Radiotherapy for metastatic spinal cord compression with increased radiation doses (RAMSES-01): a prospective multicenter study

Dirk Rades, Olfred Hansen, Lars Henrik Jensen, Liesa Dziggel, Christian Staackmann, Claudia Doemer, Jon Cacicedo, Antonio J Conde-Moreno, Barbara Segedin, Raquel Ciervide-Jurio, Carmen Rubio-Rodriguez, Luis A Perez-Romasanta, Ana Alvarez-Gracia, Kristopher Dennis, Carlos Ferrer-Albiach, Arturo Navarro-Martin, Fernando Lopez-Campos, Natalia Jankarashvili, Stefan Janssen, Denise Olbrich, Niels Henrik Holländer, Dirk Rades, Olfred Hansen, Lars Henrik Jensen, Liesa Dziggel, Christian Staackmann, Claudia Doemer, Jon Cacicedo, Antonio J Conde-Moreno, Barbara Segedin, Raquel Ciervide-Jurio, Carmen Rubio-Rodriguez, Luis A Perez-Romasanta, Ana Alvarez-Gracia, Kristopher Dennis, Carlos Ferrer-Albiach, Arturo Navarro-Martin, Fernando Lopez-Campos, Natalia Jankarashvili, Stefan Janssen, Denise Olbrich, Niels Henrik Holländer

Abstract

Background: Patients with metastatic spinal cord compression (MSCC) and favorable survival prognoses can benefit from radiation doses greater than 30Gy in 10 fractions in terms of improved local progression-free survival (LPFS) and overall survival (OS).

Methods/design: This prospective study mainly investigates LPFS after precision radiotherapy (volumetric modulated arc therapy or stereotactic body radiotherapy) with 18 × 2.33Gy in 3.5 weeks. LPFS is defined as freedom from progression of motor deficits during radiotherapy and an in-field recurrence of MSCC following radiotherapy. The maximum relative dose allowed to the spinal cord is 101.5% of the prescribed dose, resulting in an equivalent dose in 2Gy-fractions (EQD2) for radiation myelopathy is 45.5Gy, which is below the tolerance dose of 50Gy according to the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC). The EQD2 of this regimen for tumor cell kill is 43.1Gy, which is 33% higher than for 30Gy in 10 fractions (EQD2 = 32.5Gy). Primary endpoint is LPFS at 12 months after radiotherapy. Secondary endpoints include the effect of 18 × 2.33Gy on motor function, ambulatory status, sensory function, sphincter dysfunction, LPFS at other follow-up times, overall survival, pain relief, relief of distress and toxicity. Follow-up visits for all endpoints will be performed directly and at 1, 3, 6, 9 and 12 months after radiotherapy. A total of 65 patients are required for the prospective part of the study. These patients will be compared to a historical control group of at least 235 patients receiving conventional radiotherapy with 10x3Gy in 2 weeks.

Discussion: If precision radiotherapy with 18 × 2.33Gy results in significantly better LPFS than 10x3Gy of conventional radiotherapy, this regimen should be strongly considered for patients with MSCC and favorable survival prognoses.

Trial registration: Clinicaltrials.gov NCT04043156. Registered 30-07-2019.

Keywords: Favorable survival prognosis; Increased radiation dose; Local progression-free survival; Metastatic spinal cord compression; Precision radiotherapy.

Conflict of interest statement

D.R. and S.J. are associate editors of BMC Cancer. Otherwise, the authors declare that they have no competing interests related to the study presented here.

References

    1. Rades D, Dunst J, Schild SE. The first score predicting overall survival in patients with metastatic spinal cord compression. Cancer. 2008;112:157–161. doi: 10.1002/cncr.23150.
    1. Rades D, Douglas S, Veninga T, Stalpers LJ, Hoskin PJ, Bajrovic A, Adamietz IA, Basic H, Dunst J, Schild SE. Validation and simplification of a score predicting survival in patients irradiated for metastatic spinal cord compression. Cancer. 2010;116:3670–3673. doi: 10.1002/cncr.25223.
    1. Patchell R, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366:643–648. doi: 10.1016/S0140-6736(05)66954-1.
    1. Rades D, Huttenlocher S, Dunst J, Bajrovic A, Karstens JH, Rudat V, Schild SE. Matched pair analysis comparing surgery followed by radiotherapy and radiotherapy alone for metastatic spinal cord compression. J Clin Oncol. 2010;28:3597–3604. doi: 10.1200/JCO.2010.28.5635.
    1. Nieder C, Grosu AL, Andratschke NH, Molls M. Update of human spinal cord reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol Biol Phys. 2006;66:1446–1449. doi: 10.1016/j.ijrobp.2006.07.1383.
    1. Rades D, Lange M, Veninga T, Stalpers LJ, Bajrovic A, Adamietz IA, Rudat V, Schild SE. Final results of a prospective study comparing the local control of short-course and long-course radiotherapy for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys. 2011;79:524–530. doi: 10.1016/j.ijrobp.2009.10.073.
    1. Rades D, Fehlauer F, Schulte R, Veninga T, Stalpers LJ, Basic H, Bajrovic A, Hoskin PJ, Tribius S, Wildfang I, Rudat V, Engenhart-Cabilic R, Karstens JH, Alberti W, Dunst J, Schild SE. Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol. 2006;24:3388–3393. doi: 10.1200/JCO.2005.05.0542.
    1. Rades D, Panzner A, Rudat V, Karstens JH, Schild SE. Dose escalation of radiotherapy for metastatic spinal cord compression (MSCC) in patients with relatively favorable survival prognosis. Strahlenther Onkol. 2011;187:729–735. doi: 10.1007/s00066-011-2266-y.
    1. Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, Bentzen SM, Nam J, Deasy JO. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S10–S19. doi: 10.1016/j.ijrobp.2009.07.1754.
    1. Emami B. Tolerance of the normal tissue to therapeutic irradiation. Rep Radiother Oncol. 2013;1:35–48.
    1. Rades D, Cacicedo J, Conde-Moreno AJ, Doemer C, Dunst J, Lomidze D, Segedin B, Olbrich D, Holländer NH. High-precision radiotherapy of motor deficits due to metastatic spinal cord compression (PRE-MODE): a multicenter phase 2 study. BMC Cancer. 2017;17:818. doi: 10.1186/s12885-017-3844-x.
    1. Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys. 1982;8:1981–1997. doi: 10.1016/0360-3016(82)90459-X.
    1. Joiner MC, Van der Kogel AJ. The linear-quadratic approach to fractionation and calculation of isoeffect relationships. In: Steel GG, editor. Basic clinical radiobiology. New York: Oxford University Press; 1997. pp. 106–112.
    1. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55. doi: 10.1093/biomet/70.1.41.
    1. Prasad D, Schiff D. Malignant spinal cord compression. Lancet Oncol. 2005;6:15–24. doi: 10.1016/S1470-2045(05)70022-X.
    1. Rades D, Abrahm JL. The role of radiotherapy for metastatic epidural spinal cord compression. Nat Rev Clin Oncol. 2010;7:590–598. doi: 10.1038/nrclinonc.2010.137.
    1. Li KC, Poon PY. Sensitivity and specificity of MRI in detecting malignant spinal cord compression and in distinguishing malignant from benign compression fractures of vertebrae. Magn Reson Imaging. 1988;6:547–556. doi: 10.1016/0730-725X(88)90129-4.
    1. Tomita T, Galicich JH, Sundaresan N. Radiation therapy for spinal epidural metastases with complete block. Acta Radiol Oncol. 1983;22:135–143. doi: 10.3109/02841868309134353.
    1. Curt A, Dietz V. Zur Prognose traumatischer Rückenmarkläsionen. Nervenarzt. 1997;68:485–495. doi: 10.1007/s001150050151.
    1. Chow E, Hoskin P, Mitera G, Zeng L, Lutz S, Roos D, Hahn C, van der Linden Y, Hartsell W, Kumar E. International bone metastases consensus working party: update of the international consenus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Int J Radiat Oncol Biol Phys. 2012;82:1730–1737. doi: 10.1016/j.ijrobp.2011.02.008.
    1. Holland JC. Update: NCCN practice guidelines for the management of psychosocial distress. Oncology. 1999;13:459–507.
    1. Holland JC, Andersen B, Breitbart WS, Buchmann LO, Compas B, Deshields TL, Dudley MM, Fleishman S, Fulcher CD, Greenberg DB, Greiner CB, Handzo GF, Hoofring L, Hoover C, Jacobsen PB, Kvale E, Levy MH, Loscalzo MJ, McAllister-Black R, Mechanic KY, Palesh O, Pazar JP, Riba MB, Roper K, Valentine AD, Wagner LI, Zevon MA, McMillian NR, Freedman-Cass DA. Distress management. J Natl Comp Cancer Netw. 2013;11:190–209. doi: 10.6004/jnccn.2013.0027.
    1. National Institutes of Health/National Cancer Institute . Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. USA: National Institutes of Health/National Cancer Institute; 2010.
    1. Rades D, Stalpers LJ, Veninga T, Schulte R, Hoskin PJ, Obralic N, Bajrovic A, Rudat V, Schwarz R, Hulshof MC, Poortmans P, Schild SE. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol. 2005;23:3366–3375. doi: 10.1200/JCO.2005.04.754.
    1. Rades D, Šegedin B, Conde-Moreno AJ, Garcia R, Perpar A, Metz M, Badakhshi H, Schreiber A, Nitsche M, Hipp P, Schulze W, Adamietz IA, Norkus D, Rudat V, Cacicedo J, Schild SE. Radiotherapy with 4 Gy × 5 versus 3 Gy × 10 for metastatic epidural spinal cord compression: final results of the SCORE-2 trial (ARO 2009/01) J Clin Oncol. 2016;34:597–602. doi: 10.1200/JCO.2015.64.0862.
    1. Maranzano E, Bellavita R, Rossi R, De Angelis V, Frattegiani A, Bagnoli R, Mignogna M, Beneventi S, Lupattelli M, Ponticelli P, Biti GP, Latini P. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol. 2005;23:3358–3365. doi: 10.1200/JCO.2005.08.193.
    1. Maranzano E, Trippa F, Casale M, Costantini S, Lupattelli M, Bellavita R, Marafioti L, Pergolizzi S, Santacaterina A, Mignogna M, Silvano G, Fusco V. 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial. Radiother Oncol. 2009;93:174–179. doi: 10.1016/j.radonc.2009.05.012.
    1. Thirion P, O’Sullivan L, Clayton-Lea A, Small C, McArdle O, Kelly P, Parker I, O'Sullivan J, Hacking D, Collins C, Pomeroy M, Moriarty M. ICORG 05–03: Prospective randomized non-inferiority phase 3 trial comparing two radiation schedules in malignant spinal cord compression not proceeding with surgical decompression. Int J Radiat Oncol Biol Phys. 2014;90:1263–1264. doi: 10.1016/j.ijrobp.2014.10.036.
    1. Hoskin P, Misra V, Hopkins K, Holt T, Brown G, Arnott S, Thomas SS, Reczko K, Beare S, Lopes A, Forsyth S. SCORAD III: Randomized noninferiority phase III trial of single-dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC) J Clin Oncol. 2017;35(suppl):LBA10004. doi: 10.1200/JCO.2017.35.18_suppl.LBA10004.
    1. Garg AK, Shiu AS, Yang J, Wang XS, Allen P, Brown BW, Grossman P, Frija EK, McAleer MF, Azeem S, Brown PD, Rhines LD, Chang EL. Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer. 2012;118:5069–5077. doi: 10.1002/cncr.27530.
    1. Chang JH, Shin JH, Yamada YJ, Mesfin A, Fehlings MG, Rhines LD, Sahgal A. Stereotactic body radiotherapy for spinal metastases: What are the risks and how do we minimize them? Spine. 2016;41(Suppl 20):S238–S245. doi: 10.1097/BRS.0000000000001823.
    1. Lutz S, Balboni T, Jones J, Lo S, Petit J, Rich SE, Wong R, Hahn C. Palliative radiation therapy for bone metastases: update of an ASTRO evidence-based guideline. Pract Radiat Oncol. 2017;7:4–12. doi: 10.1016/j.prro.2016.08.001.
    1. Faruqi S, Tseng CL, Whyne C, Alghamdi M, Wilson J, Myrehaug S, Soliman H, Lee Y, Maralani P, Yang V, Fisher C, Sahgal A. Vertebral compression fracture after spine stereotactic body radiation therapy: a review of the pathophysiology and risk factors. Neurosurgery. 2018;83:314–322. doi: 10.1093/neuros/nyx493.
    1. Guckenberger M, Mantel F, Gerszten PC, Flickinger JC, Sahgal A, Létourneau D, Grills IS, Jawad M, Fahim DK, Shin JH, Winey B, Sheehan J, Kersh R. Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis. Radiat Oncol. 2014;9:226. doi: 10.1186/s13014-014-0226-2.

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