- Email: [email protected]
CONFORMAL RADIOTHERAPY FOR BRAIN TUMOURS
NEURO-ONCOLOGY
0889-8588/01 $15.00
+ .OO
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS Michael D. Weil, MD
Nor bring, to watch me cease to live Some doctor, full of phrase and fame To shake his sapient head and give The ill he cannot cure a name. MATTHEW ARNOLD
The topic of conforming radiation to the shape of a pathologic brain lesion often begs the issue of whether it makes a difference to the patient.30In principle, it is a good idea to localize a generally toxic agent, such as x-rays, to a target. This localization permits the elevation of dose to the tumor without increasing side effects. The outcome of most brain lesions primarily depends on histology. Benign lesions are discrete and readily targeted, whereas malignant lesions are extremely difficult to separate from invaded tissue and frequently recur in the treated area regardless of the intervention. Advances in genomics and other research relating to tumor biology23are unlikely to affect clinical radiotherapy of brain tumors in the near future. ADVANTAGES OF THREE-DIMENSIONAL RADIOTHERAPY The safe delivery of radiation to malignant or benign masses is complicated by the sensitivity of the normal surrounding tissue. The dose and volume to destroy a tumor are often similar to the radiation
From Sirius Medicine, LLC, Golden, Colorado
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 15 * NUMBER 6 * DECEMBER 2001
1007
1008
WEIL
tolerance of normal organs. Nowhere is this consideration more crucial than in the brain, where vital structures are densely packed and the therapeutic window is narrow. Efforts to target brain tumors better involve a multidisciplinary approach. Improved imaging with CT and MR imaging permits better target definiti~n.'~ Computing capable of converting acquired two-dimensional cuts of a patient to three-dimensional volumes can improve tumor definition and planning significantly. Displays of virtual dose distributions for a given beam geometry permit better evaluation of benefit versus risk of therapy. New hardware can enhance radiation field contours during treatment and deliver x-rays according to the plan. One realistic way to design the dose dispensed to the tumor safely is to optimize the geometry of the beam arrangements. Conventional design of a radiation field is performed with an outline of the patient's body and an outline of the target in one plane. The attenuation of the beam over distance and through tissue is calculated. In.this twodimensional world, there is no way to calculate a beam traveling into or out of the plane of interest. The radiation confined to this one level can travel beyond the target and hit beams on the other side and give additional dose to normal tissue. Overlap of entering and exiting radiation increases the dose to the brain without much therapeutic gain. It is possible by moving beams (arcs) to spread the entrance dose to tolerable levels and by using multiple beams at different angles and planes to decrease the intersection of bearns.'O Such designs can be accomplished best by three-dimensional planning systems. Three-dimensional planning reconstructs two-dimensional computed tomography slices and creates virtual volumes of the body and the lesion.31It then can calculate the beam's interaction with the body from any angle and integrate the dose to give a detailed view of dose to normal organs and the region containing the cancer. The simplest way to use three-dimensional planning to decrease dose to normal tissue while maintaining dose in the target is to use the geometry of multiple beam arrangements. Shooting the tumor with fractions arriving along different paths decreases the dose to any section of intervening normal tissue to a portion of the total number of beams (Fig. 1). As individual beams travel through the patient and exit the tumor, their energy is dissipated in areas that are radiated from the opposite side. By having the beams travel along different planes, this problem is avoided (Fig. 2). The integral dose of radiation absorbed by the patient does not change with these techniques; it is merely spread out. The total dose is distributed through more tissue, but a given area receives a dose that is within its tolerance. ALTERNATIVE BEAMS
Early attempts to localize treatment better employed types of radiation other than x-rays. The discrete properties of the dose deposition
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
A
1009
Bm
Figure 1. A, Tumor in the center of the body treated from the top and bottom with 100 cGy to deliver a total dose of 200 cGy to the lesion. 6, The same total dose of 200 cGy is delivered to the tumor but is divided into eight fractions of 25 cGy each coming from different directions. The dose to the tumor is unchanged and the dose to irradiated normal tissue along the path of the x-ray beam is much less in the example with multiple beams. The total integral dose to the body does not change.
Figure 2. A, Tumor in the center of the body treated from the sides with opposing beams, (#1 and #2 in the same plane of the page) targeting a central tumor. The rectangle represents an area of overlap as each beam exits the tumor into the contralateral ray. 6, The #2 beam has been moved up and away from the plane of the #1 beam (now coming out of the page) but is still aimed at the tumor. There is no longer an overlap because the beams do not run into each other as they exit the tumor.
1010
WEIL
from particle beams portended improved targeting. Particle beams (protons, neutrons, helium, and neon ions) have different physical and biologic properties than conventional x-ray beams (photons). Leksell et alZ0began the clinical use of proton therapy at Uppsala in 1954, when they used a proton beam in the first treatments of human patients. At Berkeley, Lawrence et a1 used the Bragg peak for pituitary radiation in patients with metastatic breast cancer33around the same time. In 1961, Kjellberg et all5began treating patients using protons from the Harvard cyclotron. These investigators performed a comprehensive study of arteriovenous malformations and derived the dose effects correlated to the treated volume, which resulted in radiation necrosis from proton therapy of the brain.I6 There are two accepted clinical indications for proton therapy today: choroidal melanomas (98% 5-year local control, low toxicity, and preservation of vision in 50%) and low-grade skull base chondrosarcomas and chordomas (90% long-term survival).2, Small trials with combined x-rays and protons, have been performed for glioblastoma multiforme7 and showed tolerance of large radiation doses. Proof of efficacy requires showing no selection bias (eg, no imbalance of young and highly functioning patients). Such patients often are referred to academic centers, whereas the average patient with poorer prognosis gets treated closer to home. THREE-DIMENSIONAL METHODS
The Berkeley heavy particle accelerator lost its main funding in the 1990s and no longer treats patients; however, the computer planning that was developed and used there became the basis for modern threedimensional planning programs. The three-dimensional planning software allows the user to look at the tumor from any angle and project a beam from that position. In much the way a gunner aims at a target, this beam's eye view permits better positioning of the beam onto the tumor. At the same time, it shows all of the organs that will be hit by the beam on the near and far side of the target. Beam's eye viewing and accurate pointing permit customized masking of the radiation around the perimeter of the target. Significantly less normal tissue is radiated by blocking out the area of each beam beyond the tumor plus margin. This blocking is done by drawing a line around the mass on the computer image and constructing blocks from the image for the particular beam. The blocks have been made of a low-melting-point alloy of bismuth, lead, tin, and cadmium (Cerrobend) that is poured by hand into a mold for each beam. Individual blocks are thick and heavy and often are put in place above a supine patient. Hardware that is part of the head of the machine, multileaf collimators, is also available to automate the blocking. Multileaf collimation is much less labor intensive and without the risk of dropping onto the patient. Less normal tissue is included, however, by blocking with old-fashioned lead alloy.' More accurate pointing of the x-ray and better localization to the target are
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
1011
important for optimizing therapy, but it is crucial that organ and patient movement be taken into a c c o ~ n t .Organ ~ movement in the head is minimal, but it can be greater than 1 cm in other parts of the body. Movement of the head can be much greater, and devices to immobilize the although “low-tech,” are vital to delivering accurate therapy.% In addition, physician variability in delineating targets can be an important factor in determining accuracy of treatment.21 Arranging beam geometries and shaping the beam have been applied in the clinic as a result of computing and software. These methods for the most part have been used in a static fashion (ie, the beam does not change while it is on). Techniques that permit the beam to change during irradiation are possible with dynamic, multileaf collimation. These methods have been referred to as intensity modulated radiotherapy. Although the output of the machine is unchanged, movement of collimation during the treatment can refine greatly the contours of the dose to the tumor and surrounding region^.^ There are software programs that essentially automate the planning process. So-called inverse planning allows the user first to detail the dose to be delivered to an area, then automatically assigns beams and parameters. A less appreciated and more technical advantage of three-dimensional planning is the ability to calculate the dose given to a specific volume of tissue via dose-volume histograms.28The volume of irradiated tissue increases by the cube of the radius beyond the tumor. As a result, a good deal of normal brain is included in most radiation treatments, which include several centimeters of margin beyond the radiographic abnormality. The greater the volume of normal tissue irradiated means that less total dose can be delivered. Kjellberg’s work16with protons for arteriovenous malformations showed that exceeding a tolerated dose for a given volume resulted in a greater incidence of necrosis. The ability to measure and limit the volume of normal brain receiving a near-maximal dose is necessary to decrease the incidence of necrosis. There are instances in which increased risks are necessary, and dose-volume histograms allow the patient and physician to make informed decisions.32 TOXICITY There are several regions of the brain where lesions portend short survival, and it is possible to do great harm if too much radiation is given to too large a volume. These areas include the motor strip, brainstem, thalam~s,’~ optic nerve and other cranial nerves, hypothalamuspituitary axis, visual cortex, and retina. Doses to significant volumes in these regions greater than 45 Gy can do damage. Although doses in this range may be sufficient to treat benign lesions (eg, around the pituitary’*), they are insufficient to treat malignant brainstem lesions, which require significantly greater doses.6Treating the smallest volume possible can attenuate the risk for these areas. Nonetheless, large doses to the brain with three-dimensional conformal methods have been reported for
1012
WEIL
high-grade gliomasz5and for reirradiating failed intracranial lesions.”, l4 Reports of this nature have to be viewed with caution, however, because the survival in this cohort of patients is often less than the time to morbidity. Hair loss is significant in patients after high-dose radiotherapy to the head. Scalp dose can be controlled with three-dimensional planningzzwith reduced incidence of alopecia.
FIELD SIZE AND DOSE
How much radiation is necessary to kill a particular tumor? What is the appropriate size of the tumor plus surrounding normal tissue that should be treated? What modifications to the treatment are required when radiation is delivered with other modalities? In the case of benign lesions, the answers to these questions are straightforward, but the specifics in the clinical setting for malignant brain lesions are still being pursued.
Malignant Lesions
Trials in the 1970s discredited radiation fields covering the entire brain in treatment of malignant gliomas. For most cancers, it is difficult to delineate the tumor precisely and even harder to know with certainty how far beyond the imaged perimeter cancerous cells extend. The ability to image the brain with MR imaging improves visualization to a point. It is assumed that active tumor cells extend through the area of peritumor edema defined by the T2 (water) signal. Initial radiation portals include the T2 signal on MR imaging plus a border of several centimeters. The covered region, as now defined according to MR imaging parameters, treats the large volumes to 45 Gy with daily fractions of 180 cGy. The boost volume is pared down to the enhancing lesion plus several centimeters, and the dose is increased to 60 Gy. Attempts to improve outcome with altered dosing schemes: plus or minus chemotherapy5 and usually aimed at increasing the total dose, have failed to date.27Besides dosing questions, the technical accuracy of the treatment arrangement would seem to be important for better outcome. In a review of pediatric medulloblastoma from Switzerland, technical factors were not statistically significant in predicting overall survival.” Medulloblastoma is a good example in which clinical concerns outweigh the ability to deliver a better plan with three-dimensional technology. Postoperatively, there is often no evidence of gross disease on imaging. Although it is possible and desirable to decrease the normal tissue radiated in a child with medulloblastoma,26it is uncertain as to whether it is worth the risk of missing tumor in an effort to reduce toxicity by shrinking the field.
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
1013
Benign Lesions
Meningioma and pituitary adenomas are the commonest benign lesions treated with radi~therapy.~~ There has been a trend to treat these and other nonmalignant lesions of the brain with radiosurgery rather than radiotherapy. Some centers have taken a middle ground for these lesions and perform stereotactic radiotherapy.l*Essentially the technique involves a reproducible radiosurgical setuplS and delivers radiotherapy doses with tighter margins.17Regardless, the discrete nature of these lesions allows three-dimensional conformal techniques to be employed with excellent control. Morbidity is the result of the location treated. In the case of the suprasellar and parasellar regions, hormone replacement often is required.
SUMMARY
The technical improvements of three-dimensional conformal radiotherapy can decrease the toxicity of brain treatment to acceptable levels. The adoption of the technique by more centers would allow for the potential advantages of three-dimensional radiotherapy to be employed in a greater number of patients. Further studies evaluating the use of three-dimensional conformal radiotherapy in patients with nervous system neoplasms should focus on determining the effects on quality of life for the patient and survival compared with more standard treatment techniques.
References 1. Adams EJ, Cosgrove VP, Shepherd SF, et a1 Comparison of a multi-leaf collimator with conformal blocks for the delivery of stereotactically guided conformal radiotherapy. Radiother Oncol 51205-209, 1999 2. Anonymous: Proton therapy for base of skull chordoma: A report for the Royal College of Radiologists. The Proton Therapy Working Party. Clin Oncol 12:75-79, 2000 3. Booth JT, Zavgorodni SF: Set-up error and organ motion uncertainty: A review. Australas Phys Eng Sci Med 222947, 1999 4. Cardinale RM, Benedict SH, Wu Q, et a1 A comparison of three stereotactic radiotherapy techniques: ARCS vs. noncoplanar fixed fields vs. intensity modulation. Int J Radiat Oncol Biol Phys 42431436, 1998 5. Chang CH, Horton J, Schoenfeld D, et al: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer 52997-1007, 1983 6. Debus J, Hug EB, Liebsch NJ, et a1 Brainstem tolerance to conformal radiotherapy of skull base tumors. Int J Radiat Oncol Biol Phys 39:967-975, 1997 7. Fitzek MM, Thornton AF, Rabinov JD, et al: Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: Results of a phase I1 prospective trial. J Neurosurg 91251-260, 1999 8. Fulton DS, Urtasun RC, Scott-Brown I, et a1 Increasing radiation dose intensity using
1014
WEIL
hyperfractionation in patients with malignant glioma: Final report of a prospective phase 1-11 dose response study. J Neurooncol 14:63-72, 1992 9. Habrand JL, Schlienger P, Schwartz L, et al: Clinical applications of proton therapy: Experiences and ongoing studies. Radiat Environ Biophys 34:4144, 1995 10. Hamilton RJ, Kuchnir FT, Sweeney P, et al: Comparison of static conformal field with multiple noncoplanar arc techniques for stereotactic radiosurgery or stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 33:1221-1228, 1995 11. Hudes RS, Corn BW, Werner-Wasik M, et al: A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys 43:293-298, 1999 12. Jalali R, Brada M, Perks JR, et al: Stereotactic conformal radiotherapy for pituitary adenomas: Technique and preliminary experience. Clin Endocrinol (Oxf) 52695-702, 2000 13. Khoo VS, Dearnaley DP, Finnigan DJ, et a1 Magnetic resonance imaging (MRI): Considerations and applications in radiotherapy treatment planning. Radiother Oncol 42:1-15, 1997 14. Kim HK, Thornton AF, Greenberg HS, et al: Results of re-irradiation of primary intracranial neoplasms with three-dimensional conformal therapy. Am J Clin Oncol 20:358-363, 1997 15. Kjellberg R, Shintani A, Frantz A, e t al: Proton-beam therapy in acromegaly. N Engl J Med 278689495,1968 16. Kjellberg RN, Hanamura T, Davis KR, et al: Bragg-peak proton-beam therapy for arteriovenous malformations of the brain. N Engl J Med 309269-274, 1983 17. Kneschaurek P, Stark S, Grosu AL: Treatment planning for conformal stereotactic radiotherapy. Strahlenther Onkol 175(suppl2):8-9, 1999 18. Kortmann RD, Becker G, Perelmouter J, et al: Geometric accuracy of field alignment in fractionated stereotactic conformal radiotherapy of brain tumors. Int J Radiat Oncol Biol Phys 43921-926, 1999 19. Krouwer HG, Prados M D Infiltrative astrocytomas of the thalamus. J Neurosurg 82:548-557, 1995 20. Larsson B, Leksell L, Rexed B,et al: The high energy proton beam as a neurosurgical tool. Nature 182:1222-1223, 1958 21. Leunens G, Menten J, Weltens C, et a1 Quality assessment of medical decision making in radiation oncology: Variability in target volume delineation for brain tumours. Radiother Oncol29:169-175, 1993 22. Li C, Halberg FE, Torigoe EW, et al: A conformal technique for irradiation of pituitary tumors. Med Dosim 22:47-51, 1997 23. Mehta MP, Tome WA, Olivera G H Radiotherapy for brain tumors. Curr Oncol Rep 243&444,2000 24. Miralbell R, Bleher A, Huguenin P, et al: Pediatric medulloblastoma: Radiation treatment technique and patterns of failure. Int J Radiat Oncol Biol Phys 37523-529, 1997 25. Nakagawa K, Aoki Y, Fujimaki T, et a1 High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 40:1141-1149, 1998 26. Paulino AC, Narayana A, Mohideen MN, et al: Posterior fossa boost in medulloblastoma: An analysis of dose to surrounding structures using 3-dimensional (conformal) radiotherapy. Int J Radiat Oncol Biol Phys 46:281-286, 2000 27. Prados MD, Wara WM, Sneed PK, et al: Phase I11 trial of accelerated hyperfractionation with or without difluoromethylomithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys 49:71-77, 2001 28. Roach MR, Pickett B, Weil M, et al: The ”critical volume tolerance method” for estimating the limits of dose escalation during three-dimensional conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 35:1019-1025, 1996 29. Rosenthal SJ, Gall KP, Jackson M, et al: A precision cranial immobilization system for conformal stereotactic fractionated radiation therapy. Int J Radiat Oncol Biol Phys 33~1239-1245,1995
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
1015
30. Schulz RJ: Further improvements in dose distributions are unlikely to affect cure rates. Med Phys 26:1007-1009, 1999 31. Stephenson JA, Wiley A L Current techniques in three-dimensional CT simulation and radiation treatment planning. Oncology (Huntingt) 9:1225-1240,1995 32. Theodorou K, Platoni K, Lefkopoulos D, et a1 Dose-volume analysis of different stereotactic radiotherapy mono-isocentric techniques. Acta Oncol39:157-163,2000 33. Tobias C, Lawrence J, Born J, et al: Pituitary irradiation with high-energy proton beams: A preliminary report. Cancer Res 18:121-134, 1958 34. Tsai JS, Engler MJ, Ling MN, et al: A non-invasive immobilization system and related quality assurance for dynamic intensity modulated radiation therapy of intracranial and head and neck disease. Int J Radiat Oncol Biol Phys 43:455467, 1999 35. Tsao MN, Wara WM, Larson DA: Radiation therapy for benign central nervous system disease. Semin Radiat Oncol9:120-133, 1999
Address reprint requests to Michael D. Weil, MD 584 W CR54 (Douglas Road) Fort Collins, CO 80524 e-mail: michaelQtrilemetry.com
0889-8588/01 $15.00
+ .OO
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS Michael D. Weil, MD
Nor bring, to watch me cease to live Some doctor, full of phrase and fame To shake his sapient head and give The ill he cannot cure a name. MATTHEW ARNOLD
The topic of conforming radiation to the shape of a pathologic brain lesion often begs the issue of whether it makes a difference to the patient.30In principle, it is a good idea to localize a generally toxic agent, such as x-rays, to a target. This localization permits the elevation of dose to the tumor without increasing side effects. The outcome of most brain lesions primarily depends on histology. Benign lesions are discrete and readily targeted, whereas malignant lesions are extremely difficult to separate from invaded tissue and frequently recur in the treated area regardless of the intervention. Advances in genomics and other research relating to tumor biology23are unlikely to affect clinical radiotherapy of brain tumors in the near future. ADVANTAGES OF THREE-DIMENSIONAL RADIOTHERAPY The safe delivery of radiation to malignant or benign masses is complicated by the sensitivity of the normal surrounding tissue. The dose and volume to destroy a tumor are often similar to the radiation
From Sirius Medicine, LLC, Golden, Colorado
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 15 * NUMBER 6 * DECEMBER 2001
1007
1008
WEIL
tolerance of normal organs. Nowhere is this consideration more crucial than in the brain, where vital structures are densely packed and the therapeutic window is narrow. Efforts to target brain tumors better involve a multidisciplinary approach. Improved imaging with CT and MR imaging permits better target definiti~n.'~ Computing capable of converting acquired two-dimensional cuts of a patient to three-dimensional volumes can improve tumor definition and planning significantly. Displays of virtual dose distributions for a given beam geometry permit better evaluation of benefit versus risk of therapy. New hardware can enhance radiation field contours during treatment and deliver x-rays according to the plan. One realistic way to design the dose dispensed to the tumor safely is to optimize the geometry of the beam arrangements. Conventional design of a radiation field is performed with an outline of the patient's body and an outline of the target in one plane. The attenuation of the beam over distance and through tissue is calculated. In.this twodimensional world, there is no way to calculate a beam traveling into or out of the plane of interest. The radiation confined to this one level can travel beyond the target and hit beams on the other side and give additional dose to normal tissue. Overlap of entering and exiting radiation increases the dose to the brain without much therapeutic gain. It is possible by moving beams (arcs) to spread the entrance dose to tolerable levels and by using multiple beams at different angles and planes to decrease the intersection of bearns.'O Such designs can be accomplished best by three-dimensional planning systems. Three-dimensional planning reconstructs two-dimensional computed tomography slices and creates virtual volumes of the body and the lesion.31It then can calculate the beam's interaction with the body from any angle and integrate the dose to give a detailed view of dose to normal organs and the region containing the cancer. The simplest way to use three-dimensional planning to decrease dose to normal tissue while maintaining dose in the target is to use the geometry of multiple beam arrangements. Shooting the tumor with fractions arriving along different paths decreases the dose to any section of intervening normal tissue to a portion of the total number of beams (Fig. 1). As individual beams travel through the patient and exit the tumor, their energy is dissipated in areas that are radiated from the opposite side. By having the beams travel along different planes, this problem is avoided (Fig. 2). The integral dose of radiation absorbed by the patient does not change with these techniques; it is merely spread out. The total dose is distributed through more tissue, but a given area receives a dose that is within its tolerance. ALTERNATIVE BEAMS
Early attempts to localize treatment better employed types of radiation other than x-rays. The discrete properties of the dose deposition
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
A
1009
Bm
Figure 1. A, Tumor in the center of the body treated from the top and bottom with 100 cGy to deliver a total dose of 200 cGy to the lesion. 6, The same total dose of 200 cGy is delivered to the tumor but is divided into eight fractions of 25 cGy each coming from different directions. The dose to the tumor is unchanged and the dose to irradiated normal tissue along the path of the x-ray beam is much less in the example with multiple beams. The total integral dose to the body does not change.
Figure 2. A, Tumor in the center of the body treated from the sides with opposing beams, (#1 and #2 in the same plane of the page) targeting a central tumor. The rectangle represents an area of overlap as each beam exits the tumor into the contralateral ray. 6, The #2 beam has been moved up and away from the plane of the #1 beam (now coming out of the page) but is still aimed at the tumor. There is no longer an overlap because the beams do not run into each other as they exit the tumor.
1010
WEIL
from particle beams portended improved targeting. Particle beams (protons, neutrons, helium, and neon ions) have different physical and biologic properties than conventional x-ray beams (photons). Leksell et alZ0began the clinical use of proton therapy at Uppsala in 1954, when they used a proton beam in the first treatments of human patients. At Berkeley, Lawrence et a1 used the Bragg peak for pituitary radiation in patients with metastatic breast cancer33around the same time. In 1961, Kjellberg et all5began treating patients using protons from the Harvard cyclotron. These investigators performed a comprehensive study of arteriovenous malformations and derived the dose effects correlated to the treated volume, which resulted in radiation necrosis from proton therapy of the brain.I6 There are two accepted clinical indications for proton therapy today: choroidal melanomas (98% 5-year local control, low toxicity, and preservation of vision in 50%) and low-grade skull base chondrosarcomas and chordomas (90% long-term survival).2, Small trials with combined x-rays and protons, have been performed for glioblastoma multiforme7 and showed tolerance of large radiation doses. Proof of efficacy requires showing no selection bias (eg, no imbalance of young and highly functioning patients). Such patients often are referred to academic centers, whereas the average patient with poorer prognosis gets treated closer to home. THREE-DIMENSIONAL METHODS
The Berkeley heavy particle accelerator lost its main funding in the 1990s and no longer treats patients; however, the computer planning that was developed and used there became the basis for modern threedimensional planning programs. The three-dimensional planning software allows the user to look at the tumor from any angle and project a beam from that position. In much the way a gunner aims at a target, this beam's eye view permits better positioning of the beam onto the tumor. At the same time, it shows all of the organs that will be hit by the beam on the near and far side of the target. Beam's eye viewing and accurate pointing permit customized masking of the radiation around the perimeter of the target. Significantly less normal tissue is radiated by blocking out the area of each beam beyond the tumor plus margin. This blocking is done by drawing a line around the mass on the computer image and constructing blocks from the image for the particular beam. The blocks have been made of a low-melting-point alloy of bismuth, lead, tin, and cadmium (Cerrobend) that is poured by hand into a mold for each beam. Individual blocks are thick and heavy and often are put in place above a supine patient. Hardware that is part of the head of the machine, multileaf collimators, is also available to automate the blocking. Multileaf collimation is much less labor intensive and without the risk of dropping onto the patient. Less normal tissue is included, however, by blocking with old-fashioned lead alloy.' More accurate pointing of the x-ray and better localization to the target are
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
1011
important for optimizing therapy, but it is crucial that organ and patient movement be taken into a c c o ~ n t .Organ ~ movement in the head is minimal, but it can be greater than 1 cm in other parts of the body. Movement of the head can be much greater, and devices to immobilize the although “low-tech,” are vital to delivering accurate therapy.% In addition, physician variability in delineating targets can be an important factor in determining accuracy of treatment.21 Arranging beam geometries and shaping the beam have been applied in the clinic as a result of computing and software. These methods for the most part have been used in a static fashion (ie, the beam does not change while it is on). Techniques that permit the beam to change during irradiation are possible with dynamic, multileaf collimation. These methods have been referred to as intensity modulated radiotherapy. Although the output of the machine is unchanged, movement of collimation during the treatment can refine greatly the contours of the dose to the tumor and surrounding region^.^ There are software programs that essentially automate the planning process. So-called inverse planning allows the user first to detail the dose to be delivered to an area, then automatically assigns beams and parameters. A less appreciated and more technical advantage of three-dimensional planning is the ability to calculate the dose given to a specific volume of tissue via dose-volume histograms.28The volume of irradiated tissue increases by the cube of the radius beyond the tumor. As a result, a good deal of normal brain is included in most radiation treatments, which include several centimeters of margin beyond the radiographic abnormality. The greater the volume of normal tissue irradiated means that less total dose can be delivered. Kjellberg’s work16with protons for arteriovenous malformations showed that exceeding a tolerated dose for a given volume resulted in a greater incidence of necrosis. The ability to measure and limit the volume of normal brain receiving a near-maximal dose is necessary to decrease the incidence of necrosis. There are instances in which increased risks are necessary, and dose-volume histograms allow the patient and physician to make informed decisions.32 TOXICITY There are several regions of the brain where lesions portend short survival, and it is possible to do great harm if too much radiation is given to too large a volume. These areas include the motor strip, brainstem, thalam~s,’~ optic nerve and other cranial nerves, hypothalamuspituitary axis, visual cortex, and retina. Doses to significant volumes in these regions greater than 45 Gy can do damage. Although doses in this range may be sufficient to treat benign lesions (eg, around the pituitary’*), they are insufficient to treat malignant brainstem lesions, which require significantly greater doses.6Treating the smallest volume possible can attenuate the risk for these areas. Nonetheless, large doses to the brain with three-dimensional conformal methods have been reported for
1012
WEIL
high-grade gliomasz5and for reirradiating failed intracranial lesions.”, l4 Reports of this nature have to be viewed with caution, however, because the survival in this cohort of patients is often less than the time to morbidity. Hair loss is significant in patients after high-dose radiotherapy to the head. Scalp dose can be controlled with three-dimensional planningzzwith reduced incidence of alopecia.
FIELD SIZE AND DOSE
How much radiation is necessary to kill a particular tumor? What is the appropriate size of the tumor plus surrounding normal tissue that should be treated? What modifications to the treatment are required when radiation is delivered with other modalities? In the case of benign lesions, the answers to these questions are straightforward, but the specifics in the clinical setting for malignant brain lesions are still being pursued.
Malignant Lesions
Trials in the 1970s discredited radiation fields covering the entire brain in treatment of malignant gliomas. For most cancers, it is difficult to delineate the tumor precisely and even harder to know with certainty how far beyond the imaged perimeter cancerous cells extend. The ability to image the brain with MR imaging improves visualization to a point. It is assumed that active tumor cells extend through the area of peritumor edema defined by the T2 (water) signal. Initial radiation portals include the T2 signal on MR imaging plus a border of several centimeters. The covered region, as now defined according to MR imaging parameters, treats the large volumes to 45 Gy with daily fractions of 180 cGy. The boost volume is pared down to the enhancing lesion plus several centimeters, and the dose is increased to 60 Gy. Attempts to improve outcome with altered dosing schemes: plus or minus chemotherapy5 and usually aimed at increasing the total dose, have failed to date.27Besides dosing questions, the technical accuracy of the treatment arrangement would seem to be important for better outcome. In a review of pediatric medulloblastoma from Switzerland, technical factors were not statistically significant in predicting overall survival.” Medulloblastoma is a good example in which clinical concerns outweigh the ability to deliver a better plan with three-dimensional technology. Postoperatively, there is often no evidence of gross disease on imaging. Although it is possible and desirable to decrease the normal tissue radiated in a child with medulloblastoma,26it is uncertain as to whether it is worth the risk of missing tumor in an effort to reduce toxicity by shrinking the field.
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
1013
Benign Lesions
Meningioma and pituitary adenomas are the commonest benign lesions treated with radi~therapy.~~ There has been a trend to treat these and other nonmalignant lesions of the brain with radiosurgery rather than radiotherapy. Some centers have taken a middle ground for these lesions and perform stereotactic radiotherapy.l*Essentially the technique involves a reproducible radiosurgical setuplS and delivers radiotherapy doses with tighter margins.17Regardless, the discrete nature of these lesions allows three-dimensional conformal techniques to be employed with excellent control. Morbidity is the result of the location treated. In the case of the suprasellar and parasellar regions, hormone replacement often is required.
SUMMARY
The technical improvements of three-dimensional conformal radiotherapy can decrease the toxicity of brain treatment to acceptable levels. The adoption of the technique by more centers would allow for the potential advantages of three-dimensional radiotherapy to be employed in a greater number of patients. Further studies evaluating the use of three-dimensional conformal radiotherapy in patients with nervous system neoplasms should focus on determining the effects on quality of life for the patient and survival compared with more standard treatment techniques.
References 1. Adams EJ, Cosgrove VP, Shepherd SF, et a1 Comparison of a multi-leaf collimator with conformal blocks for the delivery of stereotactically guided conformal radiotherapy. Radiother Oncol 51205-209, 1999 2. Anonymous: Proton therapy for base of skull chordoma: A report for the Royal College of Radiologists. The Proton Therapy Working Party. Clin Oncol 12:75-79, 2000 3. Booth JT, Zavgorodni SF: Set-up error and organ motion uncertainty: A review. Australas Phys Eng Sci Med 222947, 1999 4. Cardinale RM, Benedict SH, Wu Q, et a1 A comparison of three stereotactic radiotherapy techniques: ARCS vs. noncoplanar fixed fields vs. intensity modulation. Int J Radiat Oncol Biol Phys 42431436, 1998 5. Chang CH, Horton J, Schoenfeld D, et al: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer 52997-1007, 1983 6. Debus J, Hug EB, Liebsch NJ, et a1 Brainstem tolerance to conformal radiotherapy of skull base tumors. Int J Radiat Oncol Biol Phys 39:967-975, 1997 7. Fitzek MM, Thornton AF, Rabinov JD, et al: Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: Results of a phase I1 prospective trial. J Neurosurg 91251-260, 1999 8. Fulton DS, Urtasun RC, Scott-Brown I, et a1 Increasing radiation dose intensity using
1014
WEIL
hyperfractionation in patients with malignant glioma: Final report of a prospective phase 1-11 dose response study. J Neurooncol 14:63-72, 1992 9. Habrand JL, Schlienger P, Schwartz L, et al: Clinical applications of proton therapy: Experiences and ongoing studies. Radiat Environ Biophys 34:4144, 1995 10. Hamilton RJ, Kuchnir FT, Sweeney P, et al: Comparison of static conformal field with multiple noncoplanar arc techniques for stereotactic radiosurgery or stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 33:1221-1228, 1995 11. Hudes RS, Corn BW, Werner-Wasik M, et al: A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys 43:293-298, 1999 12. Jalali R, Brada M, Perks JR, et al: Stereotactic conformal radiotherapy for pituitary adenomas: Technique and preliminary experience. Clin Endocrinol (Oxf) 52695-702, 2000 13. Khoo VS, Dearnaley DP, Finnigan DJ, et a1 Magnetic resonance imaging (MRI): Considerations and applications in radiotherapy treatment planning. Radiother Oncol 42:1-15, 1997 14. Kim HK, Thornton AF, Greenberg HS, et al: Results of re-irradiation of primary intracranial neoplasms with three-dimensional conformal therapy. Am J Clin Oncol 20:358-363, 1997 15. Kjellberg R, Shintani A, Frantz A, e t al: Proton-beam therapy in acromegaly. N Engl J Med 278689495,1968 16. Kjellberg RN, Hanamura T, Davis KR, et al: Bragg-peak proton-beam therapy for arteriovenous malformations of the brain. N Engl J Med 309269-274, 1983 17. Kneschaurek P, Stark S, Grosu AL: Treatment planning for conformal stereotactic radiotherapy. Strahlenther Onkol 175(suppl2):8-9, 1999 18. Kortmann RD, Becker G, Perelmouter J, et al: Geometric accuracy of field alignment in fractionated stereotactic conformal radiotherapy of brain tumors. Int J Radiat Oncol Biol Phys 43921-926, 1999 19. Krouwer HG, Prados M D Infiltrative astrocytomas of the thalamus. J Neurosurg 82:548-557, 1995 20. Larsson B, Leksell L, Rexed B,et al: The high energy proton beam as a neurosurgical tool. Nature 182:1222-1223, 1958 21. Leunens G, Menten J, Weltens C, et a1 Quality assessment of medical decision making in radiation oncology: Variability in target volume delineation for brain tumours. Radiother Oncol29:169-175, 1993 22. Li C, Halberg FE, Torigoe EW, et al: A conformal technique for irradiation of pituitary tumors. Med Dosim 22:47-51, 1997 23. Mehta MP, Tome WA, Olivera G H Radiotherapy for brain tumors. Curr Oncol Rep 243&444,2000 24. Miralbell R, Bleher A, Huguenin P, et al: Pediatric medulloblastoma: Radiation treatment technique and patterns of failure. Int J Radiat Oncol Biol Phys 37523-529, 1997 25. Nakagawa K, Aoki Y, Fujimaki T, et a1 High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 40:1141-1149, 1998 26. Paulino AC, Narayana A, Mohideen MN, et al: Posterior fossa boost in medulloblastoma: An analysis of dose to surrounding structures using 3-dimensional (conformal) radiotherapy. Int J Radiat Oncol Biol Phys 46:281-286, 2000 27. Prados MD, Wara WM, Sneed PK, et al: Phase I11 trial of accelerated hyperfractionation with or without difluoromethylomithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys 49:71-77, 2001 28. Roach MR, Pickett B, Weil M, et al: The ”critical volume tolerance method” for estimating the limits of dose escalation during three-dimensional conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 35:1019-1025, 1996 29. Rosenthal SJ, Gall KP, Jackson M, et al: A precision cranial immobilization system for conformal stereotactic fractionated radiation therapy. Int J Radiat Oncol Biol Phys 33~1239-1245,1995
CONFORMAL RADIOTHERAPY FOR BRAIN TUMORS
1015
30. Schulz RJ: Further improvements in dose distributions are unlikely to affect cure rates. Med Phys 26:1007-1009, 1999 31. Stephenson JA, Wiley A L Current techniques in three-dimensional CT simulation and radiation treatment planning. Oncology (Huntingt) 9:1225-1240,1995 32. Theodorou K, Platoni K, Lefkopoulos D, et a1 Dose-volume analysis of different stereotactic radiotherapy mono-isocentric techniques. Acta Oncol39:157-163,2000 33. Tobias C, Lawrence J, Born J, et al: Pituitary irradiation with high-energy proton beams: A preliminary report. Cancer Res 18:121-134, 1958 34. Tsai JS, Engler MJ, Ling MN, et al: A non-invasive immobilization system and related quality assurance for dynamic intensity modulated radiation therapy of intracranial and head and neck disease. Int J Radiat Oncol Biol Phys 43:455467, 1999 35. Tsao MN, Wara WM, Larson DA: Radiation therapy for benign central nervous system disease. Semin Radiat Oncol9:120-133, 1999
Address reprint requests to Michael D. Weil, MD 584 W CR54 (Douglas Road) Fort Collins, CO 80524 e-mail: michaelQtrilemetry.com