Intraoperative Radiotherapy During Kyphoplasty/Vertebroplasty (Kypho-IORT) Versus EBRT in the Treatment of Painful Vertebral Metastases - a Randomized Prospective Phase III Study -

Due to optimized therapies life expectancy of patients with metastasizing cancer increases. Bone metastases affect 10% - 30% of all cancer patients, especially located in the vertebral column. The main clinical problems are back pain and an increased risk of pathological fracture. Therefore optimized palliative treatments to improve quality of life are necessary.

External beam radiotherapy (EBRT) is a well-established treatment option for patients with spinal metastases. EBRT often results in an adequate pain relief with good local tumor control . Of the retrospective series that described pain outcome mentioned in the systematic review by Gerszten et al., a mean of 70% of patients had improvement in pain after radiation therapy. The mean rate of local control was 77%. Although EBRT is the standard treatment for painful vertebral metastases, the optimal dose fraction schedule or the optimal standard dose has not been established. Different fractionation schedules of EBRT are discussed in a recently published review. Literature data confirm time to pain reduction of about 8-10 days after EBRT.

Balloon kyphoplasty is another valuable treatment option for patients with painful and instable metastases to the vertebral column. In the recent published trial by Berenson et al. 134 patients with vertebral compression fractures were enrolled and randomly assigned to kyphoplasty or non-surgical management. The study found that patients treated with kyphoplasty had a significant reduction of back pain after seven days. Nevertheless kyphoplasty has no direct anticancer effect and external beam radiotherapy has to follow to avoid early regrowth. But EBRT after kyphoplasty or EBRT alone takes up to 2-4 weeks. This long treatment period can often be a mental and physical strain. Moreover patients with simultaneous visceral metastases often need chemotherapy which cannot be applied concurrently to radiotherapy due to the risk of potentiated toxicity. To reduce treatment time and increase quality of life novel techniques like kyphoplasty combined with other physical methods are under development. Recently published trials showed good results relating to pain relief and local tumor control in patients with spinal metastases treated with kyphoplasty combined with intravertebral administration of 153Samarium or interstitial implantation of 125I seeds. Therefore we developed a novel approach to deliver intraoperative radiotherapy during kyphoplasty (Kypho-IORT). Based on our recently published reports Kypho-IORT is a technical feasible new treatment option without severe side effects. We observed an excellent pain relief. At the first postoperative day improvement of pain was observed in 11 of 16 (69%) patients and no change in 5 of 16 (31%) patients. During further follow-up, improvement of pain was seen in 75% - 83% of the patients compared to the preoperative status. According to these results a dose escalation study has been initiated, which has been completed (NCT 01280032). According to the results of this study a dose of 8 Gy in 10 mm depth from the applicator surface (correlates to a dose prescription from the isocenter of the radiation source of 8 Gy in 13 mm) is recommended for further Kypho-IORTs.

According to this the aim of this planned phase III study is to test the superiority of kyphoplasty or vertebroplasty + IORT (in the following abbreviated as Kypho-IORT) compared to EBRT with regard to time to pain reduction at defined points in time (day 1, week 2, 6 weeks after start of treatment).

We assume a pain reduction of VAS-3 points at day one (first day after Kypho-IORT, one day after the first EBRT) for 40% of the patients after Kypho-IORT vs. 5% of the patients after EBRT under standard pain medication (no change of the pretherapeutic pain medication 12 h after Kypho-IORT or rather 24 h after the first EBRT). Each study arm needs 22 patients, to reach an alpha of 0, 05 and a power of 0,817. Plus a dropout rate of 20% at least 54 patients have to be recruited.