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A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial).

ABSTRACT: BACKGROUND:In an oligometastatic setting, metastasis-directed treatment could render patients disease free, possibly for a protracted interval. Stereotactic ablative radiotherapy (SABR) is one of the treatment modalities that can be offered to these patients. In addition, the radiobiological qualities of SABR are promising for the use in perceived radioresistant tumours. There is also emerging evidence that SABR can stimulate the immune response, and a specific therapeutic window may exist for the optimal use of radiotherapy as an immune adjuvant. However, when SABR is considered for non-spine bone or lymph node metastases, the optimal fractionation schedule is not yet known. METHODS:The DESTROY-trial is a non-randomized prospective phase I trial determining a regimen of choice for patients with non-spine bone and lymph node metastases. A total of 90 patients will be included in three different treatment regimens. They will be offered stereotactic ablative radiotherapy in 5, 3 or 1 fractions. Dose-limiting toxicity will be recorded as primary endpoint. Acute and late toxicity, local response and local recurrence, and progression-free survival are secondary endpoints. Liquid biopsies will be collected throughout the course of this study from the second fractionation schedule on. DISCUSSION:Despite its almost universal use in (oligo-)metastatic patients, the level of evidence supporting radical local treatment in general, and stereotactic radiotherapy in particular, is low. This prospective phase I trial will evaluate different SABR regimens for metastases and the differences in immune-stimulatory effects. TRIAL REGISTRATION:The Ethics committee of the GZA Hospitals (B099201732915) approved this study on 05/07/2017. Amendment for translational research was approved on 06/02/2018. Trial registered on Clinicaltrials.gov ( NCT03486431 ) on 03/04/2018 - Retrospectively registered.

SUBMITTER: Mercier C

PROVIDER: S-EPMC6102883 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial).

Mercier Carole C Dirix Piet P Meijnders Paul P Vermeulen Peter P Van Laere Steven S Debois Hilde H Huget Philippe P Verellen Dirk D

Radiation oncology (London, England) 20180820 1

<h4>Background</h4>In an oligometastatic setting, metastasis-directed treatment could render patients disease free, possibly for a protracted interval. Stereotactic ablative radiotherapy (SABR) is one of the treatment modalities that can be offered to these patients. In addition, the radiobiological qualities of SABR are promising for the use in perceived radioresistant tumours. There is also emerging evidence that SABR can stimulate the immune response, and a specific therapeutic window may exi ...[more]

PMID: 30126440

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Project description:BackgroundMost renal cell carcinomas (RCCs) are localized and managed by active surveillance, surgery, or minimally invasive techniques. Stereotactic ablative radiation (SAbR) may provide an innovative non-invasive alternative although prospective data are limited.ObjectiveTo investigate whether SAbR is effective in the management of primary RCCs.Design, setting, and participantsPatients with biopsy-confirmed radiographically enlarging primary RCC (≤5 cm) were enrolled. SAbR was delivered in either three (12 Gy) or five (8 Gy) fractions.Outcome measurements and statistical analysisThe primary endpoint was local control (LC) defined as a reduction in tumor growth rate (compared with a benchmark of 4 mm/yr on active surveillance) and pathologic evidence of tumor response at 1 yr. Secondary endpoints included LC by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), safety, and preservation of kidney function. Exploratory tumor cell-enriched spatial protein and gene expression analysis were conducted on pre- and post-treatment biopsy samples.Results and limitationsTarget accrual was reached with the enrollment of 16 ethnically diverse patients. Radiographic LC at 1 yr was observed in 94% of patients (15/16; 95% confidence interval: 70, 100), and this was accompanied by pathologic evidence of tumor response (hyalinization, necrosis, and reduced tumor cellularity) in all patients. By RECIST, 100% of the sites remained without progression at 1 yr. The median pretreatment growth rate was 0.8 cm/yr (interquartile range [IQR]: 0.3, 1.4), and the median post-treatment growth rate was 0.0 cm/yr (IQR: -0.4, 0.1, p < 0.002). Tumor cell viability decreased from 4.6% to 0.7% at 1 yr (p = 0.004). With a median follow-up of 36 mo for censored patients, the disease control rate was 94%. SAbR was well tolerated with no grade ≥2 (acute or late) toxicities. The average glomerular filtration rate declined from a baseline of 65.6 to 55.4 ml/min at 1 yr (p = 0.003). Spatial protein and gene expression analyses were consistent with the induction of cellular senescence by radiation.ConclusionsThis clinical trial adds to the growing body of evidence suggesting that SAbR is effective for primary RCC supporting its evaluation in comparative phase 3 clinical trials.Patient summaryIn this clinical trial, we investigated a noninvasive treatment option of stereotactic radiation therapy for the treatment of primary kidney cancer and found that it was safe and effective.

Project description:Purpose:We aimed to retrospectively assess the incidence of vertebral compression fractures (VCF), examine clinicopathologic factors potentially associated with VCF, and evaluate treatment response in patients who received stereotactic body radiotherapy (SBRT) for spine metastases (spMets). Methods and Materials:We identified 78 patients with 125 spMets at baseline and subsequent assessments. Patients received SBRT doses of 16 or 18 Gy. Patients with pre-existing VCF and co-existing local progression were excluded. Spine instability neoplastic score (SINS) was used for spMets categorization. Response to SBRT and VCF were assessed according to the Positron Emission tomography Response Criteria In Solid Tumors (PERCIST) and Genant scores, respectively. Kaplan-Meier analyses were used to assess local control of disease and vertebral compression fracture-free survival (FFS). Results:We treated 103 cases with single spMets and 11 cases involving double spMets with SBRT. Progressive disease was reported in 3.2% and 8.2% of the cases in the first and last PET/CT reports, respectively. The distribution of treatment response in the remaining patients was: complete response in 30.6% of patients, partial response in 47.1% of patients, and stable disease in 22.3% of patients in the first PET/CT; complete response in 62.3% of patients, partial response in 16.7% of patients, and stable disease in 21% of patients at the last monitoring. Local failures were observed in 15 (12%) of cases. Median SINS was 5 (range: 1-13); majority of patients in our cohort (70.4%) were categorized as stable according to SINS, five (4%) patients had Grade 3 VCF at a median time of 16 months after SBRT (range: 2-22 months), and 60% of VCF occurred after an interval of at least 12 months after SBRT. No bisphosphonate usage was significantly associated with VCF (r = -0.204; p = 0.022). Median FFS was 21 months. Univariate analyses indicated that female gender (p < 0.001), bisphosphonate use (p = 0.005), >6 months of bisphosphonates use (p = 0.002), and the lowest vertebral body collapse score (p = 0.023) were associated with higher FFS. Female gender (p = 0.007), >6 months of bisphosphonates usage (p = 0.018), and the lowest vertebral body collapse score (p = 0.044) retained independent significance. Conclusions:This study demonstrated that spine SBRT with doses of 16-18 Gy promises good local control of disease with acceptable VCF rates. Lowest vertebral body collapse score, female gender, and >6 months of bisphosphonate use were significantly associated with longer FFS.

Project description:BackgroundRadiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience.MethodsThis study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival.DiscussionThis study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone.Trial registrationClinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Project description:AimsTo evaluate the efficacy and toxicity of extracranial stereotactic body radiotherapy (SBRT) in the treatment of oligometastatic lymph node involvement in the mediastinum, retroperitoneum, or pelvis, in a consecutive group of patients from real clinical practice outside clinical trials.MethodsA retrospective analysis of 90 patients with a maximum of four oligometastases and various primary tumors (the most common being colorectal cancers). The endpoints were local control of treated metastases (LC), freedom from widespread dissemination (FFWD), progression-free survival (PFS), overall survival (OS), and freedom from systemic treatment (FFST). Acute and delayed toxicities were also evaluated.ResultsThe median follow-up after SBRT was 34.9 months. The LC rate at three and five years was 68.4 and 56.3%, respectively. The observed median FFWD was 14.6 months, with a five-year FFWD rate of 33.7%. The median PFS was 9.4 months; the three-year PFS rate was 19.8%. The median FFST was 14.0 months; the five-year FFST rate was 23.5%. The OS rate at three and five years was 61.8 and 39.3%, respectively. Median OS was 53.1 months. The initial dissemination significantly shortened the time to relapse, death, or activation of systemic treatment-LC (HR 4.8, p < 0.001), FFWD (HR 2.8, p = 0.001), PFS (HR 2.1, p = 0.011), FFST (HR 2.4, p = 0.005), OS (HR 2.2, p = 0.034). Patients classified as having radioresistant tumors noticed significantly higher risk in terms of LC (HR 13.8, p = 0.010), FFWD (HR 3.1, p = 0.006), PFS (HR 3.5, p < 0.001), FFST (HR 3.2, p = 0.003). The multivariable analysis detected statistically significantly worse survival outcomes for initially disseminated patients as well as separately in groups divided according to radiosensitivity. No grade III or IV toxicity was reported.ConclusionOur study shows that targeted SBRT is a very effective and low toxic treatment for oligometastatic lymph node involvement. It can delay the indication of cytotoxic chemotherapy and thus improve and maintain patient quality of life. The aim of further studies should focus on identifying patients who benefit most from SBRT, as well as the correct timing and dosage of SBRT in treatment strategy.

Dataset Information

A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial).

Publications

A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial).

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