Liver and gall bladder

The purpose of our study is to increase the efficacy and reduce morbidity of radiotherapy directed towards the liver. It is well known that radiotherapy can create severe and incurable side effects. Today, a special technique called stereotactic radiotherapy is used. This technique delivers a high dose in a few fractions and therefore precision is of paramount importance. However, as the liver tumor itself and the organs around it, as the intestines, move a lot, there is a high need for motion management at treatment. Another challenge is the liver’s susceptibility to radiation toxicity and therefore the dose to the healthy liver tissue should be kept as low as possible. Proton therapy reduces the dose to the normal tissue around the tumor without compromising the dose to the tumor itself, which might lead to fewer side effects. This study investigates several motion management techniques as well as proton therapy as a way of securing precise dose delivery to the tumor while reducing side effects.

Aim

Our overall aim is to develop and establish the optimal way to treat patients with tumors in the liver with Stereotactic Body Radiotherapy (SBRT) in Danish centers, reduce treatment related toxicity and conduct clinical protocols using photon or proton SBRT through multi-center DLGCG studies with prospective registration of all patients undergoing liver SBRT.

Areas of interest:

New indications for SBRT – as methods improve, SBRT might become the treatment of choice in primary and secondary liver cancer instead of other localized treatment options used today.
Improved motion management during SBRT at conventional linacs. This includes motion monitoring during treatment and respiratory gated radiotherapy to improve precision and minimize the dose to normal tissue.
MR guided adaptive radiotherapy could potentially further improve precision and decrease toxicity in photon SBRT.
Proton therapy could potentially decrease radiation dose to normal liver tissue compared to photon therapy and thereby increase the possibilities of treating larger liver tumors or patients with poor liver function.

Background

Today, liver SBRT is often chosen as the last treatment option to achieve control of hepatic tumors.

One of the major concerns of SBRT is the radiation dose distributed to normal liver tissue. Patients with HCC often have poor liver function and patients with metastatic disease often have large tumors or small total liver volume due to previous resections. Also, the tumors may be located close to critical normal tissue such as the duodenum that cannot tolerate high doses of radiation. Proton therapy could prove beneficial in patients where liver volume or liver function is a concern. This could potentially increase the number of patients that are given a treatment option with SBRT.

However, motion induced uncertainties affecting the geometric and dosimetric treatment precision are a major concern in liver SBRT. Therefore, it is highly relevant to validate and ameliorate methods used to mitigate and monitor the effects of tumor motion during treatment, such as margin design, intra-treatment motion monitoring, respiratory guided radiotherapy or MR guided adaptive SBRT. Such methods may also facilitate reconstruction of the actual delivered dose to the target and normal tissue during treatment.

While x-ray based image-guided radiotherapy usually depends on implanted fiducial markers for improved target positioning at treatment, MR-guided radiotherapy enables direct tumor visualization and thereby eliminates the need of implanted markers (invasive procedure).

Since summer 2017, a national radiotherapy group including physicians and physicists from all centers has collaborated on establishing national guidelines for liver SBRT, discussing SBRT strategies and preparing for data registration in a national database. This work will be the basis for national clinical protocols.

Methods

A national database is prepared including RT parameters, baseline and follow-up data with outcome measures, toxicity data based on the CTCAE v.4.03 and Patient Reported Outcome Measures (PROM).

Several motion management strategies and modalities are explored:

1.X-ray or electromagnetic (Calypso) guided radiotherapy

2.Respiratory gated radiotherapy

3.MR-guided adaptive radiotherapy

4.Proton treatment

The motion-including dose reconstruction will be based on intra-fraction motion monitoring by pre- and post-treatment CBCT scans (assuming linear tumor drift between the scans), intra-treatment x-ray imaging, electromagnetic monitoring (Calypso) of implanted markers/transponders, or MR guided radiotherapy (MR-linac).

Clinical studies

The above mentioned motion management strategies will be explored in several interventional clinical studies:

A planned national phase II study randomising patients between percutaneous microwave ablation and SBRT. N=100. The protocol is approved by the ethical committee.
A feasibility study with proton therapy in patients with large colorectal metastases with no other treatment options than palliative chemotherapy and where a standard photon SBRT plan is not considered safe (violation of standard constraints). The study will be planned together with DCCG and the Danish Center of Particle Therapy.
A National phase II study of proton therapy in HCC was opened in April 2022. Patients can be referred from all centers in Denmark treating HCC. As proton therapy can spare large volumes of the liver from extra dose to the liver compared to photons, radiotherapy will be feasible in more patients. Therefore, the study will be open for a group of patients not previously treated with photon radiotherapy (patients with large tumors and patients with a poor liver function, Child Pugh score max 8). The study is planned together with DLCGC and Danish Center of Particle Therapy.
A feasibility study – markerless liver SBRT combined with optimal motion management strategy on MR linac.

Expected results

The thorough registration of morbidity, dose parameters and outcome after liver SBRT is needed for future comparative proton and photon liver SBRT studies.

The different motion management strategies available in different centers will give us unique possibilities to share experiences in the national group and prepare for future clinical practice changes and future protocols. The motion-including dose reconstruction will pin-point discrepancies between planned and delivered doses. This will facilitate correct dose parameter reporting and hence enable a better dose-response based prediction of both morbidity and outcome. Finally, our studies will lead to optimal motion management strategies for future use in photon and proton liver SBRT.

Impact/relevance/ethics: The results are expected to influence future national guidelines and it is our hope that future patients may be treated with an individualized technique suitable for their tumor location and size.