Pain Palliation

In the clinical trial of the FURTHER project, three treatment strategies will be compared. Below you’ll find a short explanation of these treatment strategies.


Palliative EBRT treatments with systemic therapy and analgescis.

The current standard of care for patients with uncomplicated painful bone metastases includes palliative locoregional treatment using external beam radiotherapy (EBRT), often in combination with systemic therapy and analgesics. The putative main mechanism of pain relief by EBRT involves the inactivation of osteoclasts to change the microenvironment of bone resorption followed by sterilization of cancer cells to reduce tumor-induced compression. The direct mechanism of action of EBRT is damage to DNA of tissues, including both single strand and double strand DNA breaks, originating mostly from different oxygen radicals.

Approximately 25% of patients can expect to have complete pain relief whereas a total of 60-70% of patients can expect some response to radiotherapy. However, time to optimal symptom control, even after short courses of radiotherapy, is usually measured in weeks to months after radiation treatments are delivered. On average it takes four weeks for EBRT to induce adequate pain relief. In the Dutch Bone Trial, including 1100 patients, only 71% of patients reported adequate pain response. Moreover, approximately 50% of responders experience recurrent pain. Radiotherapy retreatment of non-responders or those with recurrent bone pain is limited by cumulative doses of radiation delivered to sensitive structures surrounding the bone metastases. In addition, re-irradiation is only effective in a small majority (58%) of patients.

MR-HIFU For Pain Palliation

How MR-HIFU as non-invasive palliation treatment can reduce pain.

MR HIFU is a non-invasive outpatient treatment modality that delivers acoustic energy to heat lesions to ablative temperatures of more than 60°C. The combination of focused ultrasound with magnetic resonance imaging (MRI) enables physicians to perform localized tumor tissue ablation, with real-time temperature monitoring using magnetic resonance (MR) thermometry. The biological mechanism of pain relief induced by MR-HIFU treatment has not been completely elucidated, although it is generally assumed that periosteal denervation induced by cortical heating plays a major role. The mechanism of action of MR-HIFU is coagulative necrosis and apoptosis of tissue due to heat leading to rapid and durable pain relief from immediate periosteal nerve ablation and thermal necrosis of the targeted bone tumour. The importance of this therapy is that it offers a low-risk, non-invasive, focal therapy, avoiding side-effects to surrounding normal tissue that occur with radiation therapy. In contrast to EBRT, it does not require computed tomography (CT) for treatment planning or therapy.

Previous clinical studies on the use of MR-HIFU for palliation of painful bone metastases demonstrated excellent response rates and safety. Response to MR-HIFU was typically rapid, with about two-thirds of responses seen within days after treatment. However, these studies were performed in patients who were ineligible for radiotherapy, or who failed or declined radiation. As such, there is a lack of evidence that supports the uptake of MR-HIFU as a standard (first-line) treatment option and alternative to EBRT, even though these results show that MR-HIFU has the potential to provide added value in standard care.


Earlier pain relief and improved response durability.

There are several hypotheses about the possible synergistic effect of EBRT and MR-HIFU. By combining both modalities, a substantial proportion of patients with painful bone metastases are expected to experience early pain relief and improved response durability. Additionally, it is recognised that radiation and heat both induce tumour-specific immune responses. Since the mechanism of action of EBRT and MR-HIFU differ, MR-HIFU provides an alternative means to overcome radio-resistance and is recommended for patients with bone metastasis for whom radiotherapy (RT) is considered to have failed.

Moreover, the two methods may be synergistic in first-line, or when applied nearly simultaneously, due to their different mechanisms of action. Heat-induced coagulative ablation is the main action of MR-HIFU, hence its pain palliation effect is expected to be rapid. However, heat distribution is often spatially heterogeneous in bone metastases because absorption of ultrasound energy depends on many factors including the degree of bone lysis or formation, and incident ultrasound angle. Therefore, it might be that the more long-term, systemic responses of EBRT of the tumour and its micro-environment, reduction of tumour-induced compression and inactivation of osteoclasts, can be augmented by local ablation of periosteal nerve ablation by MR-HIFU.