A randomized controlled trial for evaluating pain response in patients with spinal metastases following local versus whole vertebral radiotherapy: study protocol for phase II clinical trial

Patients with bone metastasis often present with severe pain that is difficult to control. The ASTRO guideline and its update recommend palliative analgesic radiotherapy for bone metastases [1, 2]. However, the effects of pain control therapies vary from one patient to another. In the past, the target setting of two-dimensional radiotherapy and 3D-CRT included the whole diseased vertebral body to treat spinal metastases, despite some patients suffering from pathological fracture, spinal cord compression, and other side effects of an excessive dose or range of vertebral irradiation.

The ISRC proposed dividing vertebral body into six parts in the target setting of spinal stereotactic radiosurgery, as shown in Fig. 1. As reported by a prospective study [3], there is a need to expand the CTV in SBRT for include adjacent physiologically occurring bone marrow spaces, which may have subclinical diseases and may become local recurrent lesions. The ISRC consensus guidelines on the target volume of spinal SRS suggest that CTV should include bone marrow signals suspected of microscopic invasion and adjacent normal bone. If the spinous processes, lamina / bilateral pedicle and vertebral body are affected or there are extensive metastatic diseases around the epidural space, the circumferential TVs around the spinal cord should be used [4].

At present, there is a single-center phase II prospective cohort study comparing the effect on pain control of conventional radiotherapy and SBRT in patients with spinal metastasis. In both treatment groups, patients had a comparable decrease in pain and analgesic use in the 3 months following treatment [2, 5]. However, there have no randomized controlled trials comparing the effect of local irradiation and whole vertebral irradiation on pain control in IMRT [6]. Therefore, we designed a randomized controlled trial to evaluate if irradiation of local metastases in the vertebral body as well as whole vertebral body irradiation can effectively control pain. We also investigated if side effects such as twinkling bone pain, spinal cord radiation injury, vertebral compression fracture, and nerve root compression were reduced.

This study was registered in the ChiCTR (No: ChiCTR1900023401). This is a multicenter, prospective, phase II randomized controlled clinical trial. Patients with solid tumors diagnosed pathologically at our hospital were collected. All patients had vertebral metastases and pain symptoms. Patients will be randomized into 2 groups: study group^’s clinical target volume setting was according to the ISRC consensus guidelines that recommend the vertebral body be divided into six parts, which include the area of vertebral destruction and adjacent parts, and control group’s clinical target volume include the whole vertebral body, The two groups of clinical target volume settings are shown in Fig. 2. Two groups will receive treatment with the same dose of 95% PTV DT 30 Gy/10 f IGRT (Image Guided Radiation Therapy).

Before starting treatment, the qualified recruitment participants will explain the common ethical issues, objectives, design, description, implementation, requirements and schedule of this study to every potential study participant.

Approximately one-third of patients with advanced malignant tumors will experience bone metastasis, and the spine is the most common bone metastasis, especially the lumbar spine and thoracic [9, 10]. Patients with bone metastasis often present with severe pain that is difficult to control. Some patients with vertebral metastasis even have pathological fractures and spinal cord compression. Radiotherapy is an effective treatment for alleviating the symptoms of bone metastasis [11‐13].

The 2017 ASTRO update on palliative radiotherapy for bone metastases continues to recommend that patients with bone metastases can be selectively treated with 8 Gy/1 f, 20 Gy/5 f, 2 Gy/6 f, or 30 Gy/10 f with four different fractionation methods [14‐16]. The 30 Gy/10 f and 8 Gy/1 f doses are widely used in conventional radiotherapy. Existing research has shown that the effects on pain relief of single radiotherapy and fractional radiotherapy are similar [11, 15‐18]. However, Rades et al. showed that the recurrence of pain caused by vertebral metastases treated with large fractionation therapy could be as high as 26%, compared with conventional long-term treatment with 30 Gy/10 f, which showed better local control [19]. This is the basis for the selection of 30 Gy/10 F fractionated irradiation in our trial. We suspect that the reason for the difference in pain control and duration of pain relief may be related to the dose limitation of spinal nerves in patients with vertebral metastases. Therefore, current research on radiotherapy of vertebral metastases focuses on increasing the radiation dose without increasing the side effects to achieve better pain control [20].

According tothe2012 ISRC consensus guidelines on the target volume of spinal SRS, unless the spinous processes, lamina / bilateral pedicle and vertebral body are affected or there are extensive metastatic diseases around the epidural space, the circumferential TVs around the spinal cord should not be used. The guidelines emphasized that published guidelines on indications and practice patterns for spinal SRS are limited and there is no consensus on the definition of target volume [2]. We propose a safe and effective reduction of the target area in IGRT radiotherapy, which can effectively avoid the excessive irradiation of nerve, spinal cord and other normal tissues, and correspondingly improve the target dose setting.

If this trial can prove that local irradiation is equivalent to whole vertebral body irradiation in terms of pain relief, then the next step will be to increase the irradiation dose on the reduced target area in order to achieve higher pain control rate of vertebral metastasis and improve the quality of life of patients with vertebral metastasis.