Introduction
The spine is the most common site for the occurrence of bone metastases [ 1 ]. Additionally, intraosseous hemangiomas frequently occur as benign tumors of the spine [ 2 ]. Treatment should focus on palliation of pain, stabilization and local tumor control with therapeutic options including radiation therapy, surgical intervention or radiofrequency ablation [ 3 – 5 ]. Due to continuous advancements in systemic cancer therapy, any delay or pause of systemic treatment caused by local interventions should be avoided. With the advent of advanced therapies, life expectancy of cancer patients continues to rise and local control as well as quality of life gain further importance [ 6 – 8 ].
Kypho-IORT consists of cement augmentation kyphoplasty and intraoperative irradiation as a “one-stop-shop” intervention for the treatment of tumors in vertebral bodies of the thoracic, lumbar, and sacral spine. In a recent dose escalation and cohort expansion phase I/II trial with a total of 61 patients we showed a significant median pain reduction at the first postoperative day and a subsequent sustained pain reduction. The 3-, 6-, and 12-month local progression free survival (L-PFS without considering death as an endpoint) was 97.5, 93.8, and 93.8% [ 9 ]. To further investigate this combined approach, a multi-centric randomized phase III trial ( NCT02773966 ) was designed to test Kypho-IORT against external beam radiotherapy (EBRT) as standard-of-care for painful vertebral metastases [ 10 ]. We here report our long-term experience of 10 years with patients treated at our institution as the largest single-center cohort analysis to date.
Methods
All prospective and retrospective data acquisition and analysis was approved by the local institutional review board. All patients treated with Kypho-IORT between 2009 and 2019 at our institution were included in this analysis, whereas treatment was either carried out on trial within the prospective Kypho-IORT studies ( NCT01280032 and NCT02773966 ) or, after completion and closure of the phase I/II study or before the start of the phase III study, off trial but fully compliant with the study protocol. Patients with up to three painful and/or unstable metastases of pathologically confirmed cancer or benign tumors (hemangioma) in vertebral bodies (Tomita 1/2) of the thoracic, lumbar, and/or sacral spine were eligible for treatment. In brief, following a bi-pedicular approach and placement of guidance sleeves, a 50-kV X-ray source (Intrabeam, Carl Zeiss Meditec AG, Oberkochen, Germany) equipped with a needle applicator (diameter 4.2 mm) was inserted into the vertebral metastasis. A dose of 8 Gy was then prescribed to a distance of 8, 11, or 13 mm from the isocenter in the tip of the source. Following irradiation, transpedicular kyphoplasty with cement augmentation was performed [ 9 ]. Thereafter, patients continued with standard-of-care systemic therapy, depending on their primary cancer.
Baseline imaging was performed (computed tomography, CT, or magnetic resonance imaging, MRI) within 7 days after surgery. Follow-up spinal imaging was scheduled every 6 months, or in case new symptoms occurred (e. g. increased pain or neurological deficits). Median follow-up was defined by the time between Kypho-IORT and the last follow-up. Local recurrence was defined as tumor recurrence within a treated vertebra. Survival was measured as time frame from the intervention until death by any cause.
Local control rate (LC per treated vertebra) and overall survival rate (OS per patient) at 6, 12, 24, 36, 48, and 60 months were estimated using the Kaplan–Meier method. All statistical analyses were performed using SPSS (V. 24.0; IBM, Armonk, NY).
Results
A total of 104 patients were included in this analysis. The median age at the time of Kypho-IORT was 62 years (range 32–85 years). 56% of the patients were female and 48% were male. A total of 143 lesions were treated, with 89 lesions located in the thoracic spine, 53 in the lumbar spine, and 1 in the sacral spine. Of these, 23 treatments were performed as 2-level interventions, and 8 as 3-level interventions. All vertebral bodies were intraoperatively irradiated with 8 Gy, which were prescribed to a distance from the isocenter of 8, 11, or 13 mm in 48, 20, and 75 vertebrae, accounting for 33.6, 14.0, and 52.4% of the vertebrae treated, respectively. The median follow-up was 14.5 months (range 0.4–109). We detected 10 local recurrences with 7 located in the thoracic spine and 3 located in the lumbar spine. Dose prescription distance to the recurrent lesions was 8, 11, and 13 mm in 2, 3, and 5 lesions, accounting for 4.2, 15, and 6.7% of recurrences in the 8, 11, and 13 mm subgroup, respectively. In one patient, a locally recurrent tumor in a pre-fractured vertebra caused a vertebral compression fracture (VCF). Median time to recurrence was 22.3 months (range 1.5–73). The underlying diseases of patients with local recurrence were breast (4), prostate (2), colorectal (1), renal (1) and lung cancer (1) or soft tissue sarcoma (1). The LC at 6, 12, 24, 36, 48, and 60 months for the thoracic spine was 97.2, 95.1, 95.1, 80.1, 80.1, and 80.1%, and for the lumbar spine 97.1, 97.1, 93.4, 93.4, 83.0, and 83.0%, respectively, with no recurrence in the sacral spine resulting in a combined LC of 97.1, 95.9, 94.2, 85.5, 81.8, and 81.8% (Fig. 1 ). No difference was detected for LC between the thoracic and the lumbar spine (log-rank test, p = 0.663). A total of 66 patients died, resulting in an OS at 6, 12, 24, 36, 48, and 60 months of 74.6, 61.7, 50.3, 39.0, 37.7, and 25.2% (Fig. 2 ). None of the mortalities were related to the procedure. A single serious adverse event (SAE) of temporary painful nerve root irritation immediately after surgery was noted. No adjacent level vertebral fractures occurred. Detailed data is reported in Table 1 . Fig. 1 Local control after Kypho-IORT. Shown are the Kaplan–Meier plots for 89 vertebrae of the thoracic spine and 53 vertebrae of the lumbar spine as well as a combined plot of thoracic, lumbar, and sacral vertebrae treated with Kypho-IORT at our institution (the single patient with a treatment of 1 vertebra of the sacral spine died after 6 weeks and cannot be displayed as curve in the graph) Fig. 2 Overall survival after Kypho-IORT. Displayed is the overall survival of 104 patients as Kaplan–Meier plot Table 1 Details of the cohort. Listed are the entities with the number of patients as well as vertebrae treated and the local recurrences per entity Entities Patients/proportion Vertebrae/proportion Local recurrences (vertebrae)/proportion Breast cancer 46/44.2% 70/49.0% 4/40% Prostate cancer 16/15.4% 20/14.0% 2/20% Lung cancer 15/14.4% 21/14,7% 1/10% Gastrointestinal cancer 10/9.6% 11/7.7% 1/10% Multiple myeloma 3/2.9% 5/3.5% 0 Renal cancer 3/2.9% 4/2.8% 1/10% Melanoma 3/2.9% 4/2.8% 0 Sarcoma 3/2.9% 3/2.1% 1/10% Other gynecological cancers 3/2.9% 3/2.1% 0 Other urogenital cancers 1/1.0% 1/1.4% 0 Others (haemangioma) 1/1.0% 1/0.7% 0
Table 1
Details of the cohort. Listed are the entities with the number of patients as well as vertebrae treated and the local recurrences per entity
| Entities | Patients/proportion | Vertebrae/proportion | Local recurrences (vertebrae)/proportion |
| Breast cancer | 46/44.2% | 70/49.0% | 4/40% |
| Prostate cancer | 16/15.4% | 20/14.0% | 2/20% |
| Lung cancer | 15/14.4% | 21/14,7% | 1/10% |
| Gastrointestinal cancer | 10/9.6% | 11/7.7% | 1/10% |
| Multiple myeloma | 3/2.9% | 5/3.5% | 0 |
| Renal cancer | 3/2.9% | 4/2.8% | 1/10% |
| Melanoma | 3/2.9% | 4/2.8% | 0 |
| Sarcoma | 3/2.9% | 3/2.1% | 1/10% |
| Other gynecological cancers | 3/2.9% | 3/2.1% | 0 |
| Other urogenital cancers | 1/1.0% | 1/1.4% | 0 |
| Others (haemangioma) | 1/1.0% | 1/0.7% | 0 |
Discussion
We here report the results for the largest cohort of patients treated with Kypho-IORT to date. The findings for LC for 6 months are in line with earlier results from a smaller cohort with shorter follow-up treated within the phase I/II trial at our institution [ 9 ]. The overall excellent control rates after Kypho-IORT compare favorably with data from external beam radiotherapy (EBRT) or stereotactic body radiotherapy (SBRT) [ 11 , 12 ]. With increasing life expectancy due to improved systemic therapy (including targeted therapies and immunomodulators) and promising therapy options even for patients with metastatic cancer [ 13 ], both long-term efficacy and toxicities of local therapies for spinal metastases are gaining further importance.
EBRT, the most widespread standard, offers moderate pain reduction but with the drawback of a delayed onset within several weeks after irradiation, while pain relief in Kypho-IORT is immediate [ 9 , 11 ]. SBRT to spinal lesions frequently results in flare-up of pain (20–70%) before pain relief but shows higher local control rates than those achieved with EBRT [ 12 , 14 – 16 ]. However, a major complication after SBRT is vertebral compression fracture (VCF), which may occur in up to 40% of patients, specifically in case of pre-existing sintering [ 17 – 19 ]. Albeit occurrence or progression of VCF after SBRT resulted in a low mean increase of pain, SBRT may further pose a risk of VCF in adjacent vertebrae [ 17 , 20 ]. The inherent stabilization and restoration of the vertebral body by cement augmentation virtually eradicates the risk of VCF or further progression of VCF, especially for patients with pre-existing VCF which would have a high probability of progredient VCF after SBRT. Adjacent level fractures after kyphoplasty in patients with (oligo-)metastatic cancer seem to be less likely to occur – in contrast to osteoporotic patients – due to the rather normal bone structure in the vicinity of the treated vertebra which is not affected by the procedure [ 21 ]. Since radiation from electronic brachytherapy as part of Kypho-IORT is not only confined to the vertebral body but also of low energy (50 kV X-rays), it can be performed in any operating room suitable for c-arm fluoroscopy [ 22 ]. Combining kyphoplasty with radiofrequency ablation instead in regard of radioprotection is therefore not necessary and yielded inferior results in local control [ 5 ]. Previous findings showed that kyphoplasty with irradiation can be accomplished in an average time of 65 min and, due to its percutaneous approach, is a surgical intervention, but is considered minimally invasive [ 9 , 23 ]. Systemic therapy can thus be concomitantly administered without aggravating side-effects (e. g. prolonged wound healing time or increased radiation toxicity).
The limitations of our study, specifically when measuring LC, are the retrospective nature and the heterogeneous histologies and stages (e. g. oligometastatic vs. advanced systemic disease) with patients receiving various other therapies after Kypho-IORT [ 24 ].
One could argue that the high LC is—at least partly—aided by systemic therapies since more than half (63%) of the lesions treated in our cohort arose from breast or prostate cancers, where anti-hormonal therapy, anti-resorptive agents, targeted therapies or chemotherapy can effectively contribute to local control at the site of Kypho-IORT [ 25 ]. However, also more than half of the recurrent tumors still stemmed from breast (4 patients) or prostate cancer (2 patients) while only 4 patients with recurrent tumors suffered from cancers that are classically less susceptible to systemic therapies (lung, renal, or colorectal cancer, and soft tissue sarcoma) thus suggesting a high innate efficacy of Kypho-IORT independent of histology.
In conclusion, Kypho-IORT resembles a “one-stop-shop” procedure that offers fast pain relief, instant stabilization, and exceptional long-term local tumor control for patients with vertebral metastases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Frederic Bludau, Laura Winter, Arne Mathias Ruder, and Frank A. Giordano have contributed equally to this work and share the first authorship or the last authorship
Acknowledgements
We thank all patients and their families for their participation in this trial. The support of Matthias Benker shall be gratefully acknowledged.
Authors’ contributions
FB, UO, FW, and FG designed the underlying trials. FB, UO, FS, FW, AMR and FG performed the treatments. FB and LW obtained the follow-up data. FB, GW, AMR, and FG analyzed and interpreted the patient dataset. FB, AMR and FG were the major contributors in writing the manuscript. FB, LW, AMR, and FG contributed equally to this work and share the first authorship or the last authorship. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. The sponsor of this trial was the Mannheim Medical Faculty, Heidelberg University, and it was conducted with institutional funds.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The underlying trials ( NCT01280032 and NCT02773966 ) were approved by the institutional review board, Ethikkommission II, Mannheim Medical Faculty, Heidelberg University. All patients gave their written consent before participation.
Consent for publication
Not applicable.
Competing interests
LW, GW, UO, FW and AMR have no competing interests to disclose. FB and FS report grants and personal fees from Carl Zeiss Meditec AG, during the conduct of the study; FG reports grants, personal fees, and patents from or related to Carl Zeiss Meditec AG, grants from Elekta AB; grants and personal fees from NOXXON Pharma AG, personal fees from Bristol-Myers Squibb, personal fees from Roche Pharma AG, personal fees from MSD Sharp and Dohme GmbH, personal fees from AstraZeneca GmbH, non-financial support from Oncare GmbH, outside the submitted work.
References
1. Perrin RG Laxton AW Metastatic spine disease: epidemiology, pathophysiology, and evaluation of patients Neurosurg Clin N Am 2004 15 4 365 373 10.1016/j.nec.2004.04.018 15450871
2. Huvos AG Bone tumors: diagnosis, treatment and prognosis 1987 2 New York W.B. Saunders Company and Cbs Educational and Professional Publishing
3. Lutz S Balboni T Jones J Lo S Petit J Rich SE Palliative radiation therapy for bone metastases: update of an ASTRO evidence-based guideline Pract Radiat Oncol 2017 7 1 4 12 10.1016/j.prro.2016.08.001 27663933
4. Berenson J Pflugmacher R Jarzem P Zonder J Schechtman K Tillman JB Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial Lancet Oncol 2011 12 3 225 235 10.1016/S1470-2045(11)70008-0 21333599
5. Prezzano KM Prasad D Hermann GM Belal AN Alberico RA Radiofrequency ablation and radiation therapy improve local control in spinal metastases compared to radiofrequency ablation alone Am J Hosp Palliat Care 2019 36 5 417 422 10.1177/1049909118819460 30541334
6. Khalil DN Smith EL Brentjens RJ Wolchok JD The future of cancer treatment: immunomodulation, CARs and combination immunotherapy Nat Rev Clin Oncol 2016 13 5 273 290 10.1038/nrclinonc.2016.25 26977780 PMC5551685
7. Botta L Dal Maso L Guzzinati S Panato C Gatta G Trama A Changes in life expectancy for cancer patients over time since diagnosis J Adv Res 2019 20 153 159 10.1016/j.jare.2019.07.002 31467707 PMC6710558
8. Kokkonen K Tasmuth T Lehto JT Kautiainen H Elme A Jääskeläinen A-S Cancer patients' symptom burden and health-related quality of life (HRQoL) at tertiary cancer center from 2006 to 2013: a cross-sectional study Anticancer Res 2019 39 1 271 277 10.21873/anticanres.13107 30591468
9. Bludau F Welzel G Reis T Schneider F Sperk E Neumaier C Phase I/II trial of combined kyphoplasty and intraoperative radiotherapy in spinal metastases Spine J 2018 18 5 776 781 10.1016/j.spinee.2017.09.011 28962909
10. Bludau F Welzel G Reis T Abo-Madyan Y Sperk E Schneider F Combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) versus external beam radiotherapy (EBRT) for painful vertebral metastases—a randomized phase III study BMC Cancer 2019 19 1 430 10.1186/s12885-019-5666-5 31072314 PMC6507138
11. Koswig S Budach V Remineralisation und Schmerzlinderung von Knochenmetastasen nach unterschiedlich fraktionierter Strahlentherapie (10mal 3 Gy vs. 1mal 8 Gy)Eine prospektive Studie Strahlenther Onkol 1999 175 10 500 508 10.1007/s000660050061 10554645
12. Husain ZA Sahgal A De Salles A Funaro M Glover J Hayashi M Stereotactic body radiotherapy for de novo spinal metastases: systematic review J Neurosurg Spine 2017 27 3 295 302 10.3171/2017.1.SPINE16684 28598293
13. Palma DA Olson R Harrow S Gaede S Louie AV Haasbeek C Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial Lancet 2019 393 10185 2051 2058 10.1016/S0140-6736(18)32487-5 30982687
14. Chang U-K Cho W-I Kim M-S Cho CK Lee DH Rhee CH Local tumor control after retreatment of spinal metastasis using stereotactic body radiotherapy; comparison with initial treatment group Acta Oncol 2012 51 5 589 595 10.3109/0284186X.2012.666637 22414095
15. Balagamwala EH Naik M Reddy CA Angelov L Suh JH Djemil T Pain flare after stereotactic radiosurgery for spine metastases J Radiosurg SBRT 2018 5 2 99 105 29657890 PMC5893450
16. Chiang A Zeng L Zhang L Lochray F Korol R Loblaw A Pain flare is a common adverse event in steroid-naïve patients after spine stereotactic body radiation therapy: a prospective clinical trial Int J Radiat Oncol Biol Phys 2013 86 4 638 642 10.1016/j.ijrobp.2013.03.022 23664326
17. Mantel F Sweeney RA Klement RJ Hawkins MA Belderbos J Ahmed M Risk factors for vertebral compression fracture after spine stereotactic body radiation therapy: long-term results of a prospective phase 2 study Radiother Oncol 2019 141 62 66 10.1016/j.radonc.2019.08.026 31526672
18. Rose PS Laufer I Boland PJ Hanover A Bilsky MH Yamada J Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases J Clin Oncol 2009 27 30 5075 5079 10.1200/JCO.2008.19.3508 19738130 PMC3664037
19. Moussazadeh N Lis E Katsoulakis E Kahn S Svoboda M DiStefano NM Five-year outcomes of high-dose single-fraction spinal stereotactic radiosurgery Int J Radiat Oncol Biol Phys 2015 93 2 361 367 10.1016/j.ijrobp.2015.05.035 26232858 PMC11999723
20. Lockney DT Hopkins B Lockney NA Coleman CZ Rubin E Lis E Adjacent level fracture incidence in single fraction high dose spinal radiosurgery Ann Transl Med 2019 7 10 211 10.21037/atm.2019.04.68 31297376 PMC6595213
21. Pflugmacher R Schroeder RJ Klostermann CK Incidence of adjacent vertebral fractures in patients treated with balloon kyphoplasty: two years' prospective follow-up Acta Radiol (Stockholm, Sweden: 1987) 2006 47 8 830 840 10.1080/02841850600854928 17050364
22. Schneider F Clausen S Jahnke A Steil V Bludau F Sutterlin M Radiation protection for an intraoperative X-ray source compared to C-arm fluoroscopy Z Med Phys 2014 24 3 243 251 10.1016/j.zemedi.2013.10.006 24238628
23. Barzilai O McLaughlin L Amato M-K Reiner AS Ogilvie SQ Lis E Minimal access surgery for spinal metastases: prospective evaluation of a treatment algorithm using patient-reported outcomes World Neurosurg 2018 120 e889 e901 10.1016/j.wneu.2018.08.182 30189298 PMC6786494
24. Barzilai O Versteeg AL Sahgal A Rhines LD Bilsky MH Sciubba DM Survival, local control, and health-related quality of life in patients with oligometastatic and polymetastatic spinal tumors: a multicenter, international study Cancer 2019 125 5 770 778 10.1002/cncr.31870 30489634 PMC8020734
25. Saad F Gleason DM Murray R Tchekmedyian S Venner P Lacombe L A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma J Natl Cancer Inst 2002 94 19 1458 1468 10.1093/jnci/94.19.1458 12359855