Writing in a British Journal of Radiology special feature on Advances in Radiotherapy, researchers in Germany have summarized the complex record of accomplishments in this field. They detail new challenges that previous findings create, and the additional research needed as a precursor to clinical trials, focusing on the combination of internal and external radiotherapy (CIERT) for solid tumours (Br. J. Radiol. 88 20150042).

CIERT combines EBRT as a local therapy with RIT as a systemic treatment that offers the ability to treat localized and diffuse tumours and micrometastases. RIT uses radionuclides bound to carrier molecules that target tumour cells and are distributed according to the properties of their tracer.

Pre-clinical research

Pre-clinical CIERT studies have been conducted for more than 25 years, but published outcomes are difficult to compare due to their many differences, such as tumour and target entities, target antigens, radionuclides used, doses, treatment schedules and endpoints.

Numerous studies have been conducted to identify radionuclides that can reach a tumour target and accumulate for an appropriate period – a balancing act between the pharmacological half-life of the carrier and the half-life of the radioactive nuclide. Cytostatic drugs and hormone derivatives as well as monoclonal antibodies (mAb) have been radiolabelled and investigated. While RIT as a single treatment including the concept of pre-targeting has been extensively researched, combination with EBRT has not, according to lead author Antje Dietrich of the German Cancer Consortium (DKTK) in Dresden and colleagues.

Imaging with radionuclide-labelled conjugates, which provide pre-therapeutic information such as biodistribution, hints of the limiting critical organ or tissue dose and maximum tolerated dose, has also been investigated – as has 3D dosimetry of intravenously applied radiotracers. The authors write that future research will aim to acquire knowledge about specific distributions of mAb-based radiotracers in humans and to evaluate possible ways to influence this.

In vitro systems uncover underlying mechanisms of functional interaction and are useful to indicate efficacy. In vivo studies evaluate the therapeutic benefit of combined treatment strategies, but only a few investigators have used tumour control as an endpoint. Because tumour growth delay does not always equate to enhanced control, studies focusing on curative endpoints are imperative before clinical protocols can be developed. Also, the complex issues of investigating normal tissue toxicity have not been studied adequately, the authors report.

Developing optimal CIERT treatment schedules is a crucial aspect of pre-clinical research. Unlike standard EBRT, which is delivered in multiple fractions over time to enable normal tissue repair, numerous options and combinations exist for delivery of radiolabelled antibodies. For example, treatments may be fractionated and administered before, during or after EBRT. Studies in the 1980s and 1990s focused on these issues.

The first preclinical study of CIERT as a curative approach was conducted 10 years ago by Swiss and British researchers who analysed the tumour uptake and efficacy of treatment of two human colon cancer xenografts resistant to RIT alone. Principal investigator Franz Buchegger of the Centre Hospitalier Universitaire Vaudois and colleagues reported that the combined treatment showed a prominent advantage over single treatments, without additional toxicity.

Their subsequent studies determined that a fractionated scheme of simultaneously applied EBRT and RIT was most effective. Buchegger's team then conducted a clinical feasibility study treating six patients with colorectal cancer liver metastases with CIERT. Although not curative, four of the six responded positively.

Other studies have shown the potential of CIERT if the radiolabelled agent accumulates in the target tumour and is well distributed. However, when radiolabelled antibodies are unevenly distributed, the crossfire effect – radiation emission from targeted cells extending into adjacent cells – may have a positive impact. The magnitude of this effect relies on the radionuclide type and the tissue penetration depth of the emitted radiation.

Some studies suggest that application of RIT simultaneously or after EBRT produces more beneficial results than applying RIT before external irradiation. The authors note that the optimal treatment schedule has to be defined for each individual antigen/antibody pair, and may also be influenced by the chosen tumour model. Other radiobiological processes may also impact treatment models. As such, more pre-clinical research is required to understand the mechanisms and enhance the potential of this combined treatment approach.

Clinical translation

Clinical trials relating to CIERT of solid tumours in men are rare, the authors report. A number of clinical trials addressing tumour-targeted mechanisms have been successfully conducted in tumour entities including recurrent malignant glioma, meningioma, primary and secondary tumours of the liver, brain metastases, primary breast cancer, osteoplastic bone metastases from prostate cancer, malignant pheochromocytoma and paraganglioma.

These trials were performed on patients with advanced tumours and poor prognoses, and the vast majority were phase I/II trials to demonstrate safety, feasibility and efficacy. Only four studies were designed as prospective randomized controlled trials, all of which demonstrated the superiority of CIERT to EBRT alone.

The authors state that the biggest clinical step forward has been made in the field of 3D dosimetry. However, remaining challenges include dosimetry of internal irradiation. Additional clinical studies are needed to address CIERT design considerations, the manner of antibody application and the order of combined treatments.

In addition to emphasizing the necessity of teamwork between nuclear medicine and radiation oncologists, the authors conclude by stating: "It is an obligate precondition for CIERT that classical radiobiology needs to be adapted to the use of open radionuclides for a real comparison with external radiotherapy."

Related stories

• BJR publishes special feature on advances in radiotherapy
• Biological data personalize radiotherapy
• Radio-immunotherapy: attacking cancer from within