Radiation-induced toxicity after image-guided and intensity-modulated radiotherapy versus external beam radiotherapy for patients with spinal bone metastases (IRON-1): a study protocol for a randomized controlled pilot trial

This prospective, single-center pilot study is performed at the Department of Radiation Oncology at the University Hospital of Heidelberg for patients with spinal bone metastases with indication for radiotherapy. As shown in Fig. 1, participants will be randomized into two groups: one group receiving intensity-modulated radiotherapy treatment (group A) and the other conventional external beam radiotherapy (group B).

The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist shows the study guidelines in more detail (see Additional file 1).

Before the start of radiotherapy, the recruitment of eligible participants firstly includes the explanation, to each potential study participant, of the purpose, implementation, design, aims, requirements, and timeline of this study as well as the description of the two different radiation techniques and common ethical issues.

Patients will be included who:

Patients will be excluded who:

Criteria that will lead to the drop-out of a patient before completion of this study may be any kind of treatment for medical reasons or impairment that will result in an interruption or early completion of radiotherapy. Furthermore, the patient’s desire to exit the study or withdrawal of consent as well as any unexpected serious adverse event (SAE) occurring during treatment or in follow-up that leads to early completion of the study will result in drop-out.

All patients receive a planning computed tomography (CT) scan with a slice thickness of 3–5 mm. Patient positioning depends on the area being treated and includes the use of various fixation devices, such as Wingstep® and Prostep® (Elekta, Stockholm, Sweden) for lesions in the thoracic or lumbar spine as well as head holders such as Aquaplast masks (Aquaplast Corporation, Wyckoff, NJ, USA) for cervical spine immobilization. In addition to skin tattoo marks, this guarantees the achievement of a high reproducibility of patient positioning and accuracy of treatment delivery.

Afterwards these CT scans are used to outline organs at risk (OARs) and to contour the clinical target volume (CTV), which encompasses the metastatic vertebral body and, with a margin of 1 cm, results in the planning target volume (PTV). The target volume (=PTV) in each treatment group consists of the entire metastatic vertebral body in a craniocaudal direction including the Proc. costales et transversi to the right and left lateral sides.

In group A, treatment is being performed as intensity-modulated radiotherapy (IMRT) and planned as either tomotherapy, volumetric arc therapy (VMAT), or step-and-shoot IMRT with daily cone-beam CT imaging for rigid patient deformation during radiation. In group B radiation is delivered by conventional, three-dimensional (3D) planned, external beam radiotherapy in two to three fields. Each group uses 6 MV photon energy plans with multileaf collimator shaped radiation fields. A palliative treatment regimen with a total prescribed dose of 30 Gy in 3 Gy fraction doses and daily treatment sessions five times per week is performed, with the 90% isodose surrounding the PTV. OARs such as the skin, heart, or the esophagus are delineated, and dose limit constraints are prescribed to each of them following common considerations according to QUANTEC parameters.

During study observation, patient data are collected before the start of radiotherapy treatment (t0), at the end of treatment (t1), and in the follow-up period at scheduled visits in our department at time points of 3 months (t2) as well as 6 months (t3) after completion of treatment (Figs. 1 and 2).

Patient clinical information is carefully documented in case report forms (CRFs) using questionnaires, filled out by each patient, that measure and quantify clinical symptoms and factors such as pain, radiation-induced side effects and toxicity, as well as quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for patients with Bone Metastases and for measure of Fatigue (EORTC BM22, FA13) and visual analog scale (VAS)). Furthermore, the follow-up requirements include a CT scan 3 and 6 months after completion of radiotherapy for evaluation of treatment response, bone sclerosis, spinal stability, and possible complications such as bone fractures.

In this trial, radiation-induced toxicity 3 months after completion ofpalliative radiotherapy will be evaluated as the primary endpoint. Its extent is measured according to criteria delineated by NCI Common Toxicity Criteria for Adverse Events (CTCAE v 4.0).

Secondary endpoints will be bone re-calcification, quality of life, spinal instability and fractures, local control, and clinical symptoms such as fatigue, pain relief, or neurological deficits.

This trial is being performed as a pilot study; in the calculation for statistical analysis a total of about 30 patients in each treatment group is considered an appropriate sample size. Due to the explorative character of this study, it is not possible to estimate the total number of cases. However, with a scheduled number of 30 patients per group, it will be possible to detect a standardized mean-value effect (Cohen’s d) of 0.8 with a power of 80% and an alpha significance level of 5%. A blocked randomization is used to allocate each participant into group A or B before start of treatment. All variables were analyzed descriptively by tabulation of the measures of the empirical distributions. According to the scale level of the variables, means, standard deviations, and medians as well as minimum and maximum or absolute and relative frequencies, respectively, will be reported. Additionally, for variables with longitudinal measurements, the time courses of individual patients will be analyzed and summarized by treatment groups. Descriptive p values of the corresponding statistical tests comparing the treatment groups will be given. The Wilcoxon signed rank test will be used to compare changes in group difference. The Cohen’s effect size (ES) will be assessed for clinically relevant change in questionnaire measures (<0.3 low, 0.3–0.7 moderate, >0.7 strong difference). Moreover patient data are collected in table form at the above-mentioned time points for all completed questionnaires. All statistical analyses will be performed with SAS software v 9.3 or higher (SAS Institute, Cary, NC, USA).