First-In Man (FIM) study MR-Linac

Image Guided Radiotherapy (IGRT) has become the standard of care to optimize
the accuracy of irradiation delivery. To minimize the geometrical uncertainties
of the tumor location and shape, in-room image guidance by cone beam CT (CBCT)
prior to radiotherapy, has been introduced.

To optimize dose distribution and more precise dose delivery for sparing of the
surrounding healthy tissues, accurate tumor localization and tumor shape
determination are required. Unfortunately, CBCT has limited soft-tissue
contrast, which makes it is difficult to distinguish organs from tumors. A
small portion of additional irradiation is necessary for image generation and
improved contrast in the CBCT-image. Additionally, real-time anatomical data
during irradiation delivery is not possible when CBCT guided therapy is used.
Appliance of MRI solves both problems, without delivering an additional
radiation dose to the patient, which makes it more attractive for everyday use.

The MR-Linac integrates a radiotherapy accelerator with an MRI with a
diagnostic quality of 1.5T, enabling real-time soft-tissue visualization of
human anatomy during radiotherapy. By an improved real-time visualization of
the tumor and the surrounding healthy tissues using MRI, it is possible to
adapt the dose to the actual anatomy. Thereby, it is possible to provide an
increased radiation dose to the tumor, while damage to surrounding organs will
be minimized. It is expected that the MR-Linac has a broader therapeutic window
as compared to conventional therapy. Additionally, treatment with the MR-Linac
has the potential to replace invasive surgery in treating tumors.

When this study confirms that treatment with the MR-Linac is safe, follow-up
studies will be set-up to define the applications for which the MR-Linac is
suitable.

To confirm the pre-clinically demonstrated technical accuracy and safety of the
newly developed MR Linac in the clinical setting.

This is a first-in-man (FIM) study of the MR-Linac, conducted at the UMC
Utrecht, to evaluate the clinical safety and accuracy of the MR-Linac in
humans. In this study, five (5) patients with bone metastases will be included,
who will be treated for pain reduction (palliative policy).

Patients with palliative policy and a signed informed consent to participate in
the current PRESENT cohort study (to receive experimental care) and meet the
study criteria, will be asked to participate in this study.

When they decide to participate, patients are screened by physical examination
and their medical history, such as histological background, to determine
malignancy of the metastases. Additionally, a CBCT-scan is retrieved from the
patient to set-up an irradiation plan.

When the patient meets the eligibility criteria , the patient has two days to
consider participation in this study. At the second visit, patients will
receive a simulation MRI, after which they will be treated with the MR-Linac.
In case the target moves out of its defined boundaries, through which the
irradiation plan is not sufficient, the radiation oncologist and the clinical
physicist will evaluate the situation and decide together to restart the whole
simulation procedure for treatment with the MR-Linac or cancel the procedure
and treat the patient with the conventional Linac.

At the end of treatment, patients will be asked to complete three questions
concerning their experience with the MR-Linac treatment, to assess for
discomfort of the treatment. Additionally, the radiotherapist will follow up
the patients through a phone call. This occurs one day, two weeks, and twelve
weeks after treatment, to assess their health. Thereby, the safety of the
treatment with the MR-Linac can be determined.

The patient is treated once with a targeted irradiation dose of 8 Gy (8000
msV).

There is an increased treatment time with the MR-Linac of 30-60 minutes
compared to de regular treatment of 10-15 minutes. Additionally, standard MRI
risks apply, such as local heating and claustrophobia.

Patient burden includes an extra hospital visit, an increased treatment time
and associated risks with the MR-Linac, and three additional phone calls.
Altogether, it may take about 135 minutes of patients time.

Due to the following reasons, the intended study is classified as a low-risk
study:
Routine clinical care of bone metastases with the intention to relieve pain of
the patient consists of radiotherapy by single beam irradiation with wide
safety margins and inhomogeneous dose distribution. In the current study,
irradiation is administered with smaller margins and superior dose homogeneity.
Eventual positioning errors of up to 5 mm and dose distribution accuracy less
than 5% are still considered superior to standard treatment conditions.

In case these margins are exceeded, treatment on the MR Linac is abandoned and
the patient will be treated with the conventional Linac. A standard 1.5T MRI is
considered safe, and possible related side effects are negligible (see attached
folder *MRI* from the department of Radiotherapy, UMC Utrecht). The present
1x8Gy irradiation scheme does not exceed the tolerance dose for any of the
proximate normal tissues. In order to detect adverse events, follow-up will be
performed at day 1 after treatment, at 2 weeks and at 3 months by telephone or
by hospital visit on indication. Then, questions concerning patient health will
be asked, to determine safety of the treatment by the MR-Linac. Patient health
or morbidity will be assessed according to the presence or absence of symptoms
such as nausea, pain and fatigue, specific for the treated anatomic region.

Independent from the MR-Linac development, patients are currently already
safely being treated by other technologies based on MR-guided radiotherapy in
other centers (such as radiotherapy using cobalt sources and 0.35T MRI).