Radiotherapy for Primary and Metastatic Spinal Tumors O. Kenneth Macdonald, MD,* and Christopher M. Lee, MD†
Primary and metastatic spinal tumors as a group represent a heterogeneous mixture of benign and malignant processes. In general, primary tumors of the spine remain relatively uncommon, and the majority of spinal tumors that are treated annually represent systemic spread of extraosseous primary malignancy. The management of spinal tumors requires meticulous yet expedient attention as the consequences of failed or inappropriate treat- ment can be devastating. Radiotherapy has proven beneficial in many tumors of the spine, particularly metastatic lesions, Ewing’s sarcoma, and myeloid malignancies. A review of the use of radiotherapy for the more common primary spinal malignancies and metastasis is presented. Semin Spine Surg 21:121-128 © 2009 Elsevier Inc. All rights reserved.
KEYWORDS radiotherapy, spine, malignancy, metastasis
lthough relatively uncommon, primary spinal tumors from breast, prostate, lung, kidney, and hematopoietic can- Arepresent a heterogeneous mixture of benign and malig- cers.10-18 nant processes. These result in a broad spectrum of symp- No matter the etiology, the management of spinal tumors toms ranging from a minor backache to severe weakness that requires meticulous but expedient attention as the conse- prevents one from walking (due to neurologic structure im- quences of failed or inappropriate or careless treatment can pingement). Common benign tumors that develop in the be neurologically devastating and potentially irreversible. spine include aneurysmal bone cysts, hemangiomas, giant Surgical intervention has been established as a beneficial cell tumors of bone, osteoid osteomas, meningiomas, and treatment with durable results in the setting of primary and osteoblastomas. There are many primary malignant pro- secondary tumors of the spine.13,16,19-22 The application of cesses that can also develop in the spine, including chordo- radiotherapy (RT) can serve as an adjunct to surgery or at mas, chondrosarcomas, osteosarcomas, Ewing’s sarcomas, times might be used in place of surgery or as a preparative plasmacytomas, multiple myeloma, and lymphoma. Al- regimen to make a tumor more readily resectable. RT is used though the differential diagnosis for a spinal tumor may ap- extensively in tumors of the spine, both in primary and in pear lengthy, these primary disease processes only account metastatic lesions, and this review addresses options, tech- for a minority of all spinal tumors diagnosed annually.1-6 niques, and results of modern-day RT applications. The majority of spinal tumors treated annually represent systemic spread of an extraosseous primary malignancy. Skeletal metastases represent one of the most common man- Radiotherapy ifestations of metastatic malignancy, and vertebral column for Primary Tumors involvement is the most common site for bony metastases to 7 As mentioned previously, there are a variety of primary ma- be located. Although difficult to quantify, estimates suggest lignant tumors of the spine. The most recognized and treated that over 100,000 patients develop osseous metastasis in the malignancies typically derive from 1 of 2 tissue types, soft USA annually. In these patients, it is estimated that 20% have tissues (sarcomas) or hematopoietic cells (hematopoietic can- spinal column involvement.8,9 Most spine metastases derive cers). The frequency of use and effectiveness of primary and adjuvant RT approaches vary greatly among these primary *Department of Radiation Oncology, Mayo Clinic, Rochester, MN. cancers even within tumors of similar cell-level progenitors. †Department of Radiation Oncology, Cancer Care Northwest, Spokane, WA. Address reprint requests to O. Kenneth Macdonald, MD, Department of Chordoma Radiation Oncology, Mayo Clinic, Desk R, Charlton Subway Level, 200 First St. SW, Rochester, MN 55905. E-mail: Macdonald.Orlan@mayo. These rare, slow-growing tumors often arise in the sacrum or edu base of skull.23 Men are more commonly affected than
1040-7383/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. 121 doi:10.1053/j.semss.2009.03.006 122 O.K. Macdonald and C.M. Lee women and are more commonly identified in the fifth to myeloma. Both of these hematologic malignancies are more seventh decades.24 Surgical resection is the mainstay of treat- common in men. Although multiple myeloma is more com- ment but can be fraught with difficulty due to the complexity mon in the sixth and seventh decades of life, solitary plasma- of removing tumors that commonly are intimately associated cytoma typically presents at a younger age.48 Solitary plasma- with nerve roots. Recurrence, although typically indolent in cytoma is a rare entity and by definition is a single tumor its course, can be common.25 RT has been found to be useful involving a specific area of the spine or bone. In a good in the adjuvant and primary setting because of the difficulty proportion of patients, they are thought to predispose the of achieving a complete resection.26-31 The most favorable individual to the subsequent development of multiple my- reported results with RT combine high-dose proton beam eloma regardless of local therapy. Multiple myeloma repre- therapy (PT) with an aggressive surgical approach.32-35 There sents systemic involvement of the marrow space with likely are multiple potential reasons for the improved outcomes diffuse involvement of the spinal column. Both malignancies with PT, but it is likely that the greatest component of success are exquisitely sensitive to RT. Plasmacytoma is commonly derives from the ability to optimize the therapeutic ratio with treated with a 4- to 6-week course of tumor-directed RT with PT to a higher degree than traditional RT with photons (see excellent results in local control.49-52 However, evidence in- below for further explanation). dicates a high, albeit variable, risk of progression to myeloma with 10-year rates commonly reported as greater than Osteosarcoma 50%.53-55 RT is commonly used in multiple myeloma as a Osteosarcoma is a highly malignant tumor that commonly palliative tool to help improve patients’ quality of life, de- develops in young males. In osteosarcoma of the extremity, crease pain, and prevent pathologic fracture. Palliative RT in neoadjuvant chemotherapy followed by complete surgical this situation is commonly delivered with a shorter 2- to 56,57 resection represents the gold standard.36,37 Investigations 3-week course with good results. into adequate therapy without surgery using contemporary chemotherapy are controversial and uncommon.38 RT as a Lymphoma single modality has not been shown to be particularly effec- Lymphoma is described as a “small round blue-cell malig- tive in the primary management of osteosarcoma.39,40 RT nancy” that can develop primarily in the bones of the spine. combined with systemic agents have been infrequently inves- Resection is not typically required or recommended (unless tigated but have shown potential for improving local control necessary for prophylactic measures in stabilizing or rein- and limb preservation following induction with chemother- forcing the vertebrae). Various subtypes of lymphoma can apy.38,41,42 Typically, RT is not administered in the primary involve the bone primarily. Although generally rare, best ev- management of osteosarcoma (including in spinal presenta- idence reveals that primary lymphoma of the spine should be tions) but could be considered in the palliative setting. treated with induction chemotherapy tailored to the lym- phoma cell type, followed by consolidative RT. Several ran- Chondrosarcoma domized studies have demonstrated a significantly improved Chondrosarcomas were first described in 1943 by Lichten- disease-free survival with the combination of chemotherapy stein and Jaffe.43 Although relatively uncommon, they repre- and radiation compared to chemotherapy alone or RT alone sent the second most common primary bone tumor. Oppo- in the primary management of intermediate grade non- site of osteosarcomas, chondrosarcomas typically develop in Hodgkin’s lymphoma.58,59 Although little data regarding RT adulthood (commonly in the fourth to seventh decades). dose for spinal lymphoma are available, it is reasonable to Further, chondrosarcoma is a slow-growing tumor that can extrapolate information from the doses implemented in the develop in any portion of the bony spine. The gold standard above trials for bony primary sites. of therapy for these indolent tumors remains surgical resec- tion and this alone results in a relatively favorable prognosis Ewing’s Sarcoma 44 for patients with newly diagnosed, resectable disease. How- Another “small round blue-cell tumor,” Ewing’s sarcoma is ever, a complete resection can be hampered by the size, lo- the second most common primary tumor of bone in children cation, and extent of the tumor. Historically, it has been (behind osteosarcoma). Ewing’s class of tumor has a charac- believed that chondrosarcomas are typically resistant to both teristic age distribution with presentations uncommon in chemotherapy and RT. Studies investigating the administra- children younger than 8 years of age and in adults older than tion of RT during a course of care for a patient with chondro- 25 years.60 Although primary disease in the spine occurs in a sarcoma indicate that statistically significant improvements relative minority of patients, it historically has represented a in local control can be achieved with 3-dimensional (3D) relatively more aggressive subtype of disease based on con- conformal photon or proton therapy either as a primary or as trol and survival rates compared to other sites.61 The marked 45-47 an adjuvant modality. Nevertheless, wide-surgical resec- improvement in survival realized contemporarily with ad- tion remains the preferred definitive management option. vanced chemotherapy has created a controversy in balancing long-term local disease control with long-term function. Plasmacytoma/Multiple Myeloma It is still not clear what represents the optimal modality for Two other common malignant tumors that can develop in the local control in combination with chemotherapy—surgery, spinal column include solitary plasmacytoma and multiple RT, or some combination. Many of the available data for RT Radiotherapy for spinal tumors 123
Figure 1 Radiotherapy plan with calculated isodoses to a paraspinal/spinal Ewing’s sarcoma. (Color version of figure is available online.) alone are biased because historically many of the patients ponderance of evidence reveals that 70%-90% of patients undergoing primary RT represented an unfavorable popula- will achieve a beneficial response from analgesic-directed RT tion of tumors.62-65 More recent data, however, with modern with complete responses observed in up to 40% of pa- RT techniques, demonstrate comparable rates of local control tients.9,68,69 Further, the palliative role of RT cannot be over- and survival with primary RT compared to historical surgical stated in the patient with multiple sites of pain and tender- controls in patients with complex nonoperable tumors, such ness, as RT commonly represents the least morbid approach as those in the spine or pelvis.61,65,66 Recent and current Co- to achieving broad-spectrum, prompt symptom relief relative operative Group studies recommend using primary RT alone to other medical and surgical options. in patients with bulky tumors and in surgically difficult sites Specific dose-fractionation schedules for palliative treat- (including the spine, skull, and pelvis), as well as for those pa- ment of bone metastases can be variable and are based on the tients with poor response to induction chemotherapy and in particular clinical situation for each patient. There is no stan- which surgery would result in unacceptable functional results dard treatment approach insofar as there are many dose frac- (Fig. 1). RT would be indicated in conjunction with surgery in tionation schedules for uncomplicated spinal skeletal metas- those patients who have inadequate margins. RT typically con- tasis. Two large meta-analyses and an additional update (in sists of 5 to 7 weeks of treatment in the primary setting. addition to hundreds of single institution and collaborative group studies) have consistently revealed no significant dif- Radiotherapy for ferences in complete and partial pain response rates follow- ing single-fraction (8 Gy) vs. multifraction regimens in many Metastatic Disease randomized trials.69-71 The most recent published update re- The spine represents the most common site of skeletal me- ported no observable differences in overall and complete re- tastases with over 18,000 new cases of spinal metastases rec- sponse rates in both intention-to-treat and assessable pa- 70 ognized annually.7,8 Although surgery represents a mainstay tients. However, the likelihood of re-treatment was 2.5-fold in the management of spinal metastases, RT maintains a higher in those undergoing single fraction vs. multifraction tried-and-true role in palliating patients with metastatic dis- therapy. Further analyses have shown a statistically signifi- ease. RT techniques can be employed in a broad range of cant increase in the risk of subsequent pathologic fracture in 69,70 circumstances, including as a prophylactic measure against patients undergoing single-fraction palliative RT. Never- future pathologic fracture, palliation of bone pain, and palli- theless, re-treatment following recrudescence of pain follow- ation of severe symptoms related to cord compression and ing single- or multifraction palliative RT is feasible, well- impending neurologic compromise. tolerated, and without evidence of increased spinal cord toxicity in certain situations.72,73 Noncomplicated Spinal Metastasis Malignant Spinal Cord Compression The beneficial role of achieving analgesia of bone metastases with RT is well documented and has been recognized since The RT approach for patients with more severe spinal in- the early use of photons in medical treatment.67 Although the volvement resulting in cord compression should not be con- response to RT has been quantified and qualified by many fused with that already described for uncomplicated, painful different criteria and instruments over the decades, the pre- metastases. The symptoms of cord compression are not easily 124 O.K. Macdonald and C.M. Lee mistaken as 90% of patients will have pain and up to 50% of the patient while covering the involved spine. Alterna- will have difficulty walking and experience sensory, bowel, tively, if the patient diameter in the treated region is larger, or bladder dysfunction.74-76 the area of treatment interest is deep to the skin (generally Malignant spinal cord compression is best visualized with Ͼ7-8 cm), or if the lower portions of the spine are being magnetic resonance imaging and is identified as compression targeted, 2 directly opposed beams would be employed for of the dural sac and its contents by an extradural tumor mass. therapy with the goal of improved target coverage. When The minimum radiologic evidence for cord compression is treating the upper cervical spine, opposed lateral beams are indentation of the theca at the level corresponding to the commonly used to spare the anterior portion of the neck and clinical features.77 throat and to limit treatment of the esophagus and other Although only a minority of patients who present with radiosensitive soft tissues. malignant cord compression will be surgical candidates, the Commonly, a patient who has consented to undergo RT to role of surgical decompression followed by postoperative RT the spine will have a computed tomographic (CT) simulation was established by a randomized controlled trial reported by before treatment. During the simulation, the patient is posi- Patchell et al.78 One hundred patients with cord compression tioned either supine or prone (rarely in a decubitus position) were randomized to RT alone or surgical decompression fol- and axial CT images are obtained of the body area of interest. lowed by RT. Significantly more patients in the surgery group Using a computer interface, the radiation target area can be were able to walk after the treatment, retained the ability to specifically defined and a common safety margin of one un- walk for a longer duration after treatment, and regained the involved vertebral body above and below the affected area is ability to walk relative to those in the RT alone group. incorporated (eg, if a metastatic lesion is present at T5, radi- However, many patients presenting with malignant cord ation treatment is commonly directed at vertebral levels T4 compression are not candidates for surgery for various rea- through T6). A treatment field can then be designated di- sons, including multiple levels of spinal involvement, limited rectly on the computer or on printed digital reconstructed life expectancy, or concurrent morbidities that prevent a sur- radiographs that are reconstructed from the CT data. The gical procedure. RT represents a mainstay of therapy in those field is then digitally applied to the CT data, and tissue com- patients and is typically supplemented with high-dose corti- pensators may be applied. A dose is prescribed and the spe- costeroids.79,80 RT in both the complicated and the uncom- cific treatment time is then calculated. Verification films of plicated spinal metastasis setting is commonly prescribed to the patient in the treatment position, on the treatment ma- the posterior wall of the vertebral body (or anterior aspect of chine, using mV or kV imaging devices immediately before the spinal cord proper). Typically, most practitioners prefer a the first dose delivery are standard. Depending on the clinical more protracted course of RT in the cord compression setting situation and technology/equipment available, the simula- and courses vary from 5 daily fractions of 4 Gy to 23 daily tion, calculation, and treatment process can now be per- fractions of 2 Gy.68 The most common schema used in the formed entirely on the treatment machine. USA is 10 daily fractions of 3 Gy. However, the available Alternatively, a physician may decide to use a multiple- retrospective and prospective data would indicate no sub- beam arrangement in completing a radiation treatment for a stantial benefit of one fractionation schedule over another spinal tumor. This technique, when employing 2 opposing when analyzing for functional outcomes.81-84 Additionally, lateral beams and a single posterior beam, for example, can some of those series included patients treated with a single optimize dose to the targeted area with the benefit of decreas- 8-Gy fraction course (among other more protracted regi- ing entrance and exit dose to the contents of the anterior mens) and no substantial difference in clinical outcomes or abdomen, thereby reducing the risks of treatment-related increase in acute or late toxicity were reported.81,84 toxicity. Ideally, each treatment approach will be patient- specific in an effort to curtail the risks of therapy and maxi- Radiotherapy Techniques mize target access and thus dose to the designated target area. Modern advances in computer technology and the delivery of RT have led to the development of treatment techniques, 3D Conformal Radiotherapy such as 3D conformal, intensity-modulated, and proton and Intensity-Modulation beam therapy. However, recognizing that most spinal tumors are metastases, much of spinal RT is delivered using conven- Contemporary imaging technologies allow the practicing ra- tional 2-dimensional (2D) techniques or 3D conformal tech- diation oncologist to better define, in 3 dimensions, cancer niques. Techniques involved with each approach, including anatomy and normal tissue anatomy. Magnetic resonance advantages and disadvantages, are discussed. imaging, CT, and positron emission tomography offer an invaluable resource for clearer target delineation and treat- 2D Radiotherapy ment design. The combination of advances and access in imaging technologies with the technical growth of RT, par- 2D RT is a simple and convenient approach to treating spinal ticularly with the advent of computer-controlled multileaf tumors, particularly in the metastatic disease setting (Fig. 2). collimators, has allowed for the development and refinement Typically, a radiation oncologist would elect to use a single of 3D treatment approaches that serve to maximize tumor unopposed field directed anteriorly from the posterior aspect dose and minimize normal tissue exposure. Radiotherapy for spinal tumors 125
Figure 2 Isodose distributions obtained with (A) a single anteriorly directed beam at the thoracic spine level, and (B) a 3-beam (2 opposed-lateral beams and single posterior beam) at the level of the sacrum. (Color version of figure is available online.)
The development of 3D conformal RT plans is approached Stereotactic Body Radiotherapy in a similar manner as outlined in the 2D RT section. The difference, however, is that the 3D conformal approach often By design, stereotactic body radiotherapy (SBRT) is best ap- employs an increased number of beams that are shaped to plied to small treatment volumes, using fewer but signifi- conform to the target. Technological advances, including cantly higher dose fractions, and steep dose gradients—all of multileaf collimators, beam’s eye view, and forward or in- which act in concert to maximize cell kill and minimize the verse treatment planning, are actively used to create and de- risk of damage to normal tissues. Extracranial techniques for liver a 3D plan. Further individual modulation of beams and stereotactic RT have been investigated since the early 1990s beamlets within each beam can achieve even greater confor- and results from the treatment of medically inoperable, early- mity and in conjunction with inverse treatment planning is stage nonsmall cell lung cancer would indicate substantially better known as intensity-modulated radiation therapy improved local control compared to traditional external (IMRT). 3D and IMRT techniques can be used to obtain beam techniques.85-87 Preliminary data in lung cancer suggest greater dose conformity to targets and sharp dose fall off that in addition to high levels of control, SBRT typically re- beyond the target and to decrease dose to adjacent normal sults in low rates of treatment-related toxicity.85-87 tissues (Fig. 3). Although not particularly necessary in the Many institutions have investigated and reported clinical palliative setting where lower doses are commonly applied, outcomes with SBRT in treating metastatic spinal tumors, IMRT and 3D conformal RT have a particularly important both primarily and as re-treatment following clinical failure role in achieving significant total doses to primary malignant of previous radiation by standard dose-fractionation schema. lesions of the spinal column that otherwise would be un- Results indicate a high potential for prompt symptom relief88 achievable owing to the potential for substantial toxicity to and excellent rates of local control with minimal toxicity.89-92 the nearby normal tissues. An extensive discussion of SBRT is beyond the limits of this 126 O.K. Macdonald and C.M. Lee
Figure 3 Beam representations and isodose distributions obtained with an intensity modulated radiotherapy technique at the L2 vertebral body. (Color version of figure is available online.) review; please refer to the article on Stereotactic Radiosurgery ther development of 3D conformal, intensity-modulated, ste- by Levine in this issue. reotactic, and particle therapy techniques (such as proton beam) have changed the role of RT in several primary disease Proton Beam Therapy and metastatic disease settings. In specific tumor types, such as Ewing’s sarcoma, myeloid malignancies, or other primary The use of protons in RT has received increased attention as sarcomas of bone, technical advances and results from past a modality that is equally as effective as photons but with clinical trials have allowed for the expansion of RT’s applica- improved dose distributions.93,94 Proponents highlight the tion with improved local tumor control and patient outcomes benefit of PT in the therapeutic ratio, as PT has the capacity to primarily or as an adjuvant treatment following surgery. The deliver similar or higher doses to malignant tissues while future evolution of radiation therapy and its specific role in decreasing doses to the adjacent normal tissues.95 Although the treatment of both benign and malignant spinal tumors PT has not been extensively investigated clinically in spine will be dependent on further clinical studies in a heteroge- applications, in principle this technique could prove benefi- neous group of patients. cial in treating patients with larger tumor volumes, in com- promised adjacent organ function, or in disease or symptom References progression involving areas that were previously irradiated. 1. Erlemann R: Imaging and differential diagnosis of primary bone tumors Optimally, PT would be delivered to tumors that are more and tumor-like lesions of the spine. Eur J Radiol 58:48-67, 2006 superficial than deep because of their physical properties. 2. Fisher CG, Keynan O, Boyd MC, et al: The surgical management of PT takes advantage of delivering a particle, or proton, primary tumors of the spine: Initial results of an ongoing prospective cohort study. Spine 30:1899-1908, 2005 rather than an energy, which because of its significantly 3. Flemming DJ, Murphey MD, Carmichael BB, et al: Primary tumors of larger mass has a finite range in tissue. Clinically, this trans- the spine. Semin Musculoskelet Radiol 4:299-320, 2000 lates into a beam of “energy” derived from the proton’s inter- 4. Leone A, Costantini A, Guglielmi G, et al: Primary bone tumors and actions with tissue that generate full dose at the depth or level pseudotumors of the lumbosacral spine. Rays 25:89-103, 2000 of the target with little to no exiting energy beyond the target. 5. Rodallec MH, Feydy A, Larousserie F, et al: Diagnostic imaging of solitary tumors of the spine: What to do and say. Radiographics 28: This technique substantially lowers the dose to nontargeted 1019-1041, 2008 adjacent and downstream organs or structures, thereby re- 6. Taiji K, Takahiro H, Takahiro G: [Bone diseases with pain. Primary ducing the risk of tissue injury and toxicity. The use of PT in bone tumors of the spine]. Clin Calcium 17:1435-1440, 2007 spinal tumors is most notable in chordomas.32-35 Owing to 7. Hatrick NC, Lucas JD, Timothy AR, et al: The surgical treatment of the limited number of proton facilities and the generally well- metastatic disease of the spine. Radiother Oncol 56:335-339, 2000 8. Gokaslan ZL, York JE, Walsh GL, et al: Transthoracic vertebrectomy for tolerated use of other RT modalities, PT is not commonly metastatic spinal tumors. J Neurosurg 89:599-609, 1998 used in the metastatic tumor setting currently. 9. Jacobs WB, Perrin RG: Evaluation and treatment of spinal metastases: An overview. Neurosurg Focus 11:e10, 2001 10. Barton R, Robinson G, Gutierrez E, et al: Palliative radiation for verte- Conclusion bral metastases: The effect of variation in prescription parameters on the dose received at depth. Int J Radiat Oncol Biol Phys 52:1083-1091, RT has been used extensively in tumors of the spine, both 2002 primary and metastatic, for several decades. While used most 11. Bilsky MH: New therapeutics in spine metastases. Exp Rev Neurother commonly with palliative intent for metastatic lesions, fur- 5:831-840, 2005 Radiotherapy for spinal tumors 127
12. Chi JH, Gokaslan ZL: Vertebroplasty and kyphoplasty for spinal me- topedico Rizzoli according to the Istituto Ortopedico Rizzoli/osteosar- tastases. Curr Opin Support J Palliat Care 2:9-13, 2008 coma-2 protocol: An updated report. J Clin Oncol 18:4016-4027, 2000 13. Preciado DA, Sebring LA, Adams GL: Treatment of patients with spinal 37. Ferguson WS, Goorin AM: Current treatment of osteosarcoma. Cancer metastases from head and neck neoplasms. Arch Otolaryngol Head Invest 19:292-315, 2001 Neck Surg 128:539-543, 2002 38. Machak GN, Tkachev SI, Solovyev YN, et al: Neoadjuvant chemother- 14. Rao G, Ha CS, Chakrabarti I, et al: Multiple myeloma of the cervical apy and local radiotherapy for high-grade osteosarcoma of the extrem- spine: Treatment strategies for pain and spinal instability. J Neurosurg ities. Mayo Clin Proc 78:147-155, 2003 Spine 5:140-145, 2006 39. Beck JC, Wara WM, Bovill EG Jr, et al: The role of radiation therapy in 15. Ruckdeschel JC: Early detection and treatment of spinal cord compres- the treatment of osteosarcoma. Radiology 120:163-165, 1976 sion. Oncol Williston Park 19:81-86, discussion, 86, 89-92, 2005 40. Jenkin RD, Allt WE, Fitzpatrick PJ: Osteosarcoma. An assessment of 16. Sciubba DM, Nguyen T, Gokaslan ZL: Solitary vertebral metastasis. management with particular reference to primary irradiation and selec- Orthop Clin North Am 40:145-154, 2009 tive delayed amputation. Cancer 30:393-400, 1972 17. Selvaggi K, Abrahm J: Metastatic spinal cord compression: The hidden 41. Carrie C, Breteau N, Negrier S, et al: The role of fast neutron therapy in danger. Nat Clin Pract Oncol 3:458-461, quiz following 461, 2006 unresectable pelvic osteosarcoma: Preliminary report. Med Pediatr On- 18. Swift PS: Radiation for spinal metastatic tumors. Orthop Clin North Am col 22:355-357, 1994 40:133-144, 2009 42. Lombardi F, Gandola L, Fossati-Bellani F, et al: Hypofractionated ac- 19. Cheung G, Chow E, Holden L, et al: Percutaneous vertebroplasty in celerated radiotherapy in osteogenic sarcoma. Int J Radiat Oncol Biol patients with intractable pain from osteoporotic or metastatic fractures: Phys 24:761-765, 1992 A prospective study using quality-of-life assessment. Can Assoc Radiol 43. Lichtenstein L, Jaffe HL: Chondrosarcomas of bone. Am J Pathol 19: J 57:13-21, 2006 553-589, 1943 20. Gok B, McGirt M, Sciubba DM, et al: Surgical resection plus adjuvant 44. Marcove RC, Mike V, Hutter RV, et al: Chondrosarcoma of the pelvis radiotherapy is superior to surgery or radiotherapy alone in the pre- and upper end of the femur. An analysis of factors influencing survival vention of neurological decline in a rat metastatic spinal tumor model. time in one hundred and thirteen cases. J Bone Joint Surg Am 54:561- Neurosurgery 63:346-351, 2008, discussion 351 572, 1972 21. Healey JH, Brown HK: Complications of bone metastases: Surgical 45. Hug EB, Loredo LN, Slater JD, et al: Proton radiation therapy for chor- management. Cancer 88:2940-2951, 2000 domas and chondrosarcomas of the skull base. J Neurosurg 91:432- 22. Khan SN, Donthineni R: Surgical management of metastatic spine tu- 439, 1999 mors. Orthop Clin North Am 37:99-104, 2006 46. Munzenrider JE, Liebsch NJ: Proton therapy for tumors of the skull 23. Tai PT, Craighead P, Bagdon F: Optimization of radiotherapy for pa- base. Strahlenther Onkol 175:57-63, 1999 (suppl 2) tients with cranial chordoma. A review of dose–response ratios for 47. Rosenberg AE, Nielsen GP, Keel SB, et al: Chondrosarcoma of the base photon techniques. Cancer 75:749-756, 1995 of the skull: A clinicopathologic study of 200 cases with emphasis on its 24. Wold LE, Laws ER Jr: Cranial chordomas in children and young adults. distinction from chordoma. Am J Surg Pathol 23:1370-1378, 1999 J Neurosurg 59:1043-1047, 1983 48. Hernandez JA, Land KJ, McKenna RW: Leukemias, myeloma, and 25. Kaiser TE, Pritchard DJ, Unni KK: Clinicopathologic study of sacrococ- other lymphoreticular neoplasms. Cancer 75:381-394, 1995 cygeal chordoma. Cancer 53:2574-2578, 1984 49. Bolek TW, Marcus RB, Mendenhall NP: Solitary plasmacytoma of bone 26. al-Mefty O, Borba LA: Skull base chordomas: A management challenge. and soft tissue. Int J Radiat Oncol Biol Phys 36:329-333, 1996 J Neurosurg 86:182-189, 1997 50. Liebross RH, Ha CS, Cox JD, et al: Solitary bone plasmacytoma: Out- 27. Catton C, O’Sullivan B, Bell R, et al: Chordoma: Long-term follow-up come and prognostic factors following radiotherapy. Int J Radiat Oncol after radical photon irradiation. Radiother Oncol 41:67-72, 1996 Biol Phys 41:1063-1067, 1998 28. Cheng EY, Ozerdemoglu RA, Transfeldt EE, et al: Lumbosacral chor- 51. Liebross RH, Ha CS, Cox JD, et al: Clinical course of solitary extramed- doma. Prognostic factors and treatment. Spine 24:1639-1645, 1999 ullary plasmacytoma. Radiother Oncol 52:245-249, 1999 29. Debus J, Schulz-Ertner D, Schad L, et al: Stereotactic fractionated ra- 52. Mill WB, Griffith R: The role of radiation therapy in the management of diotherapy for chordomas and chondrosarcomas of the skull base. Int J plasma cell tumors. Cancer 45:647-652, 1980 Radiat Oncol Biol Phys 47:591-596, 2000 53. Ozsahin M, Tsang RW, Poortmans P, et al: Outcomes and patterns of 30. Foweraker KL, Burton KE, Maynard SE, et al: High-dose radiotherapy failure in solitary plasmacytoma: A multicenter Rare Cancer Network in the management of chordoma and chondrosarcoma of the skull base study of 258 patients. Int J Radiat Oncol Biol Phys 64:210-217, 2006 and cervical spine. Part 1. Clinical outcomes. Clin Oncol (R Coll Ra- 54. Tsang RW, Gospodarowicz MK, Pintilie M, et al: Solitary plasmacytoma diol) 19:509-516, 2007 treated with radiotherapy: Impact of tumor size on outcome. Int J 31. Noel G, Habrand JL, Jauffret E, et al: Radiation therapy for chordoma Radiat Oncol Biol Phys 50:113-120, 2001 and chondrosarcoma of the skull base and the cervical spine. Prognos- 55. Wilder RB, Ha CS, Cox JD, et al: Persistence of myeloma protein for tic factors and patterns of failure. Strahlenther Onkol 179:241-248, more than one year after radiotherapy is an adverse prognostic factor in 2003 solitary plasmacytoma of bone. Cancer 94:1532-1537, 2002 32. Igaki H, Tokuuye K, Okumura T, et al: Clinical results of proton beam 56. Adamietz IA, Schober C, Schulte RW, et al: Palliative radiotherapy in therapy for skull base chordoma. Int J Radiat Oncol Biol Phys 60:1120- plasma cell myeloma. Radiother Oncol 20:111-116, 1991 1126, 2004 57. Leigh BR, Kurtts TA, Mack CF, et al: Radiation therapy for the palliation 33. Nguyen QN, Chang EL: Emerging role of proton beam radiation ther- of multiple myeloma. Int J Radiat Oncol Biol Phys 25:801-804, 1993 apy for chordoma and chondrosarcoma of the skull base. Curr Oncol 58. Horning SJ, Weller E, Kim K, et al: Chemotherapy with or without Rep 10:338-343, 2008 radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lym- 34. Noel G, Feuvret L, Calugaru V, et al: Chordomas of the base of the skull phoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol and upper cervical spine. One hundred patients irradiated by a 3D 22:3032-3038, 2004 conformal technique combining photon and proton beams. Acta Oncol 59. Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone com- 44:700-708, 2005 pared with chemotherapy plus radiotherapy for localized intermediate- 35. Weber DC, Rutz HP, Pedroni ES, et al: Results of spot-scanning proton and high-grade non-Hodgkin’s lymphoma. N Engl J Med 339:21-26, radiation therapy for chordoma and chondrosarcoma of the skull base: 1998 The Paul Scherrer Institut experience. Int J Radiat Oncol Biol Phys 60. Cotterill SJ, Ahrens S, Paulussen M, et al: Prognostic factors in Ewing’s 63:401-409, 2005 tumor of bone: Analysis of 975 patients from the European InterGroup 36. Bacci G, Ferrari S, Bertoni F, et al: Long-term outcome for patients with Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 18:3108- nonmetastatic osteosarcoma of the extremity treated at the Istituto Or- 3114, 2000 128 O.K. Macdonald and C.M. Lee
61. La TH, Meyers PA, Wexler LH, et al: Radiation therapy for Ewing’s 79. Sorensen S, Helweg-Larsen S, Mouridsen H, et al: Effect of high-dose sarcoma: Results from Memorial Sloan-Kettering in the modern era. Int dexamethasone in carcinomatous metastatic spinal cord compression J Radiat Oncol Biol Phys 64:544-550, 2006 treated with radiotherapy: A randomised trial. Eur J Cancer 30A:22-27, 62. Carrie C, Mascard E, Gomez F, et al: Nonmetastatic pelvic Ewing’ 1994 sarcoma: Report of the French society of pediatric oncology. Med Pe- 80. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al: Initial bolus of diatr Oncol 33:444-449, 1999 conventional versus high-dose dexamethasone in metastatic spinal 63. Donaldson SS, Torrey M, Link MP, et al: A multidisciplinary study cord compression. Neurology 39:1255-1257, 1989 investigating radiotherapy in Ewing’s sarcoma: End results of POG # 81. Hoskin PJ, Grover A, Bhana R: Metastatic spinal cord compression: 8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42:125- Radiotherapy outcome and dose fractionation. Radiother Oncol 68: 135, 1998 175-180, 2003 64. Sailer SL, Harmon DC, Mankin HJ, et al: Ewing’s sarcoma: Surgical 82. Maranzano E, Bellavita R, Rossi R, et al: Short-course versus split- resection as a prognostic factor. Int J Radiat Oncol Biol Phys 15:43-52, course radiotherapy in metastatic spinal cord compression: Results of a 1988 phase III, randomized, multicenter trial. J Clin Oncol 23:3358-3365, 65. Schuck A, Ahrens S, Paulussen M, et al: Local therapy in localized 2005 Ewing tumors: Results of 1058 patients treated in the cess 81, cess 86, 83. Rades D, Fehlauer F, Stalpers LJ, et al: A prospective evaluation of two and EICESS 92 trials. Int J Radiat Oncol Biol Phys 55:168-177, 2003 radiotherapy schedules with 10 versus 20 fractions for the treatment of 66. Yock TI, Krailo M, Fryer CJ, et al: Local control in pelvic Ewing’ sar- metastatic spinal cord compression: Final results of a multicenter coma: Analysis from INT-0091—A report from the Children’s Oncol- study. Cancer 101:2687-2692, 2004 ogy Group. J Clin Oncol 24:3838-3843, 2006 84. Rades D, Stalpers LJ, Veninga T, et al: Evaluation of five radiation 67. Leddy ET: The roentgen treatment of metastasis to the vertebrae and schedules and prognostic factors for metastatic spinal cord compres- the bones of the pelvis from carcinoma of the breast. AJR Am J Roent- sion. J Clin Oncol 23:3366-3375, 2005 genol XXIV:657-672, 1930 85. Baumann P, Nyman J, Lax I, et al: Factors important for efficacy of 68. Agarawal JP, Swangsilpa T, van der Linden Y, et al: The role of external stereotactic body radiotherapy of medically inoperable stage I lung beam radiotherapy in the management of bone metastases. Clin Oncol cancer. A retrospective analysis of patients treated in the Nordic coun- (R Coll Radiol) 18:747-760, 2006 tries. Acta Oncol 45:787-795, 2006 69. Sze WM, Shelley M, Held I, et al: Palliation of metastatic bone pain: 86. Onishi H, Shirato H, Nagata Y, et al: Hypofractionated stereotactic Single fraction versus multifraction radiotherapy—A systematic review radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: Up- of the randomised trials. Cochrane Database Syst Rev 2:CD004721, dated results of 257 patients in a Japanese multi-institutional study. 2004 J Thorac Oncol 2:S94-100, 2007 70. Chow E, Harris K, Fan G, et al: Palliative radiotherapy trials for bone 87. Timmerman R, McGarry R, Yiannoutsos C, et al: Excessive toxicity metastases: A systematic review. J Clin Oncol 25:1423-1436, 2007 when treating central tumors in a phase II study of stereotactic body 71. Wu JS, Wong R, Johnston M, et al: Meta-analysis of dose-fractionation radiation therapy for medically inoperable early-stage lung cancer. radiotherapy trials for the palliation of painful bone metastases. Int J J Clin Oncol 24:4833-4839, 2006 Radiat Oncol Biol Phys 55:594-605, 2003 88. Ryu S, Jin R, Jin JY, et al: Pain control by image-guided radiosurgery for 72. Mithal NP, Needham PR, Hoskin PJ: Retreatment with radiotherapy for solitary spinal metastasis. J Pain Symptom Manage 35:292-298, 2008 painful bone metastases. Int J Radiat Oncol Biol Phys 29:1011-1014, 89. Chang EL, Shiu AS, Mendel E, et al: Phase I/II study of stereotactic body 1994 radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg 73. van der Linden YM, Steenland E, van Houwelingen HC, et al: Patients Spine 7:151-160, 2007 with a favourable prognosis are equally palliated with single and mul- 90. Gerszten PC, Burton SA, Ozhasoglu C, et al: Radiosurgery for spinal tiple fraction radiotherapy: Results on survival in the Dutch Bone me- metastases: Clinical experience in 500 cases from a single institution. tastasis study. Radiother Oncol 78:245-253, 2006 Spine 32:193-199, 2007 74. Loblaw DA, Perry J, Chambers A, et al: Systematic review of the diag- 91. Samuel R, Yin FF, Rock J, et al: Image-guided and intensity-modulated nosis and management of malignant extradural spinal cord compres- radiosurgery for patients with spinal metastasis. Cancer 97:2013-2018, sion: The cancer care Ontario Practice Guidelines Initiative’s Neuro- 2003 Oncology Disease Site Group. J Clin Oncol 23:2028-2037, 2005 92. Yamada Y, Bilsky MH, Lovelock DM, et al: High-dose, single-fraction 75. Perrin RG: Metastatic tumors of the axial spine. Curr Opin Oncol image-guided intensity-modulated radiotherapy for metastatic spinal 4:525-532, 1992 lesions. Int J Radiat Oncol Biol Phys 71:484-490, 2008 76. Sundaresan N, Galicich JH: Treatment of spinal metastases by vertebral 93. Glimelius B, Ask A, Bjelkengren G, et al: Number of patients potentially body resection. Cancer Invest 2:383-397, 1984 eligible for proton therapy. Acta Oncol 44:836-849, 2005 77. Laperriere NJ: The Management of Spinal Cord Compression. Toronto, 94. Goitein M, Cox JD: Should randomized clinical trials be required for ON, Canada, Princess Margaret Hospital, 1996 proton radiotherapy? J Clin Oncol 26:175-176, 2008 78. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical 95. Lee CH, Tait D, Nahum AE, et al: Comparison of proton therapy and resection in the treatment of spinal cord compression caused by meta- conformal X-ray therapy in non-small cell lung cancer (NSCLC). Br J static cancer: A randomised trial. Lancet 366:643-648, 2005 Radiol 72:1078-1084, 1999