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Pain relief following spinal lesion treatment with stereotactic radiosurgery: Clinical experience in 65 cases.

Byline: Shih-Wei. Hsu, Hsing-Lung. Chao, Kuen-Tze. Lin, Yu-Ching. Chou, Cheng-Hsiang. Lo, Shih-Yu. Lee, Wen-Yen. Huang, Chun-Shu. Lin, Chien-Min. Lin, Chao-Yueh. Fan, Da-Tong. Ju

Background: This study determines the pain-reducing effect of CyberKnife radiosurgery in the treatment of spinal lesions. Materials and Methods: We evaluated the clinical outcomes of patients treated with CyberKnife radiosurgery for spinal lesions in 65 patients with 76 spinal lesions at Tri-Service General Hospital, Taipei, Taiwan, from July 2007 to May 2013. Pre- and post-treatment visual analog scale (VAS) scores for pain were obtained. Results: In the benign cases, 12 patients had a pretreatment VAS score of 7 (46.2%); 12 patients, 8 (46.2%); and 2 patients, 9 (7.7%). For the posttreatment VAS scores, 10 patients had a score of 1 (38.4%); 15 patients, 2 (57.7%); and 1 patient, 4 (3.8%). In the malignant cases, 2 patients had a pretreatment VAS score of 8 (28.6%); 3 patients, 9 (42.9%); and 2 patients, 10 (28.6%). For the posttreatment VAS scores, 1 patient had a score of 2 (14.3%) and 6 patients had a score of 3 (85.7%). In the metastatic cases, 15 patients had a pretreatment VAS score of 8 (46.9%); 7 patients, 9 (21.9%); and 10 patients, 10 (31.3%). For the posttreatment VAS scores, 3 patients had a score of 1 (9.4%); 11 patients, 2 (34.4%); 16 patients, 3 (50%); and 2 patients, 4 (6.3%). Wilcoxon signed-rank tests to compare the pre- and post-treatment VAS scores in each patient group showed significant decreases in all groups (P < 0.05 for all comparisons). Conclusions: Collectively, these results show that significant pain relief without obvious adverse effects can be achieved when treating spinal lesions using stereotactic radiosurgery.


The use of stereotactic radiosurgery for treating both benign and malignant intracranial lesions is well-established. [sup][1],[2] It is also a practical treatment for brain metastases. [sup][3],[4] Benign lesions such as meningiomas, acoustic neuromas, pituitary adenomas, and arteriovenous malformations can be primarily treated with radiosurgery. [sup][5],[6],[7],[8] The main goals of radiotherapy in the treatment of spinal tumors are to relieve pain, prevent pathologic fractures, and preserve neurologic function. [sup][9]

Drawbacks to using the conventional radiotherapy technique include the presence of large irradiated areas and overdoses in the surrounding normal organs. The tumor locations, which can often be difficult to reach surgically, and the general condition of the patients often limit the success rate of surgical tumor removal. Another treatment option is radiosurgery, a noninvasive technique that can treat the tumor more precisely. Gamma knife radiosurgery can treat intracranial, but not extracranial, tumors, and requires an additional fixed frame. CyberKnife radiosurgery (Accuray Inc., Sunnyvale, CA, USA), on the other hand, is frameless and can target both intra- and extra-cranial tumors using the intrafraction image-guided tracking technique (through fiducial marker implantation or using a bony structure as a marker).

CyberKnife is different from the conventional linear accelerator because it has a dynamic tracking system. It consists of diagnostic-quality X-ray imaging devices with a computer-controlled robotic arm. Multiple noncoplanar and nonisocentric radiation beams can be delivered by CyberKnife. Thus, CyberKnife can send updated position information to the robot, allowing adaptive beam algorithms to adjust for patient movement, which permits accurate radiotherapy. In view of the radiation source can track the target, complete target immobilization is unnecessary. [sup][10],[11],[12] For spine lesions, the Xsight spine-tracking mode is useful. In addition, the average set-up error is around 0.52-0.61 mm. Use of this technique for treating spinal lesions (benign, malignant, or metastatic) can improve patients' quality of life and decrease the adverse effects of radiotherapy. [sup][13],[14],[15],[16],[17]

The spine is the most common site of cancer metastasis to bone. Bone pain is a major patient concern, and the degree of bone pain is often underestimated. Spinal compression can lead to a poor quality of life, as it can significantly affect motor and sensory functions. [sup][18],[19] Breast cancer, lung cancer, and prostate cancer are easily metastatic to bone. Subsequently, metastatic bone pain, compression fractures, and spinal cord compression develop. Hence, the palliative intent of spinal metastasis treatment is to relieve pain and reduce neurologic deficits. The purpose of this study, therefore, was to determine the pain-reducing effects of CyberKnife radiosurgery in patients being treated for spinal lesions.

Materials and Methods

Patient selection

We retrospectively reviewed the files of patients who received CyberKnife radiosurgery for spinal lesions from July 2007 to May 2013 in the stereotactic radiosurgery center of a single medical center at Tri-Service General Hospital, Taipei, Taiwan. The eligibility criteria were as follows:

*Primary spinal lesions where surgery was not considered feasible or appropriate, *Spine metastases in the context of oligometastatic disease, and *Symptomatic spine metastases. A total of 65 patients with 76 spinal lesions treated by CyberKnife radiosurgery were identified (34 men and 31 women; mean age: 53 years; age range: 8-87 years).

The length of follow-up ranged from 3 to 61 months (median: 16 months). [Table 1], [Table 2] and [Table 3] provide summaries of the clinical characteristics and treatment in each of the patient groups. The protocol was approved by the Institutional Review Boards of the Medical Centers in Taiwan.{Table 1}{Table 2}{Table 3}

Radiosurgery technique

All patients wore a custom-made aquaplast mask (WFR/Aquaplast Corp., Wyckoff, NJ, USA) and were immobilized on the treatment table. For treatment planning, before computed tomography and magnetic resonance imaging (MRI) using T1-weighted images were performed, 125 mL of omnipaque contrast (350 mg I/mL; Nycomed, Inc., Princeton, NJ, USA) was administered intravenously. The neurosurgeon offered lesion and critical organ contours and the radiation oncologist supplied the prescription dose and dose constraints for the critical organs. The CyberKnife treatment planning system (Multiplan v2.1) and Xsight spine-tracking mode were used in all patients. We evaluated each treatment plan using the tumor coverage, homogeneity index (HI), conformity index (CI), and new CI (nCI). The HI = D [sub]max /prescribed dose, where D [sub]max is the maximum dose, while CI = prescription isodose volume (PIV)/tumor isodose volume (TIV), where PIV is the total three-dimensional volume of the isodose line and TIV is the tumor volume covered by the isodose volume. The nCI = tumor volume (TV) x plan target volume/(target isodose volume). [sup][2],[20]

Radiation dosage and isodose lines

The doses and fractionation were different because of the different nature of each lesion. For benign cases, the average prescription dose (Gy) was 25.9 [+ or -] 7.8 (range: 12-60 Gy), and the average fraction was 4.6 [+ or -] 1 fractions (range: 1-5 fractions). For malignant cases, the average prescription dose (Gy) was 26.7 [+ or -] 6.1 (range: 21-40 Gy), and the average fraction was 4.3 [+ or -] 1 fractions (range: 3-5 fractions). For metastatic cases, the average prescription dose (Gy) was 27.7 [+ or -] 7.7 (range: 7.6-50 Gy), and the average fraction was 4.4 [+ or -] 1.2 fractions (range: 1-5 fractions). The radiation dose prescribed was between 70% and 80% of the isodose lines.

Pre- and post-treatment pain scores and follow-up

We evaluated the patients' pretreatment pain levels on the first clinical visit before CyberKnife radiosurgery. We assessed the degree of pain using a visual analog scale (VAS) with scores ranging from 0 to 10. [sup][21],[22] The first posttreatment clinical visit was scheduled 1-month after CyberKnife radiosurgery. Each change in the prescribed analgesics was recorded. Further evaluation and MRI images were obtained at 3, 9, and 18 months after treatment. When comparing the pretreatment MRI images to the ones acquired 3 months after treatment, [sup][23] we checked the tumor size and measured the tumor volume (Vol) with the following formula: Vol (mm [sup]3 ) = Tr (a x b x c)/6, where a, b, and c are the width, height, and thickness, respectively. The World Health Organization Handbook for Reporting Results of Cancer Treatment was used to classify the response to therapy as a complete response, partial response, stable disease, or progression.

Based on the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0), toxicity was evaluated during and after the treatment at 1-2 month intervals for the first 6 months and then every 3 months until 18 months.

Statistical analysis

Descriptive summaries were used to describe the clinical characteristics. The Wilcoxon signed-rank test was used to compare the VAS scores and tumor volumes before and after radiosurgery between groups. We used Spearman correlation coefficients to clarify the correlation between the observed pain reduction effect and other related factors, such as the dose, prescribed isodose lines, tumor percentage covered, and the difference in tumor volume before and after radiosurgery. All statistical tests were two-tailed, and P < 0.05 was considered as statistically significant. Data analyses were performed using SPSS Statistics version 22 (IBM[R], SPSS[R], Statistics 22, Chicago, IL, USA).


Patient demographics

We identified 65 patients with 76 spinal lesions treated by CyberKnife radiosurgery between July 2007 and May 2013 at Tri-Service General Hospital, Taipei, Taiwan. Of these patients, 26 patients had benign spinal lesions, 7 patients had primary malignant spinal lesions, and 32 patients had metastatic spinal lesions. [Table 1], [Table 2] and [Table 3] provide summaries of the clinical characteristics and treatment in each patient group.

Pain evaluation

We used the VAS to assess the degree of pain before and after radiosurgery [Table 4]. The Wilcoxon signed-rank test and a nonparametric group comparison test were used to examine the differences between the VAS scores assessed before and after radiosurgery in the benign, malignant, and metastatic groups. All three groups showed significant decreases in the VAS scores after radiosurgery ( P < 0.001, P = 0.017, and P < 0.001, respectively) [Table 5].{Table 4}{Table 5}

However, it is possible that the observed pain relief was secondary to the effect of radiotherapy on the tumors. Indeed, tumor volume significantly decreased after radiosurgery in both the benign and metastatic groups ( P = 0.005 and 0.015, respectively) [Table 5]. To determine the associations between the obtained outcomes (pain) and potential confounders, we performed Spearman correlation analyses. Spearman correlation analyses of the associations between the VAS differences and the clinical parameters, including the dose, prescription isodose lines, tumor percentage covered, and tumor volume differences revealed no significant correlations ( P values were 0.930, 0.965, 0.301, and 0.058, respectively) [Table 6].{Table 6}

Treatment-related toxicities

No radiation-induced myelopathy or radiculopathy was noted at the 1-month follow-up examination. Furthermore, there were no clinically detectable neurologic signs caused by radiation-induced spinal cord injury. Only 5 patients experienced Grade 1 nausea during treatment.


The results of the present study show that a significant pain-relieving effect occurs after CyberKnife radiosurgery in patients with benign, malignant, and metastatic spinal lesions. Furthermore, we showed for the 1 [sup]st time that this pain-relieving effect was not associated with the treatment dose, prescription isodose line, tumor percentage covered, or reduction in tumor volume.

According to a recent survey, up to 40% of practicing oncologists in the United States routinely use this procedure. [sup][24] Treating spinal cord associated lesions is one of the four primary uses of this technique outlined by the National Library of Medicine. Although a number of large-scale clinical trials have used this approach to treat pain associated malignancies, [sup][25],[26],[27],[28] and the use of low-dosage radiation and radiosurgery for pain relief in bone metastasis is also reasonably well-established, [sup][29] our study still provides some new and interesting findings. First, we showed that the pain-relieving effect was not associated with the treatment dose, prescription isodose line, tumor percentage covered, or reduction in tumor volume, which has not been reported previously. Furthermore, our clinical data suggest the possibility of a radiotherapy-related mechanism of bone pain reduction.

The mechanism for reducing bone pain using conventional radiotherapy or radiosurgery is still controversial. Some preclinical studies confirmed that the effect may be caused by reduced cancer burden, reduced osteolysis, or alterations in nociceptive transmission in the central nervous system. [sup][30],[31],[32] In our study, we used Spearman correlation analyses to show that the pain-reducing effect has little correlation with the dose, prescription isodose line, tumor percentage covered, and reduced tumor volume. These findings echo the above preclinical data.

Compared to conventionally fractionated radiotherapy for spinal lesions, CyberKnife technology can shorten the total treatment time, improve the treatment accuracy, and increase patient comfort during treatment. However, it is expensive and the National Health Insurance does not pay for this technique in Taiwan. Thus, the availability and feasibility of using CyberKnife radiosurgery to treat spinal lesions are still restricted. Our data show that most patients with spinal tumors suffer from pain rather than from progressive neurologic deficits. The life span of these patients is limited by systemic disease rather than by spinal metastasis. Therefore, pain control is the most important treatment goal for patients with spinal tumors. Several studies have demonstrated the feasibility and safety of delivering radiation doses to the spine using CyberKnife technology. [sup][1],[10],[33],[34],[35],[36] In our study, significant pain relief was achieved in all patient groups without obvious adverse effects by using stereotactic radiosurgery.

In a retrospective study conducted by Chang et al ., [sup][37] 30 benign spinal tumors in 20 patients were treated with CyberKnife radiosurgery from 2002 to 2008. Significant relief of radicular and myelopathic pain was achieved after radiosurgery in most cases (94%). These findings suggest that CyberKnife has the ability to control benign spinal tumors without complications in most cases. [sup][37]

A prospective case-series study conducted by Wowra et al . [sup][38] offered clinical results of CyberKnife spinal radiosurgery without fiducial implantation. A total of 134 malignant spinal tumors in 102 patients were evaluated. Patients were only included if they had metastatic spinal lesions and not more than two tumors. The spinal pain was scored using the VAS. Within 1-week of CyberKnife radiosurgery, the pretreatment VAS score of 7 was dramatically reduced to 1. The authors concluded that CyberKnife radiosurgery for spinal lesions was a noninvasive, safe, and effective radiotherapeutic treatment method for patients with severe pain and 1 or 2 small spinal malignant tumors. [sup][38]

Although we believe that the results presented here are compelling, we cannot exclude potential effects related to the heterogeneity of treatment regiments and the variety of confounding factors related to prior pain management. We did not observe correlations between the radiation dosage and VAS differences; nevertheless, additional trials with larger groups treated with consistent dosages of radiation would improve the treatment protocols with respect to pain management. The consistent pain relief that we observed in this study indicates that stereotactic radiosurgery is a feasible and effective approach for improving the quality of life in patients with spinal tumors compared with the traditional fractionated radiotherapy.

In the present study, we focused on the pain relief after radiosurgery, which were obtained from the medical records. In addition, we found that 15 patients of benign cases and 17 patients with metastatic cases were treated with CyberKnife radiosurgery because of muscle weakness and numbness. However, the detailed neurological function is lacking in the medical records. The assessment, such as 36-item or 12-item Short Form Health Survey, to evaluate the recovery of neurological function is definitely needed in the future study.

To summarize, CyberKnife radiosurgery is an effective method for relieving pain in patients with spinal lesions. This technique is underused and needs to be promoted in Taiwan.


The authors thank Mr. Chen Kuan-Yu and Cactus Communications Pvt., Ltd., for their assistance with the English editing.


1. Chang SD, Murphy M, Geis P, Martin DP, Hancock SL, Doty JR, et al . Clinical experience with image-guided robotic radiosurgery (the Cyberknife) in the treatment of brain and spinal cord tumors. Neurol Med Chir (Tokyo) 1998;38:780-3.

2. Chang SD, Adler JR Jr. Current status and optimal use of radiosurgery. Oncology (Williston Park) 2001;15:209-16.

3. Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Goodman ML, Shaw EG, et al . A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994;28:797-802.

4. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427-434.

5. Ganz JC, Backlund EO, Thorsen FA. The effects of Gamma Knife surgery of pituitary adenomas on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 1993;61 (Suppl 1):30-7.

6. Colombo F, Pozza F, Chierego G, Casentini L, De Luca G, Francescon P. Linear accelerator radiosurgery of cerebral arteriovenous malformations: An update. Neurosurgery 1994;34:14-20.

7. Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC. Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 1998;339: 1426-33.

8. Kondziolka D, Levy EI, Niranjan A, Flickinger JC, Lunsford LD. Long-term outcomes after meningioma radiosurgery: Physician and patient perspectives. J Neurosurg 1999;91:44-50.

9. Lu C, Stomper PC, Drislane FW, Wen PY, Block CC, Humphrey CC, et al . Suspected spinal cord compression in breast cancer patients: A multidisciplinary risk assessment. Breast Cancer Res Treat 1998;51:121-31.

10. Degen JW, Gagnon GJ, Voyadzis JM, McRae DA, Lunsden M, Dieterich S, et al . CyberKnife stereotactic radiosurgical treatment of spinal tumors for pain control and quality of life. J Neurosurg Spine 2005;2:540-9.

11. Adler JR Jr, Chang SD, Murphy MJ, Doty J, Geis P, Hancock SL. The Cyberknife: A frameless robotic system for radiosurgery. Stereotact Funct Neurosurg 1997;69(1-4 Pt 2):124-8.

12. Yeoh EE, Botten RJ, Butters J, Di Matteo AC, Holloway RH, Fowler J. Hypofractionated versus conventionally fractionated radiotherapy for prostate carcinoma: Final results of phase III randomized trial. Int J Radiat Oncol Biol Phys 2011;81:1271-8.

13. Pollock BE, Stafford SL, Link MJ. Gamma knife radiosurgery for skull base meningiomas. Neurosurg Clin N Am 2000;11:659-66.

14. Ogilvy CS, Stieg PE, Awad I, Brown RD Jr, Kondziolka D, Rosenwasser R, et al . Recommendations for the management of intracranial arteriovenous malformations: A statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Circulation 2001;103:2644-57.

15. Pollock BE, Driscoll CL, Foote RL, Link MJ, Gorman DA, Bauch CD, et al . Patient outcomes after vestibular schwannoma management: A prospective comparison of microsurgical resection and stereotactic radiosurgery. Neurosurgery 2006;59:77-85.

16. Muacevic A, Staehler M, Drexler C, Wowra B, Reiser M, Tonn JC. Technical description, phantom accuracy, and clinical feasibility for fiducial-free frameless real-time image-guided spinal radiosurgery. J Neurosurg Spine 2006;5:303-12.

17. Ho AK, Fu D, Cotrutz C, Hancock SL, Chang SD, Gibbs IC, et al . A study of the accuracy of cyberknife spinal radiosurgery using skeletal structure tracking. Neurosurgery 2007;60(2 Suppl 1):ONS147-56.

18. Bremer M, Rades D, Blach M, Krenkel B, Karstens JH. Effectiveness of hypofractionated radiotherapy in painful bone metastases. Two prospective studies with 1 x 4 Gy and 4 x 4 Gy. Strahlenther Onkol 1999;175:382-6.

19. Brenner DJ, Martel MK, Hall EJ. Fractionated regimens for stereotactic radiotherapy of recurrent tumors in the brain. Int J Radiat Oncol Biol Phys 1991;21:819-24.

20. Tsai JT, Lin JW, Lin CM, Chen YH, Ma HI, Jen YM, et al . Clinical evaluation of CyberKnife in the treatment of vestibular schwannomas. Biomed Res Int 2013;2013:297093.

21. Kanda M, Matsuhashi M, Sawamoto N, Oga T, Mima T, Nagamine T, et al . Cortical potentials related to assessment of pain intensity with visual analogue scale (VAS). Clin Neurophysiol 2002;113:1013-24.

22. Kelly AM. The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain. Emerg Med J 2001;18:205-7.

23. Ju DT, Lin JW, Lin MS, Lee LM, Tseng HM, Wei CP, et al . Hypofractionated CyberKnife stereotactic radiosurgery for acoustic neuromas with and without association to neurofibromatosis Type 2. Acta Neurochir Suppl 2008;101:169-73.

24. Pan H, Simpson DR, Mell LK, Mundt AJ, Lawson JD. A survey of stereotactic body radiotherapy use in the United States. Cancer 2011;117:4566-72.

25. Sohn S, Chung CK. The role of stereotactic radiosurgery in metastasis to the spine. J Korean Neurosurg Soc 2012;51:1-7.

26. Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: Clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976) 2007;32:193-9.

27. Crop F, Lacornerie T, Szymczak H, Felin A, Bailleux C, Mirabel X, et al . Treatment and technical intervention time analysis of a robotic stereotactic radiotherapy system. Technol Cancer Res Treat 2014;13:29-35.

28. Chang UK, Lee DH. Stereotactic radiosurgery for spinal neoplasms: Current status and future perspective. J Neurosurg Sci 2013;57:87-101.

29. Wang XS, Rhines LD, Shiu AS, Yang JN, Selek U, Gning I, et al . Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: A phase 1-2 trial. Lancet Oncol 2012;13:395-402.

30. Goblirsch M, Mathews W, Lynch C, Alaei P, Gerbi BJ, Mantyh PW, et al . Radiation treatment decreases bone cancer pain, osteolysis and tumor size. Radiat Res 2004;161:228-34.

31. Goblirsch M, Lynch C, Mathews W, Manivel JC, Mantyh PW, Clohisy DR. Radiation treatment decreases bone cancer pain through direct effect on tumor cells. Radiat Res 2005;164(4 Pt 1):400-8.

32. Vit JP, Ohara PT, Tien DA, Fike JR, Eikmeier L, Beitz A, et al . The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception. Pain 2006;120:188-201.

33. Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP. An analysis of the accuracy of the CyberKnife: A robotic frameless stereotactic radiosurgical system. Neurosurgery 2003;52:140-6.

34. Gerszten PC, Ozhasoglu C, Burton SA, Vogel WJ, Atkins BA, Kalnicki S, et al . CyberKnife frameless stereotactic radiosurgery for spinal lesions: Clinical experience in 125 cases. Neurosurgery 2004;55:89-98.

35. Nakamura JL, Verhey LJ, Smith V, Petti PL, Lamborn KR, Larson DA, et al . Dose conformity of gamma knife radiosurgery and risk factors for complications. Int J Radiat Oncol Biol Phys 2001;51:1313-9.

36. Shiomi H, Inoue T, Nakamura S, Inoue T. Quality assurance for an image-guided frameless radiosurgery system using radiochromic film. Radiat Med 2000;18:107-13.

37. Chang UK, Rhee CH, Youn SM, Lee DH, Park SQ. Radiosurgery using the Cyberknife for benign spinal tumors: Korea Cancer Center Hospital experience. J Neurooncol 2011;101:91-9.

38. Wowra B, Zausinger S, Drexler C, Kufeld M, Muacevic A, Staehler M, et al . CyberKnife radiosurgery for malignant spinal tumors: Characterization of well-suited patients. Spine (Phila Pa 1976) 2008;33:2929-34.
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Title Annotation:Original Article
Author:Hsu, Shih-Wei; Chao, Hsing-Lung; Lin, Kuen-Tze; Chou, Yu-Ching; Lo, Cheng-Hsiang; Lee, Shih-Yu; Huan
Publication:Journal of Medical Sciences
Article Type:Report
Date:Jul 1, 2015
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