen, M., Wannenmacher, M., 2000. Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI). Int. J. Radiat. Oncol. Biol. Phys. 48, 1497–1501. Wheldon, T.E., Barrett, A., 2001. Radiobiological modelling of the treatment of leukaemia by total body irradiation. Radiother. Oncol. 58, 227–233.
Applied Radiation and Isotopes 61 (2004) 1083–1087
Tolerance of normal human brain to boron neutron capture therapy J.A. Coderrea,*, J.W. Hopewellb, J.C. Turcottea, K.J. Rileyc, P.J. Binnsc, W.S. Kiger IIId, O.K. Harlinga a
Nuclear Engineering Department, Massachusetts Institute of Technology, 150 Albany Street, Cambridge, MA 02139, USA b Department of Clinical Oncology, The Churchill Hospital, Oxford OX3 7LJ, UK c Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA d Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Abstract Data from the Harvard–MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1 cm3) dose and average whole-brain dose show a steep dose–response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED507SE) were 6.271.0 Gy(w) for average wholebrain dose and 14.171.8 Gy(w) for peak brain dose. r 2004 Elsevier Ltd. All rights reserved. Keywords: BNCT; Brain; Tolerance; Somnolence syndrome
1. Introduction The initial boron neutron capture therapy (BNCT) clinical studies, using epithermal neutrons, were primarily for dose-escalation and safety. In these studies, a dose for BNCT was prescribed to a specific volume or critical region of the normal brain. In the clinical studies of BNCT conducted between 1994 and 1999, for patients with glioblastoma multiforme (GBM) at Brookhaven National Laboratory (BNL) and by the group at Harvard and the Massachusetts Institute of Technology (Harvard–MIT), the peak dose to a 1 cm3 volume of normal brain was escalated in a systematic way. As the dose escalation studies progressed, the treatments changed from a single-field irradiation or parallelopposed fields, to multiple non-coplanar irradiation fields arranged so as to maximize the dose to the tumor. *Corresponding author. Tel.: +1-617-452-3383. E-mail address: [email protected] (J.A. Coderre).
A consequence of this approach is a concomitant increase in the average dose to the normal brain. The initial BNCT clinical studies at BNL and Harvard–MIT, which have now been completed, involved the use of the amino acid analog p-boronophenylalanine (BPA) as the boron delivery agent and epithermal neutron beams (Busse et al., 2003; Diaz, 2003). In the first 37 patients treated at BNL, the incidence of side effects was minimal and the patterns of local control and the time to progression were similar to those of conventional radiotherapy (Chanana et al., 1999). In the subsequent higher dose groups, where patients were treated with three fields, the incidence of side effects, in particular CNS side effects, increased; some patients developed a subacute toxicity known as the somnolence syndrome. The somnolence syndrome is a poorly understood complication in patients receiving cranial irradiation (Faithfull and Brada, 1998). The clinical signs include a tiredness, drowsiness and fatigue that shows onset B1–3 weeks after the irradiation. The syndrome
0969-8043/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.apradiso.2004.05.009
ARTICLE IN PRESS J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
lasts for a period of weeks and generally resolves. In patients with GBM, somnolence may be hard to distinguish from the symptoms of tumor re-growth. The diagnosis can be subjective and is often made retrospectively after it becomes apparent that the cause was the radiation and not recurrent tumor. Somnolence is not a well-defined endpoint and is not generally considered to be a major complication after conventional radiation therapy and is considered to be acceptable in patients undergoing conventional radiation therapy to the brain. Somnolence is observed in >50% of pediatric patients undergoing craniospinal irradiation as part of a bone marrow ablation protocol for treatment of lymphoma or leukemia (Ryan, 2000). A recent physical dosimetry inter-comparison of the Brookhaven Medical Research Reactor and the MIT reactor-based epithermal neutron beams now provides a basis for combining the clinical data from the two studies for further analysis. Systematic differences between the methodology for photon dosimetry used at BNL (thermoluminescent dosimeters) and at Harvard–MIT (ionization chambers) have been identified and quantified (Riley et al., 2002). The photon component of the calculated peak brain doses and average whole-brain doses in the BNL patients have now been normalized to measurements made using the MIT methodology. In this report, the combined BNL and Harvard–MIT series of patients are analyzed, providing the most complete data set yet reported for the estimation of brain tolerance to the complex mixture of radiation components produced during BNCT.
2. Materials and methods Published data for peak and average whole-brain doses to patients receiving BNCT at BNL and Harvard– MIT have been combined and analyzed. The gamma-ray component of the BNL doses to brain have been lowered by 20%, based on the analysis of a dosimetry interchange described by (Riley et al., 2002). All brain doses are expressed in weighted (Gy(w)) units using RBE and CBE factors reported previously (Coderre and Morris, 1999; Coderre et al., 2003). Briefly, the CBE factor for BPA in normal brain is 1.3; the RBE used for the fast neutron and thermal neutron dose components is 3.2. At Harvard–MIT, a dose reduction factor (DRF) of 0.5 was applied to the gamma-ray dose component to brain due to the low dose-rate of gamma-rays in this beam (Palmer et al., 2002). No DRF was applied for the low dose rate gamma-rays in the BNL beam. A total of 53 patients were entered into a series of dose-escalation protocols at BNL between 1994 and 1999 (Chanana et al., 1999; Diaz, 2003). All but one of these patients had gross or subtotal tumor resection, 3–5 weeks prior to BNCT. The patients all received BPA,
solubilized with fructose (BPA-F), as a 2-h i.v. infusion. The radiation dose was escalated in several ways: (1) by increasing the peak dose (maximum dose to 1 cm3 of brain) from 8.4 to 14.8 Gy(w), (2) by increasing the number of radiation fields from 1 to 3 (Fig. 1), and (3) by increasing the amount of BPA infused, from 250, to 290, to 330 mg/kg body weight. This increased the 10B concentrations in blood from 12 to 16 mg/g at the time of irradiation. The increased number of radiation fields proved to be the major reason for the increases in the average whole-brain dose, which ranged from as low as 1.8 Gy(w) with one-field technique to as high as 8.5 Gy(w) using 3 fields (Fig. 1). In the period between 1994 and 1999, researchers at Harvard–MIT carried out similar clinical studies for patients with glioblastoma, melanoma metastatic to the brain, or subcutaneous melanoma of the extremities (Palmer et al., 2002; Busse et al., 2003). Twenty-four patients were treated with escalating doses: 18 glioblastomas, 2 intracranial melanomas, and 4 subcutaneous melanomas. A significant difference from the BNL study was the use of two fractions on consecutive days; this required a second BPA infusion for the second dose. Their rationale for the two-fraction approach was: (1) the second BPA administration could lead to a redistribution of boron into tumor cells missed on the first fraction, i.e. an attempt to improve the uniformity of tumor cell kill, (2) to provide some sparing of normal brain by fractionation of the photon component of the dose and (3) as the doses were escalated, the irradiation times in the MITR-II M67 beam became excessively long (2–3 h per field compared to 20–40 min per field at BNL): splitting the treatment into two fractions was a major practical consideration for the patients. BPA was delivered at escalating doses of 250, 300 and 350 mg/kg, administered i.v., over 60, 90 and 90 min, respectively,
100
80
% Brain Volume
1084
2 fields
60
3 fields
40
20 1 field 0 0
2
4
6
8
10
12
14
16
Dose (Gy(w))
Fig. 1. Representative dose volume histograms for patients treated at BNL with either 1, 2 or 3 fields. Reproduced from Coderre et al. (2003), with permission from Adenine Press.
ARTICLE IN PRESS J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
3. Results The reports from both the Harvard-MIT and the BNL studies indicate that the use of BNCT on residual tumor volumes of X60 cm3 leads to a greater incidence of neurological toxicity associated with increased intracranial pressure (Chanana et al., 1999; Busse et al., 2003), but this is an acute effect related to tumor cell killing and the associated edema. Other than side effects related to the residual tumor volume, the most commonly observed neurological side effect was a somnolence syndrome. Somnolence was observed in patients treated with BNCT in both the BNL and the Harvard–MIT studies. The median age of the patients treated at Harvard–MIT and at BNL was the same: 56 years (Busse et al., 2003; Diaz, 2003). There was no apparent correlation between age and the incidence of the somnolence syndrome. The combined data for 68 evaluable patients from the Harvard–MIT and BNL BNCT clinical studies are shown in Fig. 2. The data are plotted as peak dose versus average whole-brain dose. Dose escalations in both studies involved incremental increases in the peak dose as well as a progression from a 1-field to a 3-field treatment. The solid symbols represent patients who were diagnosed as having the somnolence syndrome. It is clear that neither the peak dose nor the average whole-brain dose is totally
100
somnolence probability (%)
producing 10B concentrations in blood during irradiation of 10–15 mg/g (Kiger III et al., 2001). In the GBM patients treated in the Harvard–MIT study, the peak brain doses ranged from 8.7 to 16.4 Gy(w), and the average whole-brain doses from 2.7 to 7.4 Gy(w) (Palmer et al., 2002).
1085
80
60
40
Average Brain Dose
20 ........
Peak Brain Dose 95% confidence
0 0
5
10
15
20
25
Dose (Gy(w))
Fig. 3. Dose-related changes in the probability of developing a somnolence syndrome. Dose is expressed as either the average brain or peak brain dose. The doses associated with a 50% incidence of the effect (ED507SE) were 6.271.0 Gy(w) and 14.171.8 Gy(w) for the average brain dose and peak brain dose, respectively. These data represent the combined results from 68 patients in both the BNL and the Harvard–MIT clinical studies.
predictive for the development of somnolence. However, average whole-brain doses in the range of 5–7 Gy(w) do seem to mark the threshold for the development of somnolence. When the data are re-plotted to indicate the variation in the incidence of patients developing the somnolence syndrome as a function of either the peak or the average whole-brain dose (Fig. 3) a clear dose effect relationship is seen. When these data are fitted by probit analysis the doses associated with a 50% incidence of the effect (ED507SE) were calculated. These were 6.271.0 and 14.171.8 Gy(w) for the average whole-brain doses and peak brain doses, respectively.
18 BNL BNL with somnolence MIT MIT with somnolence
Peak Dose (Gy(w))
16
4. Discussion
14
12
10
8
6 1
2
3
4
5
6
7
8
9
Average Whole-Brain Dose (Gy(w))
Fig. 2. Average whole-brain dose versus peak dose for the patients treated in the BNL and Harvard–MIT BNCT studies. Solid symbols denote those patients that developed a somnolence syndrome. Reproduced from Coderre et al. (2003), with permission from Adenine Press.
The frequently adopted endpoint for brain tolerance in humans to conventional photon radiation therapy is the development of necrosis. It is well accepted in the radiotherapy literature that brain tolerance depends critically on the dose, the fractionated irradiation schedule and the volume of the brain receiving that dose. In a widely quoted survey of literature on normal tissue tolerance, Emami lists brain tolerance doses to conventional fractionated therapy (2 Gy per fraction) as total doses (TD) producing e.g. 5% or 50% incidence of necrosis within 5 years (TD5/5, TD50/5) as follows (Emami et al., 1991): 1=3 brain volume irradiated : TD5=5 ¼ 60 Gy; TD50=5 ¼ 75 Gy; 2=3 brain volume irradiated : TD5=5 ¼ 50 Gy; TD50=5 ¼ 65 Gy; 3=3 brain volume irradiated : TD5=5 ¼ 45 Gy; TD50=5 ¼ 60 Gy:
ARTICLE IN PRESS 1086
J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
Different photon radiotherapy dose fractionation schemes can be compared by converting them to a biologically effective dose (BED) according to the rearranged linear quadratic formalism, BED ¼ nd½1 þ d=ða=bÞ; where ‘n’ is the number of fractions, ‘d’ is the dose per fraction, and the a=b ratio is a tissue-specific parameter (Thames and Hendry, 1987). For normal CNS tissue, a value of 2 Gy is frequently accepted for the a=b ratio (van der Kogel, 1991). The above formula allows the singledose equivalent of various fractionated photon irradiation dose schedules to be calculated for comparison with BNCT doses. Assuming that the fractionated doses are delivered in 30 fractions, and using an a=b ratio of 2 Gy (van der Kogel, 1991) in the calculation, the TD5/5 dose of 60 Gy to 1/3 of the brain volume is equivalent to a single dose of 14.5 Gy of photons and the TD5/5 dose of 45 Gy to 3/3 of the brain volume is equivalent to a single dose of 11.6 Gy of photons. Patients undergoing total-body irradiation as part of the conditioning regimen prior to bone marrow transplantation receive doses between 9 and 15 Gy in various fractionation schedules. For instance, six fractions of 2 Gy to the whole brain, delivered over 3 days, or twelve fractions of 1.2 Gy given over 4 days, are well tolerated and correspond to single, uniform wholebrain doses of 6 and 5.8 Gy of photons, respectively (Wenz et al., 2000; Wheldon and Barrett, 2001). The proportion of brain tissue irradiated has been shown to be a determining factor in the development of late side effects (Emami et al., 1991; Flickinger et al., 2000). Flickinger et al. analyzed the risks of brain necrosis following stereotactic radiosurgery for arteriovenous malformations (Flickinger et al., 2000). In this multivariate analysis, the two most important predictive factors were tumor location and the volume of normal brain receiving a single dose greater than 12 Gy. For lesions with parietal and temporal locations in the brain, when brain volumes of 20–30 cm3 are irradiated with doses of X12 Gy, there is approximately a 5% incidence of brain necrosis. There are not sufficient data from BNCT patients that developed somnolence to attempt this type of analysis, and though similar, in that both treatments are delivered in a single dose, the overall dose/volume relationships are very different between stereotactic radiosurgery and BNCT. In addition, these authors cautioned, ‘‘Extrapolating these findings to treatment of other targets and/or with other techniques (especially more homogeneous dose distributions with doses near 12 Gy) is likely to be unreliable.’’ However, there does appear to be a case to suggest that the incidence of somnolence in the patients treated with BNCT at BNL and Harvard–MIT is in some way related to the irradiated volume. In the BNL study, average whole-brain doses were higher than those in the Harvard–MIT trial (Fig. 2). In the highest dose group in
the BNL study, those treated with 3 fields, the incidence of somnolence was 7/7. In the Harvard–MIT series, of the three patients that developed the somnolence syndrome, one patient received the highest average whole-brain dose of the entire series, but the other two patients who developed somnolence received lower doses than a number of patients that did not develop somnolence, so the issue is not as clear-cut as it appears to be in the BNL data and could be related to the extent of the follow-up data for each particular patient. Peak dose does not appear to be the critical factor in the development of somnolence (Fig. 2). On the other hand, average wholebrain doses above about 5.5 Gy(w) are associated with somnolence in the BNL patients, but not in all cases in the Harvard–MIT patients. However, peak and average whole-brain doses do appear to be related to the incidence of the neurological side effect somnolence, but both, and in particular averaged whole-brain doses in BNCT mask much important information. All of the published photon data related to brain tolerance cited above are for a relatively uniformly delivered dose to the specified brain volume. Whole-brain doses in BNCT are not uniform (see Fig. 1) and calculation of average whole-brain doses are misleading, these averaged doses should be used with caution in comparison to more uniformly delivered photon data. It is necessary to examine the dose volume histograms (DVHs) for normal brain in BNCT treatments using 1, 2, or 3 fields and in particular for those associated with a somnolence syndrome. Representative dose volume histograms shown in Fig. 1 illustrate how the number of treatment fields is the major factor in determining the average whole-brain dose. However, even the most uniformly delivered BNCT treatment (three fields) still represents a wide range of doses. The three-field DVH shown in Fig. 1 represents an average whole brain dose of approximately 7 Gy(w) but the doses delivered to this brain range from 2 to 13.5 Gy(w). In such a situation, a value of 7 Gy(w) for the average dose is of little biological relevance. The neurological side effect (somnolence) in such a patient will most likely be determined by the dose received by a smaller volume of brain, analogous to the stereotactic radiosurgery data for brain necrosis (Flickinger et al., 2000). In all of the BNCT patients that developed a somnolence syndrome, a significant volume of brain received a dose in excess of 10 Gy(w), indeed, in some of these patients as much as 10% of the brain volume received a dose greater than 12 Gy(w). The relationship between the risk of developing somnolence and volume (or region) of brain irradiated is not certain in the literature relating to conventional photon irradiation.
5. Conclusions The two completed clinical studies described have demonstrated that BNCT can be delivered safely to
ARTICLE IN PRESS J.A. Coderre et al. / Applied Radiation and Isotopes 61 (2004) 1083–1087
patients with brain tumors. Normal brain tolerance, defined as the development of somnolence, has been defined. The average brain doses are relatively low, which opens the possibility of future studies with combination therapies. Other results from ongoing clinical studies of BNCT should eventually be included in the combined analysis described here for the patients treated at BNL and Harvard–MIT.
Acknowledgements Supported, in part, by the Norman C. Rasmussen Career Development Award, Department of Nuclear Engineering, Massachusetts Institute of Technology to JAC.
References Busse, P.M., Harling, O.K., Palmer, M.R., Kiger III, W.S., Kaplan, J., Kaplan, I., Chuang, C.F., Goorley, J.T., Riley, K.J., Newton, T.H., Santa Cruz, G.A., Lu, X.Q., Zamenhof, R.G., 2003. A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease. J. Neurooncol. 62, 111–121. Chanana, A.D., Capala, J., Chadha, M., Coderre, J.A., Diaz, A.Z., Elowitz, E.H., Iwai, J., Joel, D.D., Liu, H.B., Ma, R., Pendzick, N., Peress, N.S., Shady, M.S., Slatkin, D.N., Tyson, G.W., Wielopolski, L., 1999. Boron neutron capture therapy for glioblastoma multiforme: Interim results from the phase I/II dose-escalation studies. Neurosurgery 44, 1182–1193. Coderre, J.A., Morris, G.M., 1999. The radiation biology of boron neutron capture therapy. Radiat. Res. 151, 1–18. Coderre, J.A., Turcotte, J.C., Riley, K.J., Binns, P.J., Harling, O.K., Kiger III, W.S., 2003. Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation. Technol. Cancer Res. Treatment 2, 355–375. Diaz, A.Z., 2003. Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven
1087
National Laboratory from a clinician’s point of view. J. Neurooncol. 62, 101–109. Emami, B., Lyman, J., Brown, A., Coia, L., Goitein, M., Munzenrider, J.E., Shank, B., Solin, L.J., Wesson, M., 1991. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21, 109–122. Faithfull, S., Brada, M., 1998. Somnolence syndrome in adults following cranial irradiation for primary brain tumors. Clin. Oncol. 10, 250–254. Flickinger, J.C., Kondziolka, D., Lunsford, L.D., Kassam, A., Phuong, L.K., Liscak, R., Pollock, B., 2000. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous malformation radiosurgery study group. Int. J. Radiat. Oncol. Biol. Phys. 46, 1143–1148. Kiger III, W.S., Palmer, M.R., Riley, K.J., Zamenhof, R.G., Busse, P.M., 2001. A pharmacokinetic model for the concentration of 10B in blood after boronophenylalaninefructose administration in humans. Radiat. Res. 155, 611–618. Palmer, M.R., Goorley, J.T., Kiger III, W.S., Busse, P.M., Riley, K.J., Harling, O.K., Zamenhof, R.G., 2002. Treatment planning and dosimetry for the Harvard–MIT Phase I clinical trial of cranial neutron capture therapy. Int. J. Radiat. Oncol. Biol. Phys. 53, 1361–1379. Riley, K.J., Binns, P.J., Greenberg, D.D., Harling, O.K., 2002. A physical dosimetry intercomparison for BNCT. Med. Phys. 29, 898–904. Ryan, J., 2000. Radiation somnolence syndrome. J. Pediatr. Oncol. Nurs. 17, 50–53. Thames, H.D., Hendry, J.H., 1987. Radiobiological guide for radiotherapists. Fractionation in Radiotherapy. Taylor & Francis, Philadelphia, pp. 229–230. van der Kogel, A.J., 1991. Central nervous system radiation injury in small animal models. In: Gutin, P.H., Leibel, S.A., Sheline, G.E. (Eds.), Radiation Injury to the Nervous System. Raven Press, New York, pp. 91–111. Wenz, F., Steinvorth, S., Lohr, F., Fruehauf, S., Wildermuth, S., van Kampen, M., Wannenmacher, M., 2000. Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI). Int. J. Radiat. Oncol. Biol. Phys. 48, 1497–1501. Wheldon, T.E., Barrett, A., 2001. Radiobiological modelling of the treatment of leukaemia by total body irradiation. Radiother. Oncol. 58, 227–233.