- Email: [email protected]
Decreasing Temporal Lobe Dose With Five-Field Intensity-Modulated Radiotherapy for Treatment of Pituitary Macroadenomas
Int. J. Radiation Oncology Biol. Phys., Vol. 78, No. 2, pp. 379–384, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2009.07.1695
CLINICAL INVESTIGATION
Brain
DECREASING TEMPORAL LOBE DOSE WITH FIVE-FIELD INTENSITY-MODULATED RADIOTHERAPY FOR TREATMENT OF PITUITARY MACROADENOMAS PREETI K. PARHAR, M.D., M.P.H.,* TAMARA DUCKWORTH, M.S.,* PARINDA SHAH, M.D.,y J. KEITH DEWYNGAERT, PH.D.,* ASHWATHA NARAYANA, M.D.,* SILVIA C. FORMENTI, M.D.,* z AND JINESH N. SHAH, M.D. From the *Department of Radiation Oncology and y Division of Neuroradiology, New York University School of Medicine, New York, NY; and z Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, New York, NY Purpose: To compare temporal lobe dose delivered by three pituitary macroadenoma irradiation techniques: three-field three-dimensional conformal radiotherapy (3D-CRT), three-field intensity-modulated radiotherapy (3F IMRT), and a proposed novel alternative of five-field IMRT (5F IMRT). Methods and Materials: Computed tomography–based external beam radiotherapy planning was performed for 15 pituitary macroadenoma patients treated at New York University between 2002 and 2007 using: 3D-CRT (two lateral, one midline superior anterior oblique [SAO] beams), 3F IMRT (same beam angles), and 5F IMRT (same beam angles with additional right SAO and left SAO beams). Prescription dose was 45 Gy. Target volumes were: gross tumor volume (GTV) = macroadenoma, clinical target volume (CTV) = GTV, and planning target volume = CTV + 0.5 cm. Structure contouring was performed by two radiation oncologists guided by an expert neuroradiologist. Results: Five-field IMRT yielded significantly decreased temporal lobe dose delivery compared with 3D-CRT and 3F IMRT. Temporal lobe sparing with 5F IMRT was most pronounced at intermediate doses: mean V25Gy (% of total temporal lobe volume receiving $25 Gy) of 13% vs. 28% vs. 29% for right temporal lobe and 14% vs. 29% vs. 30% for left temporal lobe for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–7 for 5F IMRT vs. 3D-CRT and 5F IMRT vs. 3F IMRT). Five-field IMRT plans did not compromise target coverage, exceed normal tissue dose constraints, or increase estimated brain integral dose. Conclusions: Five-field IMRT irradiation technique results in a statistically significant decrease in the dose to the temporal lobes and may thus help prevent neurocognitive sequelae in irradiated pituitary macroadenoma patients. Ó 2010 Elsevier Inc. Pituitary adenoma, Radiation, IMRT, Temporal lobe, Cognition.
located in the medial part of the temporal lobes is necessary for short-term memory and information processing. Radiation-related temporal lobe damage can range from the rare case of necrosis with associated significant functional impairment, to more common subtle neurocognitive dysfunction resulting from disruption of hippocampal neurogenesis (without obvious radiographic or pathologic temporal lobe changes) even after relatively low radiation dose exposure (3, 9, 10). Attempts to minimize the radiation dose to the temporal lobes are warranted because of the progressive and dose-dependent nature of the cognitive decline associated with radiotherapy (4). A common approach to decrease temporal lobe irradiation in the delivery of EBRT for pituitary tumors is a three-field (3F) technique that adds an additional midline superior anterior oblique (SAO) field to the original two-field opposed
INTRODUCTION Pituitary adenomas comprise approximately 10% of adult brain tumors (1). Although these tumors are benign, they can be hormonally active and can grow large enough to cause mass effect on adjacent brain structures, thereby potentially resulting in significant morbidity. Treatment consists of medical management (in the case of hormonally active tumors), surgery, radiotherapy, radiosurgery, or a combination of these modalities. Patients with pituitary macroadenomas (tumors >1 cm in size) are frequently treated with external beam radiotherapy (EBRT), with excellent local control and long-term survival (2). However, a potential late complication of such treatment is neurocognitive decline (3–8). Cognitive changes are related to radiation-induced damage to the temporal lobes and are volume- and dose-dependent. Specifically, the hippocampus Reprint requests to: Jinesh N. Shah, M.D., Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032. Tel: (212) 305-1058; Fax: (212) 342-0814; E-mail: [email protected]
Conflict of interest: none Received June 1, 2009, and in revised form July 20, 2009. Accepted for publication July 22, 2009. 379
380
I. J. Radiation Oncology d Biology d Physics
lateral technique. Additional approaches include serial adjacent axial arcs, coplanar and noncoplanar arcs, intensitymodulated radiotherapy (IMRT), fractionated stereotactic radiotherapy, and radiosurgery (11–18). Indeed, many centers now use a 3F method, either with three-dimensional conformal radiotherapy (3D-CRT) or IMRT (7, 11, 12, 18). However, 3F techniques still deliver a significant dose to the temporal lobes (7). The purpose of this dosimetric study was to determine if a proposed novel alternative five-field (5F) IMRT approach could reduce temporal lobe irradiation when compared with standard 3F 3D-CRT and IMRT techniques, doing so without compromising tumor target coverage, exceeding tolerance doses of other normal structures, or increasing estimated brain integral dose. METHODS AND MATERIALS This dosimetric study was performed on 15 patients with pituitary macroadenomas measuring >1 cm in diameter who were previously treated with EBRT at New York University between 2002 and 2007. Patients had undergone computed tomography (CT) simulation in the supine position with a thermoplastic mask for immobilization. CT images were obtained with 2.5-mm slice thickness. Having obtained institutional review board approval for this study, each patient’s simulation CT data were used to generate hypothetical treatment plans for this study. Specifically, three different techniques were employed to create three hypothetical EBRT plans for each patient: 3F 3D-CRT entailing two lateral beams and one midline SAO beam; 3F IMRT with same beam angles as 3DCRT; and 5F IMRT with same beam angles as the previous two approaches, but with additional right SAO and left SAO beams (Fig. 1). The right SAO and left SAO beam angles were chosen to avoid the ipsilateral temporal lobe. Contouring of tumor volumes and normal structures (right and left temporal lobes, optic chiasm, optic nerves, eyes, lenses, brainstem, hypothalamus, cochleas) was performed by two radiation oncologists (J.N.S., P.P.) and confirmed by an expert neuroradiologist (P.S.). Planning was performed by one physicist (T.D.) using the Varian Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system. The prescription dose chosen was 45 Gy. Tumor volumes were as follows: gross tumor volume (GTV) consisted of the macroadenoma as seen on a diagnostic MRI scan, which was typically coregistered to the treatment planning CT scan. The clinical target volume (CTV) was the same as the GTV. The planning target volume (PTV) was a 0.5 cm isotropic expansion of the CTV. The dosimetric parameters of the three types of plans
Volume 78, Number 2, 2010
were compared with respect to temporal lobe dose, as well as tumor coverage, maintenance of normal tissue dose constraint limits, and estimated temporal lobe and brain integral dose. Estimated integral dose (J) was calculated as: mean dose (Gy) to structure mass (kg) of structure, assuming water density for temporal lobe and brain tissue. In addition, a random subset of 6 patients was chosen from among the 15 cases studied, and 3F IMRT and 5F IMRT planning were repeated with specific temporal lobe dose optimization employed. These ‘‘temporal lobe optimized’’ plans were generated by using an upper dose–volume constraint of 0% of temporal lobe volume receiving 45 Gy or more with a priority weighting of 75. The optimized 3F IMRT and 5F IMRT plans were then compared with each another, as well as with the previous plans, which did not have specific temporal lobe optimization, to assess for potential differences in temporal lobe dosing.
RESULTS All three EBRT techniques yielded similar coverage of the GTV and PTV target volumes (p > 0.05 for all comparisons between techniques for mean V100, the percentage of the total target volume receiving $100% of the prescription dose) (Table 1). In addition, the means of the maximum dose to critical normal structures were within conventional tolerance limits with all three techniques (Table 2). For each of the 15 patients, 5F IMRT significantly decreased temporal lobe dose deposition compared with 3D-CRT and 3F IMRT (Fig. 2). Temporal lobe dose sparing with 5F IMRT was most pronounced at intermediate doses: right temporal lobe mean V25 Gy (percentage of total right temporal lobe volume receiving $25 Gy) was 13% for 5F IMRT vs. 28% for 3D-CRT (p < 10–7) and 29% for 3F IMRT (p < 10–7); left temporal lobe mean V25 Gy was 14% for 5F IMRT vs. 29% for 3D-CRT (p < 10–9) and 30% for 3F IMRT (p < 10–10). Although temporal lobe sparing was most pronounced with 5F IMRT for V25 Gy, differences were noted at lower doses as well. The right temporal lobe mean V20 Gy was 25% for 5F IMRT vs. 33% for 3D-CRT (p < 10–6) and 32% for 3F IMRT (p < 10–6); left temporal lobe mean V20 Gy was 27% for 5F IMRT vs. 34% for 3DCRT (p < 10–6) and 33% for 3F IMRT (p < 10–6). Likewise, the right temporal lobe mean V15 Gy was 32% for 5F IMRT vs. 36% for 3D-CRT (p < 10–4) and 34% for 3F IMRT (p < 10–4); left temporal lobe mean V15 Gy was
Fig. 1. Representative three-field and five-field beam arrangements.
IMRT Decreases temporal lobe dose d P. K. PARHAR et al.
Table 1. Mean (SD) of tumor coverage for the three irradiation techniques (n = 15)
381
Table 2. Mean (SD) of maximum dose (Gy) to critical normal structures for the three irradiation techniques (n = 15)
Dosimetric parameter
Mean (SD)
Normal structure
3D-CRT
3F IMRT
5F IMRT
GTV V100* for 3D-CRT GTV V100 for 3F IMRT GTV V100 for 5F IMRT PTV V100 for 3D-CRT PTV V100 for 3F IMRT PTV V100 for 5F IMRT
100.00 (0.00) 100.00 (0.00) 99.98 (0.059) 99.02 (1.04) 98.68 (0.76) 98.06 (4.07)
Optic chiasm Left optic nerve Right optic nerve Left eye Right eye Left lens Right lens Brainstem Hypothalamus Left cochlea Right cochlea
47.35 (1.33) 47.33 (1.13) 47.34 (1.11) 4.04 (7.50) 4.86 (9.32) 0.38 (0.45) 0.29 (0.15) 44.24 (5.22) 42.67 (6.63) 19.58 (15.18) 16.73 (14.58)
49.37 (2.72) 46.87 (1.85) 46.82 (2.40) 2.63 (5.16) 3.34 (6.44) 0.31 (0.41) 0.28 (0.29) 42.89 (9.84) 42.30 (11.58) 17.00 (16.14) 16.28 (15.15)
49.08 (2.20) 46.66 (1.85) 46.98 (2.08) 8.18 (7.77) 8.66 (8.70) 0.92 (2.28) 1.11 (2.62) 43.84 (7.35) 42.72 (10.86) 19.52 (11.51) 18.20 (11.24)
Abbreviations: 3D-CRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiotherapy; GTV = gross tumor volume; PTV = planning target volume; SD = standard deviation. * V100 = percentage of total tumor volume (GTV, PTV) receiving $100% of the prescription dose.
Abbreviations: 3D-CRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiotherapy; SD = standard deviation.
33% for 5F IMRT vs. 36% for 3D-CRT (p < 10–5) and 35% for 3F IMRT (p < 10–4). Of note, although 5F IMRT yielded statistically improved temporal lobe dosing vs. 3D-CRT and 3F IMRT for V15 Gy, V20 Gy, and V25 Gy, at higher doses no such advantage was demonstrated. Five-field IMRT also yielded lower estimated temporal lobe integral dose (estimated temporal lobe integral dose [J] = mean temporal lobe dose [Gy] mass [kg], assuming water density for temporal lobe brain tissue). The mean estimated integral dose for the right temporal lobe was 0.93 J, 1.07 J, and 1.16 J for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–3 for 5F IMRT vs. 3D-CRT; p < 10–6 for 5F IMRT vs. 3F IMRT). The mean estimated integral dose for the left temporal lobe was 0.97 J, 1.10 J, and 1.19 J for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–4 for 5F IMRT vs. 3D-CRT; p < 10–8 for 5F IMRT vs. 3F IMRT). Moreover, there was no increase in the estimated brain integral dose with 5F IMRT (estimated brain integral dose [J] = mean brain dose [Gy] mass [kg], assuming water density for brain tissue). The mean estimated brain integral dose was 6.87 J, 7.65 J, and 6.78 J for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–5 for 5F IMRT vs. 3DCRT with lower integral dose for 5F IMRT; p = 0.22 for 5F IMRT vs. 3F IMRT). For the random subset of 6 patients who had 3F IMRT and 5F IMRT planning repeated using specific temporal lobe dose optimization, temporal lobe V25 Gy with 5F IMRT was again lower than that with 3F IMRT (p = 0.002 and p = 0.00001 for right and left temporal lobe comparisons, respectively) (Table 3). Furthermore, the difference in V25 Gy between 3F IMRT and 5F IMRT was not lost after temporal lobe dose optimization was employed. In fact, the mean temporal lobe V25 Gy difference between 3F IMRT and 5F IMRT plans was larger for the temporal lobe optimized plans than for the non-optimized plans (Table 4). Thus, even after applying a temporal lobe dose optimization strategy, 5F IMRT was superior compared with 3F IMRT in terms of decreased temporal lobe dose delivery.
DISCUSSION Patients treated with external beam radiotherapy for pituitary adenomas have been shown to have higher than expected decline in cognition (3). This observation is likely influenced by a number of factors including baseline cognitive function, endocrine abnormalities that are suboptimally managed, use of combined surgery and radiotherapy and resulting effects on vasculature, and comorbid conditions resulting in hypoxic conditions (e.g., hypertension, smoking, hypercholesterolemia) (6). In one patient series, it was determined that cognitive impairment is multifactorial, with up to 40% of patients having a decline from the tumor itself or associated pituitary hormone function changes (19). Some investigators have reported that radiotherapy is associated with effects on executive function without effects on mood, general well-being, or mental health; others have found effects to be restricted to a deficit in memory (3, 5, 6). As one may predict, combined therapy of surgery and radiotherapy has been associated with worse neurocognitive effects than either modality alone (5). In a retrospective review of 81 pituitary adenoma patients treated with radiotherapy between 1963 and 2005, van Beek et al. reported that there was no association between radiation therapy and cognitive decline based on self-reported survey data (20). However, self-reported surveys are a potentially inaccurate tool for measuring cognitive impairment (21). In addition, there were no baseline cognitive assessments because this was a retrospective analysis. In contrast, Noad et al. studied 71 patients treated with surgery with or without radiotherapy between 1994 and 1997; these patients underwent neuropsychological testing conducted by a blinded psychologist, with several different parameters including memory, cognition, mood, well-being, and depression assessed (3). They found that those patients who received radiotherapy in addition to surgery did worst on the Stroop test, which measures executive function; this difference persisted after other factors were controlled for, including number of hormones replaced, surgery, age, gender, and general IQ (3).
I. J. Radiation Oncology d Biology d Physics
382
Volume 78, Number 2, 2010
Fig. 2. Left and right temporal lobe dose–volume histograms for the three irradiation techniques (n = 15).
Guinan et al. assessed 90 pituitary tumor patients for general intellectual function, memory, executive function, and speed of mental processing; these patients were treated with surgery (with or without radiation), radiotherapy, or bromocriptine (6). They reported that all groups (after controlling for baseline cognitive status) had significant memory deficits, especially when tested for anterograde memory. McCord et al. examined 141 patients retrospectively, of which 25% were treated with an opposed laterals radiotherapy technique (5). Patients receiving surgery and radiotherapy were more likely to self-report cognitive decline compared with patients treated with either modality alone (5). Because of the location of the hippocampus in the medial portion of the temporal lobes and its crucial role in short-term memory function and information processing, a radiation technique that spares dose to the temporal lobes may decrease the contribution of radiation therapy to cognitive decline. The extensive connections between the hippocampus and the neocortex are critical for memory formation, learning new tasks, and overall executive function. Radiation has been shown to cause damage to the normal parenchyma of the temporal lobes via vascular damage and glial cell damage, as well as by depleting—even after relatively low
radiation doses—neural stem cells that are needed for hippocampal cell renewal, which is a continuous process that persists in adulthood (10). Additionally, the CA1 subregion of the hippocampus controls executive function and is particularly sensitive to hypoxia and microcirculation defects (4). As a result, there can be progressive memory loss and intellectual compromise from radiation damage, with severity that is dose-dependent (22). Accordingly, minimizing the dose to the temporal lobes to as low as possible may be beneficial for preserving neurocognitive function postradiotherapy, especially in those patients with expected long life expectancies after radiotherapy, such as pituitary adenoma patients. It should be noted that the ‘‘classical’’ temporal lobe radiation dose constraint of a maximum of 50–60 Gy is based on risk of necrosis as the outcome. Given the sensitivity of the hippocampus to radiation effects and the possibility of subtle changes in cognition with relatively low doses, this constraint may not be appropriate for a patient population with a long life expectancy such as pituitary adenoma patients. In this dosimetric proof of principle study, we demonstrated that a significant reduction of the radiation dose to the temporal lobes can be achieved with a novel 5F IMRT technique for pituitary macroadenoma irradiation, one that uses a configuration of opposed lateral, midline superior anterior oblique, and right and left superior anterior oblique
Table 3. Mean (SD) of temporal lobe V25Gy for temporal lobe optimized IMRT plans (n = 6) V25 Gy Right temporal lobe 3F IMRT 5F IMRT Left temporal lobe 3F IMRT 5F IMRT
p value for comparison
37.98 (12.15) 20.21 (8.71)
0.002
38.85 (10.91) 22.25 (10.22)
0.00001
Abbreviations: IMRT = intensity-modulated radiotherapy; SD = standard deviation.
Table 4. Mean (SD) of V25Gy difference between 3F IMRT and 5F IMRT plans for temporal lobe nonoptimized (n = 15) and optimized (n = 6) approaches
Right temporal lobe Left temporal lobe
Nonoptimized
Optimized
p value for comparison
16.99 (6.69) 15.28 (2.75)
17.77 (7.09) 16.60 (2.33)
0.05 0.04
Abbreviation: IMRT = intensity-modulated radiotherapy; SD = standard deviation.
IMRT Decreases temporal lobe dose d P. K. PARHAR et al.
beams. Mackley et al. have shown the use of IMRT for pituitary adenomas to be effective and safe (11). In their series, several adjacent arcs were used as the radiation technique. Although cognition was not formally evaluated, 13% of patients reported subjective cognitive decline with a median follow-up of 42.5 months (11). In our study, the relative improvement in sparing of the temporal lobes with 5F IMRT was accomplished while maintaining tumor coverage, respecting standard dose constraints of other normal critical structures, and not increasing the estimated brain integral dose (this last end point may be especially important for radiation-induced malignancy risk). Notably, the superiority of 5F IMRT was most pronounced in the intermediate range of delivered dose. We observed a consistent statistical superiority for 5F IMRT in temporal lobe dose-sparing for the intermediate doses of V15 Gy, V20 Gy, and V25 Gy (with no advantage for 30 Gy and higher doses). Although it is possible that this relative sparing achieved with 5F IMRT for doses lower than 30 Gy may not be clinically meaningful, it is important to appreciate that this relative dose-sparing below 30 Gy may indeed be critical because these lower relative doses can potentially have significant neurocognitive consequences given the sensitivity of the hippocampal tissue and its constituent stem cells to relatively low radiation doses as already described. Notably, the superiority of the 5F IMRT technique persisted in this study even when specific temporal lobe dose optimization was employed for IMRT planning in our analysis. To our knowledge, only a few reports have systematically examined methods to reduce the dose to the temporal lobes from radiotherapy for pituitary adenomas. Sohn et al. compared three standard coplanar techniques (two-field parallel opposed, three-field, and 110 bilateral arcs), 330 single rotational arc, and a four noncoplanar arc technique for pituitary adenoma irradiation to a tumor dose of 45 Gy (7). They demonstrated that the four noncoplanar arc technique delivered less temporal lobe dose than the other approaches (7). When examining the temporal lobe volume receiving 25 Gy, the method that offered the lowest V25 Gy value was indeed the four noncoplanar arc plan (38%); notably, our 5F IMRT technique compares favorably with this approach, with V25 Gy values of 13% and 14% for the right and left
383
temporal lobes, respectively. In a stereotactic radiosurgery series in which treatment consisted of 18 Gy in one fraction and in which various radiation techniques were examined, an IMRT technique using 8–10 fields resulted in an advantage in temporal lobe dose-sparing (V10 Gy) for 2 of the 10 patients (13). However, in the case of stereotactic radiosurgery, the dose that results in unwanted cognitive effects is even less clearly known (13). Fogliotta et al. examined normal tissue sparing with single arc, helical arc, and fixed gantry techniques in 11 patients with benign conditions, 2 of whom were pituitary adenoma patients; they found IMRT to be better at the low dose levels, whereas RapidArc was better at limiting doses in the medium-high dose levels (23). Future studies should systematically examine the potential clinical benefit of radiotherapy techniques such as the 5F IMRT technique reported in this analysis, as well as report temporal lobe volumes receiving lower doses than conventionally examined in radiotherapy treatment planning; specifically, attention should be paid to temporal lobe volumes receiving intermediate doses below 30 Gy, as this dose region represented the area of benefit demonstrated by 5F IMRT in this study. It is critical to rigorously examine neurocognitive function in a longitudinal manner before and after delivery of radiotherapy when using different radiation techniques, and to specifically determine if methods that offer relative dosimetric sparing of the temporal lobes (such as the 5F IMRT technique described in this study) ultimately translate into a decreased incidence of neurocognitive late effects. CONCLUSION In summary, a novel 5F IMRT technique yielded decreased temporal lobe dosing when compared with 3F 3D-CRT and 3F IMRT methods for pituitary macroadenoma EBRT. Such relative temporal lobe sparing was achieved without compromising target coverage, exceeding normal tissue dose constraints, or increasing estimated brain integral dose. This 5-field IMRT approach may thus offer a means to help decrease the risk of neurocognitive decline in pituitary macroadenoma patients treated with EBRT.
REFERENCES 1. Devita VT, Hellman S, Rosenberg S. Cancer principles and practice of oncology. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. 2. Rush SC, Newall J. Pituitary adenoma: the efficacy of radiotherapy as the sole treatment. Int J Radiat Oncol Biol Phys 1989;17:165–169. 3. Noad R, Narayanan KR, Howlett T, et al. Evaluation of the effect of radiotherapy for pituitary tumours on cognitive function and quality of life. Clin Oncol (R Coll Radiol) 2004;16:233–237. 4. Abayomi OK. Pathogenesis of cognitive decline following therapeutic irradiation of head and neck tumors. Acta Oncol 2002;41:346–351.
5. McCord MW, Buatti JM, Fennell EM, et al. Radiotherapy for pituitary adenoma: Long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437–444. 6. Guinan EM, Lowy C, Stanhope N, et al. Cognitive effects of pituitary tumours and their treatments: Two case studies and an investigation of 90 patients. J Neurol Neurosurg Phsychiatry 1998;65:870–876. 7. Sohn JW, Dalzell JG, Suh JH, et al. Dose-volume histogram analysis of techniques for irradiating pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;32:831–837. 8. Byrne TN. Cognitive sequelae of brain tumor treatment. Curr Opin Neurol 2005;18:662–666.
384
I. J. Radiation Oncology d Biology d Physics
9. Hoshi M, Hayashi T, Kagami H, et al. Late bilateral temporal lobe necrosis after conventional radiotherapy. Neurol Med Chir (Tokyo) 2003;43:213–216. 10. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol 2003;16:129–134. 11. Mackley HB, Reddy CA, Lee SY, et al. Intensity-modulated radiotherapy for pituitary adenomas: The preliminary report of the Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;67:232–239. 12. Minniti G, Jaffrain-Rea ML, Osti M, et al. Radiotherapy for nonfunctioning pituitary adenomas: From conventional to modern stereotactic radiation techniques. Neurosurg Rev 2007;30:167–175. 13. Grabenbauer GG, Ernst-Stecken A, Schneider F, et al. Radiosurgery of functioning pituitary adenomas: Comparison of different treatment techniques including dynamic and conformal arcs, shaped beams, and IMRT. Int J Radiat Oncol Biol Phys 2006;66:S33–S39. 14. Zierhut D, Flentje M, Adolph J, et al. External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;33: 307–314. 15. Tsao MN, Wara WM, Larson DA. Radiation therapy for benign central nervous system disease. Semin Radiat Oncol 1999;9: 120–133. 16. Perks JR, Jalali R, Cosgrove VP, et al. Optimization of stereotactically-guided conformal treatment planning of sellar and parasellar tumors, based on normal brain dose
Volume 78, Number 2, 2010
17. 18.
19.
20.
21. 22. 23.
volume histograms. Int J Radiat Oncol Biol Phys 1999;45: 507–513. Robinson D, Murray B, Underwood L, et al. Escalated median dose for pituitary macroadenomas using intensity-modulated radiation therapy. Med Dosim 2004;29:26–30. Ahmad M, Fontenla DP, Lai PP, et al. Three-dimensional external-beam radiation treatment planning and real-time dose verification of pituitary adenoma: Clinical and physical considerations. Radiat Oncol Invest 1995;3:141–148. Peace KA, Orme SM, Padayatty SJ, et al. Cognitive dysfunction in patients with pituitary tumour who have been treated with transfrontal or transsphenoidal surgery or medication. Clin Endocrinol (Oxf) 1998;49:391–396. van Beek AP, van den Bergh AC, van den Berg LM, et al. Radiotherapy is not associated with reduced quality of life and cognitive function in patients treated for nonfunctioning pituitary adenomas. Int J Radiat Oncol Biol Phys 2007;68:986–991. Cull A, Hay C, Love SB, et al. What do cancer patients mean when they complain of concentration and memory problems? Br J Cancer 1996;74:1674–1679. Armstrong CL, Gyato K, Awadalla A, et al. A critical review of the clinical effects of therapeutic irradiation damage to the brain: The roots of controversy. Neuropsychol Rev 2004;14:65–86. Fogliata A, Clivio A, Nicolino G, et al. Intensity modulation with photons for benign intracranial tumours: A planning comparison of volumetric single arc, helical arc and fixed gantry techniques. Radiother Oncol 2008;89:254–262.
doi:10.1016/j.ijrobp.2009.07.1695
CLINICAL INVESTIGATION
Brain
DECREASING TEMPORAL LOBE DOSE WITH FIVE-FIELD INTENSITY-MODULATED RADIOTHERAPY FOR TREATMENT OF PITUITARY MACROADENOMAS PREETI K. PARHAR, M.D., M.P.H.,* TAMARA DUCKWORTH, M.S.,* PARINDA SHAH, M.D.,y J. KEITH DEWYNGAERT, PH.D.,* ASHWATHA NARAYANA, M.D.,* SILVIA C. FORMENTI, M.D.,* z AND JINESH N. SHAH, M.D. From the *Department of Radiation Oncology and y Division of Neuroradiology, New York University School of Medicine, New York, NY; and z Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, New York, NY Purpose: To compare temporal lobe dose delivered by three pituitary macroadenoma irradiation techniques: three-field three-dimensional conformal radiotherapy (3D-CRT), three-field intensity-modulated radiotherapy (3F IMRT), and a proposed novel alternative of five-field IMRT (5F IMRT). Methods and Materials: Computed tomography–based external beam radiotherapy planning was performed for 15 pituitary macroadenoma patients treated at New York University between 2002 and 2007 using: 3D-CRT (two lateral, one midline superior anterior oblique [SAO] beams), 3F IMRT (same beam angles), and 5F IMRT (same beam angles with additional right SAO and left SAO beams). Prescription dose was 45 Gy. Target volumes were: gross tumor volume (GTV) = macroadenoma, clinical target volume (CTV) = GTV, and planning target volume = CTV + 0.5 cm. Structure contouring was performed by two radiation oncologists guided by an expert neuroradiologist. Results: Five-field IMRT yielded significantly decreased temporal lobe dose delivery compared with 3D-CRT and 3F IMRT. Temporal lobe sparing with 5F IMRT was most pronounced at intermediate doses: mean V25Gy (% of total temporal lobe volume receiving $25 Gy) of 13% vs. 28% vs. 29% for right temporal lobe and 14% vs. 29% vs. 30% for left temporal lobe for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–7 for 5F IMRT vs. 3D-CRT and 5F IMRT vs. 3F IMRT). Five-field IMRT plans did not compromise target coverage, exceed normal tissue dose constraints, or increase estimated brain integral dose. Conclusions: Five-field IMRT irradiation technique results in a statistically significant decrease in the dose to the temporal lobes and may thus help prevent neurocognitive sequelae in irradiated pituitary macroadenoma patients. Ó 2010 Elsevier Inc. Pituitary adenoma, Radiation, IMRT, Temporal lobe, Cognition.
located in the medial part of the temporal lobes is necessary for short-term memory and information processing. Radiation-related temporal lobe damage can range from the rare case of necrosis with associated significant functional impairment, to more common subtle neurocognitive dysfunction resulting from disruption of hippocampal neurogenesis (without obvious radiographic or pathologic temporal lobe changes) even after relatively low radiation dose exposure (3, 9, 10). Attempts to minimize the radiation dose to the temporal lobes are warranted because of the progressive and dose-dependent nature of the cognitive decline associated with radiotherapy (4). A common approach to decrease temporal lobe irradiation in the delivery of EBRT for pituitary tumors is a three-field (3F) technique that adds an additional midline superior anterior oblique (SAO) field to the original two-field opposed
INTRODUCTION Pituitary adenomas comprise approximately 10% of adult brain tumors (1). Although these tumors are benign, they can be hormonally active and can grow large enough to cause mass effect on adjacent brain structures, thereby potentially resulting in significant morbidity. Treatment consists of medical management (in the case of hormonally active tumors), surgery, radiotherapy, radiosurgery, or a combination of these modalities. Patients with pituitary macroadenomas (tumors >1 cm in size) are frequently treated with external beam radiotherapy (EBRT), with excellent local control and long-term survival (2). However, a potential late complication of such treatment is neurocognitive decline (3–8). Cognitive changes are related to radiation-induced damage to the temporal lobes and are volume- and dose-dependent. Specifically, the hippocampus Reprint requests to: Jinesh N. Shah, M.D., Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032. Tel: (212) 305-1058; Fax: (212) 342-0814; E-mail: [email protected]
Conflict of interest: none Received June 1, 2009, and in revised form July 20, 2009. Accepted for publication July 22, 2009. 379
380
I. J. Radiation Oncology d Biology d Physics
lateral technique. Additional approaches include serial adjacent axial arcs, coplanar and noncoplanar arcs, intensitymodulated radiotherapy (IMRT), fractionated stereotactic radiotherapy, and radiosurgery (11–18). Indeed, many centers now use a 3F method, either with three-dimensional conformal radiotherapy (3D-CRT) or IMRT (7, 11, 12, 18). However, 3F techniques still deliver a significant dose to the temporal lobes (7). The purpose of this dosimetric study was to determine if a proposed novel alternative five-field (5F) IMRT approach could reduce temporal lobe irradiation when compared with standard 3F 3D-CRT and IMRT techniques, doing so without compromising tumor target coverage, exceeding tolerance doses of other normal structures, or increasing estimated brain integral dose. METHODS AND MATERIALS This dosimetric study was performed on 15 patients with pituitary macroadenomas measuring >1 cm in diameter who were previously treated with EBRT at New York University between 2002 and 2007. Patients had undergone computed tomography (CT) simulation in the supine position with a thermoplastic mask for immobilization. CT images were obtained with 2.5-mm slice thickness. Having obtained institutional review board approval for this study, each patient’s simulation CT data were used to generate hypothetical treatment plans for this study. Specifically, three different techniques were employed to create three hypothetical EBRT plans for each patient: 3F 3D-CRT entailing two lateral beams and one midline SAO beam; 3F IMRT with same beam angles as 3DCRT; and 5F IMRT with same beam angles as the previous two approaches, but with additional right SAO and left SAO beams (Fig. 1). The right SAO and left SAO beam angles were chosen to avoid the ipsilateral temporal lobe. Contouring of tumor volumes and normal structures (right and left temporal lobes, optic chiasm, optic nerves, eyes, lenses, brainstem, hypothalamus, cochleas) was performed by two radiation oncologists (J.N.S., P.P.) and confirmed by an expert neuroradiologist (P.S.). Planning was performed by one physicist (T.D.) using the Varian Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system. The prescription dose chosen was 45 Gy. Tumor volumes were as follows: gross tumor volume (GTV) consisted of the macroadenoma as seen on a diagnostic MRI scan, which was typically coregistered to the treatment planning CT scan. The clinical target volume (CTV) was the same as the GTV. The planning target volume (PTV) was a 0.5 cm isotropic expansion of the CTV. The dosimetric parameters of the three types of plans
Volume 78, Number 2, 2010
were compared with respect to temporal lobe dose, as well as tumor coverage, maintenance of normal tissue dose constraint limits, and estimated temporal lobe and brain integral dose. Estimated integral dose (J) was calculated as: mean dose (Gy) to structure mass (kg) of structure, assuming water density for temporal lobe and brain tissue. In addition, a random subset of 6 patients was chosen from among the 15 cases studied, and 3F IMRT and 5F IMRT planning were repeated with specific temporal lobe dose optimization employed. These ‘‘temporal lobe optimized’’ plans were generated by using an upper dose–volume constraint of 0% of temporal lobe volume receiving 45 Gy or more with a priority weighting of 75. The optimized 3F IMRT and 5F IMRT plans were then compared with each another, as well as with the previous plans, which did not have specific temporal lobe optimization, to assess for potential differences in temporal lobe dosing.
RESULTS All three EBRT techniques yielded similar coverage of the GTV and PTV target volumes (p > 0.05 for all comparisons between techniques for mean V100, the percentage of the total target volume receiving $100% of the prescription dose) (Table 1). In addition, the means of the maximum dose to critical normal structures were within conventional tolerance limits with all three techniques (Table 2). For each of the 15 patients, 5F IMRT significantly decreased temporal lobe dose deposition compared with 3D-CRT and 3F IMRT (Fig. 2). Temporal lobe dose sparing with 5F IMRT was most pronounced at intermediate doses: right temporal lobe mean V25 Gy (percentage of total right temporal lobe volume receiving $25 Gy) was 13% for 5F IMRT vs. 28% for 3D-CRT (p < 10–7) and 29% for 3F IMRT (p < 10–7); left temporal lobe mean V25 Gy was 14% for 5F IMRT vs. 29% for 3D-CRT (p < 10–9) and 30% for 3F IMRT (p < 10–10). Although temporal lobe sparing was most pronounced with 5F IMRT for V25 Gy, differences were noted at lower doses as well. The right temporal lobe mean V20 Gy was 25% for 5F IMRT vs. 33% for 3D-CRT (p < 10–6) and 32% for 3F IMRT (p < 10–6); left temporal lobe mean V20 Gy was 27% for 5F IMRT vs. 34% for 3DCRT (p < 10–6) and 33% for 3F IMRT (p < 10–6). Likewise, the right temporal lobe mean V15 Gy was 32% for 5F IMRT vs. 36% for 3D-CRT (p < 10–4) and 34% for 3F IMRT (p < 10–4); left temporal lobe mean V15 Gy was
Fig. 1. Representative three-field and five-field beam arrangements.
IMRT Decreases temporal lobe dose d P. K. PARHAR et al.
Table 1. Mean (SD) of tumor coverage for the three irradiation techniques (n = 15)
381
Table 2. Mean (SD) of maximum dose (Gy) to critical normal structures for the three irradiation techniques (n = 15)
Dosimetric parameter
Mean (SD)
Normal structure
3D-CRT
3F IMRT
5F IMRT
GTV V100* for 3D-CRT GTV V100 for 3F IMRT GTV V100 for 5F IMRT PTV V100 for 3D-CRT PTV V100 for 3F IMRT PTV V100 for 5F IMRT
100.00 (0.00) 100.00 (0.00) 99.98 (0.059) 99.02 (1.04) 98.68 (0.76) 98.06 (4.07)
Optic chiasm Left optic nerve Right optic nerve Left eye Right eye Left lens Right lens Brainstem Hypothalamus Left cochlea Right cochlea
47.35 (1.33) 47.33 (1.13) 47.34 (1.11) 4.04 (7.50) 4.86 (9.32) 0.38 (0.45) 0.29 (0.15) 44.24 (5.22) 42.67 (6.63) 19.58 (15.18) 16.73 (14.58)
49.37 (2.72) 46.87 (1.85) 46.82 (2.40) 2.63 (5.16) 3.34 (6.44) 0.31 (0.41) 0.28 (0.29) 42.89 (9.84) 42.30 (11.58) 17.00 (16.14) 16.28 (15.15)
49.08 (2.20) 46.66 (1.85) 46.98 (2.08) 8.18 (7.77) 8.66 (8.70) 0.92 (2.28) 1.11 (2.62) 43.84 (7.35) 42.72 (10.86) 19.52 (11.51) 18.20 (11.24)
Abbreviations: 3D-CRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiotherapy; GTV = gross tumor volume; PTV = planning target volume; SD = standard deviation. * V100 = percentage of total tumor volume (GTV, PTV) receiving $100% of the prescription dose.
Abbreviations: 3D-CRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiotherapy; SD = standard deviation.
33% for 5F IMRT vs. 36% for 3D-CRT (p < 10–5) and 35% for 3F IMRT (p < 10–4). Of note, although 5F IMRT yielded statistically improved temporal lobe dosing vs. 3D-CRT and 3F IMRT for V15 Gy, V20 Gy, and V25 Gy, at higher doses no such advantage was demonstrated. Five-field IMRT also yielded lower estimated temporal lobe integral dose (estimated temporal lobe integral dose [J] = mean temporal lobe dose [Gy] mass [kg], assuming water density for temporal lobe brain tissue). The mean estimated integral dose for the right temporal lobe was 0.93 J, 1.07 J, and 1.16 J for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–3 for 5F IMRT vs. 3D-CRT; p < 10–6 for 5F IMRT vs. 3F IMRT). The mean estimated integral dose for the left temporal lobe was 0.97 J, 1.10 J, and 1.19 J for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–4 for 5F IMRT vs. 3D-CRT; p < 10–8 for 5F IMRT vs. 3F IMRT). Moreover, there was no increase in the estimated brain integral dose with 5F IMRT (estimated brain integral dose [J] = mean brain dose [Gy] mass [kg], assuming water density for brain tissue). The mean estimated brain integral dose was 6.87 J, 7.65 J, and 6.78 J for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10–5 for 5F IMRT vs. 3DCRT with lower integral dose for 5F IMRT; p = 0.22 for 5F IMRT vs. 3F IMRT). For the random subset of 6 patients who had 3F IMRT and 5F IMRT planning repeated using specific temporal lobe dose optimization, temporal lobe V25 Gy with 5F IMRT was again lower than that with 3F IMRT (p = 0.002 and p = 0.00001 for right and left temporal lobe comparisons, respectively) (Table 3). Furthermore, the difference in V25 Gy between 3F IMRT and 5F IMRT was not lost after temporal lobe dose optimization was employed. In fact, the mean temporal lobe V25 Gy difference between 3F IMRT and 5F IMRT plans was larger for the temporal lobe optimized plans than for the non-optimized plans (Table 4). Thus, even after applying a temporal lobe dose optimization strategy, 5F IMRT was superior compared with 3F IMRT in terms of decreased temporal lobe dose delivery.
DISCUSSION Patients treated with external beam radiotherapy for pituitary adenomas have been shown to have higher than expected decline in cognition (3). This observation is likely influenced by a number of factors including baseline cognitive function, endocrine abnormalities that are suboptimally managed, use of combined surgery and radiotherapy and resulting effects on vasculature, and comorbid conditions resulting in hypoxic conditions (e.g., hypertension, smoking, hypercholesterolemia) (6). In one patient series, it was determined that cognitive impairment is multifactorial, with up to 40% of patients having a decline from the tumor itself or associated pituitary hormone function changes (19). Some investigators have reported that radiotherapy is associated with effects on executive function without effects on mood, general well-being, or mental health; others have found effects to be restricted to a deficit in memory (3, 5, 6). As one may predict, combined therapy of surgery and radiotherapy has been associated with worse neurocognitive effects than either modality alone (5). In a retrospective review of 81 pituitary adenoma patients treated with radiotherapy between 1963 and 2005, van Beek et al. reported that there was no association between radiation therapy and cognitive decline based on self-reported survey data (20). However, self-reported surveys are a potentially inaccurate tool for measuring cognitive impairment (21). In addition, there were no baseline cognitive assessments because this was a retrospective analysis. In contrast, Noad et al. studied 71 patients treated with surgery with or without radiotherapy between 1994 and 1997; these patients underwent neuropsychological testing conducted by a blinded psychologist, with several different parameters including memory, cognition, mood, well-being, and depression assessed (3). They found that those patients who received radiotherapy in addition to surgery did worst on the Stroop test, which measures executive function; this difference persisted after other factors were controlled for, including number of hormones replaced, surgery, age, gender, and general IQ (3).
I. J. Radiation Oncology d Biology d Physics
382
Volume 78, Number 2, 2010
Fig. 2. Left and right temporal lobe dose–volume histograms for the three irradiation techniques (n = 15).
Guinan et al. assessed 90 pituitary tumor patients for general intellectual function, memory, executive function, and speed of mental processing; these patients were treated with surgery (with or without radiation), radiotherapy, or bromocriptine (6). They reported that all groups (after controlling for baseline cognitive status) had significant memory deficits, especially when tested for anterograde memory. McCord et al. examined 141 patients retrospectively, of which 25% were treated with an opposed laterals radiotherapy technique (5). Patients receiving surgery and radiotherapy were more likely to self-report cognitive decline compared with patients treated with either modality alone (5). Because of the location of the hippocampus in the medial portion of the temporal lobes and its crucial role in short-term memory function and information processing, a radiation technique that spares dose to the temporal lobes may decrease the contribution of radiation therapy to cognitive decline. The extensive connections between the hippocampus and the neocortex are critical for memory formation, learning new tasks, and overall executive function. Radiation has been shown to cause damage to the normal parenchyma of the temporal lobes via vascular damage and glial cell damage, as well as by depleting—even after relatively low
radiation doses—neural stem cells that are needed for hippocampal cell renewal, which is a continuous process that persists in adulthood (10). Additionally, the CA1 subregion of the hippocampus controls executive function and is particularly sensitive to hypoxia and microcirculation defects (4). As a result, there can be progressive memory loss and intellectual compromise from radiation damage, with severity that is dose-dependent (22). Accordingly, minimizing the dose to the temporal lobes to as low as possible may be beneficial for preserving neurocognitive function postradiotherapy, especially in those patients with expected long life expectancies after radiotherapy, such as pituitary adenoma patients. It should be noted that the ‘‘classical’’ temporal lobe radiation dose constraint of a maximum of 50–60 Gy is based on risk of necrosis as the outcome. Given the sensitivity of the hippocampus to radiation effects and the possibility of subtle changes in cognition with relatively low doses, this constraint may not be appropriate for a patient population with a long life expectancy such as pituitary adenoma patients. In this dosimetric proof of principle study, we demonstrated that a significant reduction of the radiation dose to the temporal lobes can be achieved with a novel 5F IMRT technique for pituitary macroadenoma irradiation, one that uses a configuration of opposed lateral, midline superior anterior oblique, and right and left superior anterior oblique
Table 3. Mean (SD) of temporal lobe V25Gy for temporal lobe optimized IMRT plans (n = 6) V25 Gy Right temporal lobe 3F IMRT 5F IMRT Left temporal lobe 3F IMRT 5F IMRT
p value for comparison
37.98 (12.15) 20.21 (8.71)
0.002
38.85 (10.91) 22.25 (10.22)
0.00001
Abbreviations: IMRT = intensity-modulated radiotherapy; SD = standard deviation.
Table 4. Mean (SD) of V25Gy difference between 3F IMRT and 5F IMRT plans for temporal lobe nonoptimized (n = 15) and optimized (n = 6) approaches
Right temporal lobe Left temporal lobe
Nonoptimized
Optimized
p value for comparison
16.99 (6.69) 15.28 (2.75)
17.77 (7.09) 16.60 (2.33)
0.05 0.04
Abbreviation: IMRT = intensity-modulated radiotherapy; SD = standard deviation.
IMRT Decreases temporal lobe dose d P. K. PARHAR et al.
beams. Mackley et al. have shown the use of IMRT for pituitary adenomas to be effective and safe (11). In their series, several adjacent arcs were used as the radiation technique. Although cognition was not formally evaluated, 13% of patients reported subjective cognitive decline with a median follow-up of 42.5 months (11). In our study, the relative improvement in sparing of the temporal lobes with 5F IMRT was accomplished while maintaining tumor coverage, respecting standard dose constraints of other normal critical structures, and not increasing the estimated brain integral dose (this last end point may be especially important for radiation-induced malignancy risk). Notably, the superiority of 5F IMRT was most pronounced in the intermediate range of delivered dose. We observed a consistent statistical superiority for 5F IMRT in temporal lobe dose-sparing for the intermediate doses of V15 Gy, V20 Gy, and V25 Gy (with no advantage for 30 Gy and higher doses). Although it is possible that this relative sparing achieved with 5F IMRT for doses lower than 30 Gy may not be clinically meaningful, it is important to appreciate that this relative dose-sparing below 30 Gy may indeed be critical because these lower relative doses can potentially have significant neurocognitive consequences given the sensitivity of the hippocampal tissue and its constituent stem cells to relatively low radiation doses as already described. Notably, the superiority of the 5F IMRT technique persisted in this study even when specific temporal lobe dose optimization was employed for IMRT planning in our analysis. To our knowledge, only a few reports have systematically examined methods to reduce the dose to the temporal lobes from radiotherapy for pituitary adenomas. Sohn et al. compared three standard coplanar techniques (two-field parallel opposed, three-field, and 110 bilateral arcs), 330 single rotational arc, and a four noncoplanar arc technique for pituitary adenoma irradiation to a tumor dose of 45 Gy (7). They demonstrated that the four noncoplanar arc technique delivered less temporal lobe dose than the other approaches (7). When examining the temporal lobe volume receiving 25 Gy, the method that offered the lowest V25 Gy value was indeed the four noncoplanar arc plan (38%); notably, our 5F IMRT technique compares favorably with this approach, with V25 Gy values of 13% and 14% for the right and left
383
temporal lobes, respectively. In a stereotactic radiosurgery series in which treatment consisted of 18 Gy in one fraction and in which various radiation techniques were examined, an IMRT technique using 8–10 fields resulted in an advantage in temporal lobe dose-sparing (V10 Gy) for 2 of the 10 patients (13). However, in the case of stereotactic radiosurgery, the dose that results in unwanted cognitive effects is even less clearly known (13). Fogliotta et al. examined normal tissue sparing with single arc, helical arc, and fixed gantry techniques in 11 patients with benign conditions, 2 of whom were pituitary adenoma patients; they found IMRT to be better at the low dose levels, whereas RapidArc was better at limiting doses in the medium-high dose levels (23). Future studies should systematically examine the potential clinical benefit of radiotherapy techniques such as the 5F IMRT technique reported in this analysis, as well as report temporal lobe volumes receiving lower doses than conventionally examined in radiotherapy treatment planning; specifically, attention should be paid to temporal lobe volumes receiving intermediate doses below 30 Gy, as this dose region represented the area of benefit demonstrated by 5F IMRT in this study. It is critical to rigorously examine neurocognitive function in a longitudinal manner before and after delivery of radiotherapy when using different radiation techniques, and to specifically determine if methods that offer relative dosimetric sparing of the temporal lobes (such as the 5F IMRT technique described in this study) ultimately translate into a decreased incidence of neurocognitive late effects. CONCLUSION In summary, a novel 5F IMRT technique yielded decreased temporal lobe dosing when compared with 3F 3D-CRT and 3F IMRT methods for pituitary macroadenoma EBRT. Such relative temporal lobe sparing was achieved without compromising target coverage, exceeding normal tissue dose constraints, or increasing estimated brain integral dose. This 5-field IMRT approach may thus offer a means to help decrease the risk of neurocognitive decline in pituitary macroadenoma patients treated with EBRT.
REFERENCES 1. Devita VT, Hellman S, Rosenberg S. Cancer principles and practice of oncology. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. 2. Rush SC, Newall J. Pituitary adenoma: the efficacy of radiotherapy as the sole treatment. Int J Radiat Oncol Biol Phys 1989;17:165–169. 3. Noad R, Narayanan KR, Howlett T, et al. Evaluation of the effect of radiotherapy for pituitary tumours on cognitive function and quality of life. Clin Oncol (R Coll Radiol) 2004;16:233–237. 4. Abayomi OK. Pathogenesis of cognitive decline following therapeutic irradiation of head and neck tumors. Acta Oncol 2002;41:346–351.
5. McCord MW, Buatti JM, Fennell EM, et al. Radiotherapy for pituitary adenoma: Long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437–444. 6. Guinan EM, Lowy C, Stanhope N, et al. Cognitive effects of pituitary tumours and their treatments: Two case studies and an investigation of 90 patients. J Neurol Neurosurg Phsychiatry 1998;65:870–876. 7. Sohn JW, Dalzell JG, Suh JH, et al. Dose-volume histogram analysis of techniques for irradiating pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;32:831–837. 8. Byrne TN. Cognitive sequelae of brain tumor treatment. Curr Opin Neurol 2005;18:662–666.
384
I. J. Radiation Oncology d Biology d Physics
9. Hoshi M, Hayashi T, Kagami H, et al. Late bilateral temporal lobe necrosis after conventional radiotherapy. Neurol Med Chir (Tokyo) 2003;43:213–216. 10. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol 2003;16:129–134. 11. Mackley HB, Reddy CA, Lee SY, et al. Intensity-modulated radiotherapy for pituitary adenomas: The preliminary report of the Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;67:232–239. 12. Minniti G, Jaffrain-Rea ML, Osti M, et al. Radiotherapy for nonfunctioning pituitary adenomas: From conventional to modern stereotactic radiation techniques. Neurosurg Rev 2007;30:167–175. 13. Grabenbauer GG, Ernst-Stecken A, Schneider F, et al. Radiosurgery of functioning pituitary adenomas: Comparison of different treatment techniques including dynamic and conformal arcs, shaped beams, and IMRT. Int J Radiat Oncol Biol Phys 2006;66:S33–S39. 14. Zierhut D, Flentje M, Adolph J, et al. External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;33: 307–314. 15. Tsao MN, Wara WM, Larson DA. Radiation therapy for benign central nervous system disease. Semin Radiat Oncol 1999;9: 120–133. 16. Perks JR, Jalali R, Cosgrove VP, et al. Optimization of stereotactically-guided conformal treatment planning of sellar and parasellar tumors, based on normal brain dose
Volume 78, Number 2, 2010
17. 18.
19.
20.
21. 22. 23.
volume histograms. Int J Radiat Oncol Biol Phys 1999;45: 507–513. Robinson D, Murray B, Underwood L, et al. Escalated median dose for pituitary macroadenomas using intensity-modulated radiation therapy. Med Dosim 2004;29:26–30. Ahmad M, Fontenla DP, Lai PP, et al. Three-dimensional external-beam radiation treatment planning and real-time dose verification of pituitary adenoma: Clinical and physical considerations. Radiat Oncol Invest 1995;3:141–148. Peace KA, Orme SM, Padayatty SJ, et al. Cognitive dysfunction in patients with pituitary tumour who have been treated with transfrontal or transsphenoidal surgery or medication. Clin Endocrinol (Oxf) 1998;49:391–396. van Beek AP, van den Bergh AC, van den Berg LM, et al. Radiotherapy is not associated with reduced quality of life and cognitive function in patients treated for nonfunctioning pituitary adenomas. Int J Radiat Oncol Biol Phys 2007;68:986–991. Cull A, Hay C, Love SB, et al. What do cancer patients mean when they complain of concentration and memory problems? Br J Cancer 1996;74:1674–1679. Armstrong CL, Gyato K, Awadalla A, et al. A critical review of the clinical effects of therapeutic irradiation damage to the brain: The roots of controversy. Neuropsychol Rev 2004;14:65–86. Fogliata A, Clivio A, Nicolino G, et al. Intensity modulation with photons for benign intracranial tumours: A planning comparison of volumetric single arc, helical arc and fixed gantry techniques. Radiother Oncol 2008;89:254–262.