Reduction of Pain Symptoms With Stereotactic Radiotherapy on Bone Metastases (PREST)

PREST: Pain REduction With Bone Metastases STereotactic Radiotherapy: A Phase III Randomized Multicentric Trial

Interventional study without medicinal, randomized 1: 1 open-label, multicenter, phase 3 to evaluate the response in terms of reduction of pain symptomatology from bone metastases, comparing the conformational radiotherapy (3D-CRT) administered in conventional fractionation vs. extracranial stereotactic radiotherapy (SBRT) administered with concomitant integrated simultaneous boost (Simultaneous Integrated Boost-SIB)

Palliative antalgic oncological treatments, e.g. For patients in the chronic-evolutionary phase of the disease with need for pain control, are a serious problem from the point of view: management, clinical and scientific research. However, they are affecting an ever-increasing volume of patients due to the increased incidence of cancer in all its phases and the potential chronicity of illness linked to new therapies. The use of palliative anti-radiation radiotherapy treatments potentially involves up to 40% of patients in a Radiotherapy Center. Radiotherapy is commonly used in palliative treatment of symptomatic bone metastases (Furfari A, 2017) being an effective treatment to improve symptoms and consequently improve the quality of life (QoL) of these patients. Due to the peculiar characteristics of the patients who need these treatments, scientific research aimed at optimizing these therapies is a need for assistance and even ethics. Ideally, this treatment should be as short as possible to re-direct them to systemic therapies or to home care or long-term care systems (e.g.: Hospice). In order to deliver a clinically effective dose in a short period of time, hypofractionated regimens must be used. Stereotactic radiotherapy is a type of radiotherapy that allows to deliver a high equivalent biological dose in a highly conformed manner, with a favorable toxicity profile (Correa RJ, 2016), and generally in a few fractions. The possibility of using special techniques such as stereotactic radiotherapy has been investigated in several phase 2 studies, in terms of symptom response with good results at 3 months (van der Velden JM, 2016) (Murai T1, 2014) (Braam P , 2016) (Deodato F, 2014) (Ryu S, 2014). Further studies have suggested, in order to better manage the toxicity profile linked to the hypofractioned regimen, the possibility of using a hypofractionated regimen over the entire bone compartment and going to over-dose with a stereotaxic regimen only the macroscopically visible disease to the instrumental examinations. In particular, in patients with favorable prognostic scores, this regimen would improve the possible onset of acute and late complications. Although there are indications in the literature (generated by the Consensus Conference) about the radiation treatment schedules to be preferred, there is no globally coded and clinically applied therapeutic prescription standard (Chow E1 & Party, 2012). The most commonly applied conventional radiation treatment schedules include: i) 8 Gy in 1 therapy session; ii) 20 Gy in 5 therapy sessions; iii) 30 Gy in 10 therapy sessions. With the same pain control, multiple fractionation boards report, according to some authors, better symptom control over time and are therefore very often preferred for patients with a prognosis> 6 months. Routine use of prognostic scores to characterize life expectancy and define the most appropriate treatment regimen is very rarely used in everyday clinical practice. Modern oncology radiotherapy can take advantage of advanced technologies and exploit the personalization of treatments. To date, some randomized trials are underway investigating the role of stereotactic radiotherapy for these patients compared to conventional approaches, but not all of them use adequate personalization of treatment. Furthermore, none of the ongoing and currently registered trials analyzes the "ii) 20 Gy in 5 treatment sessions" versus stereotactic in the direct comparison between two single randomized arms. The aim of this randomized multicenter prospective trial study is to evaluate the pain control effectiveness of an unconventional fractionation delivered with the most innovative stereotactic technique approach available in this clinical scenario against the conventional one; enrollment of patients will be specifically selected with prognosis> 6 months according to the Mizumoto score (Mizumoto M, 2008) and structural stability defined according to Spine Instability Neoplastic Score (SINS) <7, with indication to radiotherapy on bone metastases. Highlights of this study include: the high level of treatment customization for both accurate selection and ultraconformed radiation therapy planning; the reduction in the number of sessions to which the patient must be subjected, which reduces his discomfort; the approach innovation; the location of the study group (multicentric, in the Italian panorama) in a central position in the international scenario of the specific sector. The results of this trial are potentially "practice-changing".

The study is a randomized, controlled superiority trial. The study will appear as an interventionist without medicinal, multicentric, spontaneous. Randomization will take place in a 1: 1 ratio. The study involves the enrollment of 330 patients divided into two groups of 165 patients for each of the two study arms (arm A (gold standard): 4 Gy x 5 fractions (fr); arm B: 5 Gy x 3 fr (Whole Vertebra) + SIB 10 Gy x 3 fr on the Gross Tumor Volume - GTV). The expected difference between the two treatments in terms of three-month pain control rates is 15% more in the experimental arm compared to the standard arm. The calculation of the sample size took into account a 95% CI with a coefficient α of 0.05 and a drop-out rate of 10%.

For each patient the following variables for balancing the study arms will be considered: Gender, age, performance status, histology, site and primary tumor and presence of visceral metastases; Randomization will be performed at the Gemelli ART of the Gemelli Polyclinic Foundation and will be done by e-mail. Patients will be randomized after verification of inclusion and exclusion criteria. Randomization will be performed according to a random list generated by the computer.

Intervention: Radiotherapy with Simultaneous Integrated Boost-SIB on macroscopic metastases Delivery of a boost on macroscopic secondary lesion with Simultaneous Integrated Boost technique according this schedule: - 5 Gy x 3 fr (Whole Vertebra) + SIB 10 Gy x 3 fr on the macroscopic disease Gross Tumor Volume - (GTV)

Delivery of a boost on macroscopic secondary lesion with Simultaneous Integrated Boost technique according this schedule: - 5 Gy x 3 fr (Whole Vertebra) + SIB 10 Gy x 3 fr on the macroscopic disease Gross Tumor Volume - (GTV)

Pain control measured with Numeric Rating Scale (NRS) score, a 11-point scale for patient self-reporting of pain. NRS score presents a total range between 0 (no pain) and 10 maximum pain. NRS subscale are the sequent: 0: no pain [better outcome ] 1-3: mild pain 4-6: moderate pain 7-10 severe pain [worse outcome]

Interval from the end of radiotherapy and progressive disease with symptoms according to the criteria of Chow et al. in 2012

QoL score according to European Organization for Research and Treatment of Cancer (EORTC): QLQ-C15-PAL

Inclusion Criteria: Patients diagnosed with spinal bone metastases from solid, uncomplicated tumor Established primary or secondary tumor histology related to the treatment lesion Patients aged> 18 years Obtaining informed consent ECOG 0-2 Symptomatic patients (NRS> = 4) at the treatment site Spine Instability Neoplastic Score (SINS) <7 Prognosis> 6 months according to Mizumoto Prognostic Score (i.e. Class A and B) Spinal metastases verified at MRI including the sites to be enrolled No more than 3 non-contiguous spinal segments (e.g. separated by at least two metamers) involved in the study Exclusion Criteria: Impossibility to assign specific NRS for each CTV to be enrolled Impossibility to express autonomous consent to therapies Pregnancy Patient in Hospice or with prognosis <6 months Unavailability forecast for 3 month follow-up Absence of MRI pre-treatment study Impossibility to maintain the treatment position for SBRT Previous radiotherapy at the same site or at the level of adjoining metamers (higher or lower than the one to be enrolled) Radiometabolic therapy Previous enrollment of the same patient for 3 irradiated lesions Epidural compression of the spinal cord or of the cauda equina Injuries affecting> 25% of the medullary canal and / or a distance <5 mm from the medulla or from the cauda Injuries with indication of surgical stabilization Chemotherapy or target therapy within the previous 7 days and 7 days after SBRT

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