Observational cohort of patients treated with stereotactic radiotherapy for
Oligo LYMPh nOde and other soft tissue metastasiS

Population: patients with lymph node, adrenal, liver, muscle and other soft
tissue oligometastases
With technological improvements in the fields of radiology and nuclear
medicine, metastases can be diagnosed in an earlier stage [1]. The improved
diagnostic tools have boosted interest in the oligometastatic paradigm: the
existence of a clinical state between localized and wide-spread metastatic
disease [2-4]. When patients are diagnosed with (very) limited metastatic
disease, it remains unknown what is the most appropriate therapy for these
patients. The current trend is to treat patients with oligometastases locally
whenever possible, aiming for local control and for postponement of the start
of potentially toxic systemic therapy, such as chemotherapy or androgen
deprivation therapy (ADT). By postponing systemic therapies, local treatment
may help maintain optimal quality of life [5]. Without treatment, soft tissue
metastases will continue to grow and can eventually cause complaints such as
pain, lymph edema, dyspnea, hoarseness, plexopathy, ureter obstruction and
biliary obstruction [6-9].

Local treatment of soft tissue oligometastases
Surgery has long been the treatment modality of first choice for local
treatment of oligometastases in liver, lung and adrenal gland [10-15]. New,
minimally invasive therapies such as stereotactic body radiotherapy (SBRT) [16]
now provide established alternative treatment options for patients with liver
and lung oligometastases, mainly used for inoperable patients [17-20]. More
recently, SBRT has also been introduced for patients with lymph node or adrenal
oligometastases [21,22-24]. Especially for small target structures as lymph
node oligometastases, the minimal invasive nature of SBRT is may be an
important advantage, compared with surgical resection.

Previous research from literature
Most studies have investigated SBRT for lymph node oligometastases after
treatment with curative intent for prostate cancer [2325-3133]. This is a
patient population with the best diagnostic tools available for early diagnosis
of oligometastases. With prostate specific antigen (PSA) as a sensitive
biomarker for biochemical recurrence and with prostate specific membrane
antigen positron emission tomography (PSMA-PET) imaging as very sensitive
imaging modality [1], it is now possible to identify (very) small pathologic
lymph nodes.

With local treatment of these lymph node oligometastases, the goal is to gain
local control, defer ADT and thereby keep quality of life as good as possible
[3234,3335]. It has been shown that SBRT for patients with prostate cancer
lymph node oligometastases can achieve high rates of local control (ranging 84%
- 100%) [2325,2527,2729,2931], with progression free survival rates at 24
months ranging 30% - 44% [2628,2729,2931]. Median time to ADT initiation was
17-24 months after SBRT [2426,2628,3133]. Furthermore, in the study of
Bouman-Wammes time to castration resistance was found to be prolonged for
patients treated with SBRT compared with a control group who were started on
ADT after a median of 4 months (time to progression under ADT mean 66.6, 95%
CI, 53.5 - 79.8, vs. 36.41, 95% CI, 26.0 - 46.8 months, p = 0.020).

SBRT for lymph node oligometastases from other primary tumors than prostate
cancer has also been investigated [3436-4139]. The patient groups in these
retrospective reports are very heterogeneous, but the potential of safely
obtaining local control with SBRT has been established. For most of these
patients, SBRT is a non-invasive alternative to surgery; again the aim is to
postpone potentially toxic systemic treatments such as palliative chemotherapy
[4042,4143].
Three randomized controlled trials investigating the benefit of SBRT for the
treatment of oligometastases have been set up recently: the SABR-COMET, STOMP
and ORIOLE trials [4244-4446]. All three trials include both lymph node and
bone oligometastases; the STOMP and ORIOLE trials focus exclusively on patients
with prostate cancer as primary tumor.

Literature regarding SBRT for liver metastases has been evolving for a longer
period of time, with 5 years of follow-up being completed for a phase II trial
[47] and with systematic reviews and reviews on future indications being
available [48,49]. Some studies on patient reported quality of life have been
published [50,51].
Adrenal gland metastases SBRT has been described in several recent publications
[52-57], including a report on video-assisted, respiration-gated, MR-guided
SBRT with daily plan adaptation [57].

As described, research into SBRT for soft tissue oligometastases is mounting.
However, almost all previously published studies suffer from small sample
sizes, especially considering the heterogeneous patient population, and from
heterogeneity in treatment strategies, such as SBRT fractionation schedules and
administration of adjuvant systemic therapy after SBRT. Patient reported
quality of life has only been described in a few studies to this date, mainly
for liver metastases SBRT.

Purpose of this study
The main clinical challenge remains to identify patients who may benefit from
aggressive local treatment (SBRT) of lymph nodesoft tissue oligometastases: for
which patients can systemic treatment be postponed? Patients who are diagnosed
with additional metastases in <6 months after the radiotherapy treatment, could
have been spared the radiotherapy treatment: achieving local control has little
clinical relevance in the palliative setting that follows. Patients who
experience complaints from lymph nodesoft tissue metastases, such as pain or
neurological symptoms, may be treated with a true palliative intention with
more appropriate radiotherapy treatment schedules.

By embracing the cohort multiple Randomized Clinical Trial (cmRCT) design
[45,4658,59], we want to facilitate future intervention studies within the
OLYMPOS cohort study. Such future intervention studies may shed light on other
challenges in SBRT for lymph nodesoft tissue oligometastases. One of these
lacunas is the optimal radiotherapy treatment schedule for SBRT. Currently, in
our department we treat patients with lymph node oligometastases with 5
fractions of 7 gray (Gy), but various treatment schedules have been reported in
literature [17,2325-3941]. The administration of radiation dose on the target
volume is very precise in SBRT, but the dose received by surrounding healthy
organs may show important variations between the different treatment sessions.
Currently this limits us in choices regarding the radiotherapy treatment
schedule; it has been advocated that a higher biological effective dose may be
needed for achieving optimal long-term local control [17]. With better
knowledge of the radiation dose that will be received by surrounding healthy
organs, and improved sparing of these organs at risk (OAR), it may be possible
to safely increase the radiation dose per fraction (dose escalation).
Furthermore, it may be possible to decrease the number of treatment sessions
(hypofractionation).
Investigating the potential for dose escalation and hypofractionation in nodal
SBRT are goals for future studies that we want to facilitate in the OLYMPOS
cohort. The cmRCT design provides an efficient way to study multiple different
interventions (or treatment schedules) simultaneously.

2. OBJECTIVES

The prospective OLYMPOS cohort will serve the following purposes:

1. Providing detailed information about treatment response, toxicity,
complications, postponement of systemic treatment, quality of life and survival.
2. Multi-trial facility for efficient (partly simultaneous) evaluation of
innovative interventions according to the cohort multiple Randomized Controlled
Trial (cmRCT) design.

3. STUDY DESIGN

The OLYMPOS cohort is a prospective study, which allows for systematic
registration of clinical data of patients with lymph nodesoft tissue
oligometastases. It allows for systematic registration of clinical data and
will serve as a facility for efficient, systematic and simultaneous evaluation
of new radiotherapy interventions. Patients will be followed prospectively and
information on survival, quality of life (including fatigue), toxicity and
postponement of systemic treatment in relation to radiotherapy treatment will
be prospectively collected. By adopting the cmRCT design, we can efficiently
facilitate multiple new intervention studies (Figure 1).

3.1 Inclusion
All patients who are referred to the UMC Utrecht Department of Radiotherapy for
stereotactic radiotherapy of soft tissue oligometastases, such as lymph node,
adrenal, liver or muscle metastases are eligible for participation in the
prospective arm of the OLYMPOS cohort. Patients will be included preferably
before the start of the treatment, but when patients are missed, inclusion can
also take place during or after treatment. If patients are included during or
after the treatment, this may influence the eligibility of a patient to be
approached for or serve as control in intervention studies.

3.2 Informed consent
Patients can sign informed consent for four separate parts of the study:
1. Use of routinely collected clinical data for research purposes (including
follow up data in other hospitals) and willing to participate in a short
biannual questionnaire to adequately register (serious) adverse events ((S)AEs).
2. Prospective registration of patient reported outcome measures (QoL, fatigue).
3. Approval to be approached for participation in future (intervention) studies.
4. Approval to share data with industry

Only informed consent for the first study part (Use of routinely collected
clinical data for research purposes and participation in short biannual SAE
questionnaire) is mandatory for participation in the OLYMPOS cohort. Patients
can only be approached for participation in or serve as control in future
studies (study part 3) if they also gave informed consent for prospective
registration of patient reported outcome measures (QoL and fatigue, study part
2).

If, after signing informed consent, the patient will not receive SBRT treatment
(this equals a minimum radiation dose of 5 Gy per treatment session), the
patient will only be able to continue with the first study part (Use of
routinely collected clinical data for research purposes). These patients will
not receive the biannual SAE questionnaire and will not be taken into account
for prospective registration of patient reported outcome measures (QoL and
fatigue, study part 2). Study part 3 is also not applicable for these patients.
By keeping these patients in the OLYMPOS cohort, we will be able to monitor why
these patients did not receive SBRT treatment. With the lower radiation dose
per treatment session, these patients are unsuitable for the SAE and patient
reported outcome measures study analyses, as they focus solely on the
prescribed treatment schedules with a minimum radiation dose of 5 Gy per
treatment session.

Besides the OLYMPOS study parts, patients can also consent to participation in
the MOMENTUM study.
Then they do not need to sign a separate informed consent form, they can be
included based on the combined information letter.
They will only be able to participate in the MOMENTUM study if they will
undergo treatment on the MR-linac, otherwise they will just continue
participation in only OLYMPOS.

Risks and extent of burden associated with participation
Patients are not exposed to any intervention or alternative treatment as part
of the OLYMPOS cohort study. Data will be captured/used that has been collected
as part of standard clinical care, with the Quality of Life (QoL)
questionnaires as additional information that will be collected especially for
this study. No (additional) risks are known from participation in this cohort
study. Any risks associated with future intervention studies within the OLYMPOS
cohort study will be described separately in the application process for each
specific (intervention) study.
The burden for patients will be the time it takes to fill in the QoL
questionnaires, ~10 minutes at each time point and ~120 minutes in total.
Questionnaire sending will be terminated when the patient will undergo a next
oncological treatment, this limits the burden for patients.

Benefits and risks assessment, group relatedness
Patients will not experience direct benefit from participation in the OLYMPOS
cohort. By participating, patients will contribute to the evidence on clinical
and environmental factors associated with treatment outcome, QoL and survival.
This will lead to better and a more personalized cancer care for future
patients. Risks associated by participating in the OLYMPOS cohort study are
negligible since it is observational.