Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial

Francesco Cellini, Stefania Manfrida, Francesco Deodato, Savino Cilla, Ernesto Maranzano, Stefano Pergolizzi, Fabio Arcidiacono, Rossella Di Franco, Francesco Pastore, Matteo Muto, Valentina Borzillo, Costanza Maria Donati, Giambattista Siepe, Salvatore Parisi, Antonia Salatino, Antonino D'Agostino, Giampaolo Montesi, Anna Santacaterina, Vincenzo Fusco, Mario Santarelli, Maria Antonietta Gambacorta, Renzo Corvò, Alessio Giuseppe Morganti, Valeria Masiello, Paolo Muto, Vincenzo Valentini, Francesco Cellini, Stefania Manfrida, Francesco Deodato, Savino Cilla, Ernesto Maranzano, Stefano Pergolizzi, Fabio Arcidiacono, Rossella Di Franco, Francesco Pastore, Matteo Muto, Valentina Borzillo, Costanza Maria Donati, Giambattista Siepe, Salvatore Parisi, Antonia Salatino, Antonino D'Agostino, Giampaolo Montesi, Anna Santacaterina, Vincenzo Fusco, Mario Santarelli, Maria Antonietta Gambacorta, Renzo Corvò, Alessio Giuseppe Morganti, Valeria Masiello, Paolo Muto, Vincenzo Valentini

Abstract

Background: Palliative antalgic treatments represent an issue for clinical management and a challenge for scientific research. Radiotherapy (RT) plays a central role. Techniques such as stereotactic body radiotherapy (SBRT) were largely investigated in several phase 2 studies with good symptom response, becoming widely adopted. However, evidence from randomized, direct comparison of RT and SBRT is still lacking.

Methods/design: The PREST trial was designed as an interventional study without medicinal treatment. It is a phase 3, open-label, multicentric trial randomized 1:1. Inclusion criteria include painful spinal bone metastases presenting with a pain level > 4 (or > 1 if being treated with an analgesic) on the Numeric Rating Scale (NRS); expected intermediate/high prognosis (greater than 6 months) according to the Mizumoto prognostic score; low spine instability neoplastic score (SINS) sores (< 7); magnetic resonance imaging (MRI) assessment of the bulky lesion. Patients will be assigned to either standard conventional radiotherapy involving 4 Gy × 5 fractions (fx) to the whole involved vertebra or SBRT by intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) involving 7 Gy × 3 fx to the whole involved vertebra + 10 Gy × 3 fx on the macroscopic lesion (gross tumor volume (GTV)). In the experimental arm, the GTV will be contoured by registration with baseline MRI.

Discussion: The primary endpoint is overall pain reduction, defined in terms of variation between baseline and 3-month evaluation; pain will be measured using the NRS. Secondary endpoints include pain control duration; retreatment rates (after a minimum interval of 1 month); local control assessed with RECIST criteria; symptom progression free survival; progression-free survival; overall survival; and quality of life (at 0, 30, and 90 days). Accrual of 330 lesions is planned. The experimental arm is expected to have an improvement in overall pain response rates of 15% with respect to the standard arm (60% according to Chow et al. (Int J Radiat Oncol Biol Phys. 82(5):1730-7, 2012)).

Trial registration: ClinicalTrials.gov, NCT03597984 . Registered on July 2018.

Keywords: Bone metastases; Pain control; Randomised controlled trial; Simultaneous integrated boost.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
PREST trial (NCT03597984) schema

References

    1. Mizumoto M, et al. Prognostic factors and a scoring system for survival after radiotherapy for metastases to the spinal column: A review of 544 patients at Shizuoka Cancer Center Hospital. Cancer. 2008;113(10):2816–2822. doi: 10.1002/cncr.23888.
    1. Blomgren H, Lax I, Naslund I, Svanstrom ER. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncologica. 1995;34(6):861–870. doi: 10.3109/02841869509127197.
    1. Correa R, Salama J, Milano M, Palma ED. Stereotactic body radiotherapy for oligometastasis: Opportunities for biology to guide clinical management. Cancer J. 2016;22(4):247–256. doi: 10.1097/PPO.0000000000000202.
    1. Xu C. Intensity-modulated arc therapy with dynamic multileaf collimation: an alternative to tomotherapy. Phys Med Biol. 1995;40(9):1435–1449. doi: 10.1088/0031-9155/40/9/004.
    1. Fisher C, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976) 2010;35(22):E1221–E1229. doi: 10.1097/BRS.0b013e3181e16ae2.
    1. Benedict SH, et al. Stereotactic body radiation therapy: The report of AAPM Task Group 101: Stereotactic body radiation therapy: The report of TG101. Med Phys. 2010;37(8):4078–4101. doi: 10.1118/1.3438081.
    1. Bentzen SM, et al. Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): An introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010;76(3):S3–S9. doi: 10.1016/j.ijrobp.2009.09.040.
    1. Chow E, et al. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases. Int J Radiat Oncol Biol Physi. 2012;82(5):1730–1737. doi: 10.1016/j.ijrobp.2011.02.008.
    1. Lam K, et al. Predictive factors of overall well-being using the EORTC QLQ-C15-PAL extracted from the EORTC QLQ-C30. J Palliat Med. 2013;16(4):402–408. doi: 10.1089/jpm.2012.0398.
    1. National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 27, 2017. .
    1. Furfari A, et al. Genetic biomarkers associated with pain flare and dexamethasone response following palliative radiotherapy in patients with painful bone metastases. Ann Palliat Med. 2017;6(S2):S240–S247. doi: 10.21037/apm.2017.09.04.
    1. van der Velden JM, et al. Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases: study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design. BMC Cancer. 2016;16:1. doi: 10.1186/s12885-015-2026-y.
    1. Murai T, et al. Intensity modulated stereotactic body radiation therapy for single or multiple vertebral metastases with spinal cord compression. Pract Radiat Oncol. 2014;4(6):e231–e237. doi: 10.1016/j.prro.2014.02.005.
    1. Braam P, Lambin P, Bussink EJ. Stereotactic versus conventional radiotherapy for pain reduction and quality of life in spinal metastases: study protocol for a randomized controlled trial. Trials. 2016;17:1. doi: 10.1186/s13063-016-1178-7.
    1. Deodato F, et al. Stereotactic radiosurgery (SRS) with volumetric modulated arc therapy (VMAT): interim results of a multi-arm phase I trial (DESTROY-2) Clin Oncol (R Coll Radiol) 2014;26(12):748–756. doi: 10.1016/j.clon.2014.08.005.
    1. Ryu S, et al. RTOG 0631 Phase II/III study of image-guided stereotactic radiosurgery for localized spine metastases: Phase II results. Int J Radiat Oncol Biol Phys. 2011;81(2):S131–S132. doi: 10.1016/j.ijrobp.2011.06.271.
    1. Sprave T, et al. Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy. Radiother Oncol. 2018;128(2):274–282. doi: 10.1016/j.radonc.2018.04.030.
    1. Faruqi S, et al. Vertebral compression fracture after spine stereotactic body radiation therapy: A review of the pathophysiology and risk factors. Neurosurgery. 2018;83(3):314–322. doi: 10.1093/neuros/nyx493.
    1. Lee YK, Bedford JL, McNair HA, Hawkins EMA. Comparison of deliverable IMRT and VMAT for spine metastases using a simultaneous integrated boost. Br J Radiol. 2013;86(1022):20120466. doi: 10.1259/bjr.20120466.
    1. Wu Q, Yoo S, Kirkpatrick J, Thongphiew D, Yin EF. Volumetric arc intensity-modulated therapy for spine body radiotherapy: comparison with static intensity-modulated treatment. Int J Radiat Oncol Biol Phys. 2009;75(5):1596–1604. doi: 10.1016/j.ijrobp.2009.05.005.
    1. Chow E, Wu J, Hoskin P, Coia L, Bentzen S, Blitzer EP. International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Radiotherapy and Oncology. 2002;64(3):275–280. doi: 10.1016/S0167-8140(02)00170-6.
    1. Rich S, et al. Update of the systematic review of palliative radiation therapy fractionation for bone metastases. Radiother Oncol. 2018;126(3):547–557. doi: 10.1016/j.radonc.2018.01.003.
    1. Chow R, et al. Efficacy of multiple fraction conventional radiation therapy for painful uncomplicated bone metastases: A systematic review. Radiother Oncol. 2017;122(3):323–331. doi: 10.1016/j.radonc.2016.12.031.

Source: PubMed

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