REtroperitoneal SArcoma Registry: an International Prospective Initiative

Retroperitoneal sarcomas (RPS) are rare tumors accounting for 10-15% of all soft tissue
sarcomas (STS). They arise between retroperitoneal organs and among vital structures (ie
major abdominal vessels) in an anatomical compartment that is not readily accessible by
physical examination. Four main histotypes account for about 80% of all cases:
well-differentiated liposarcoma (WDLPS), dedifferentiated liposarcoma (DDLPS), leiomyosarcoma
(LMS) and solitary fibrous tumor (SFT).

Compared to sarcomas at other anatomic sites, RPS are burdened by a higher local recurrence
(LR) rate (50% at 5 years) and a poorer overall survival (OS) rate (50% at 5-years). The
natural history of RPS as a whole group reflects the strong tendency of lipomatous tumors
(WDLPS and DDLPS, which account for about 50% of RPS) to recur locally. Indeed, outcome of
primary RPS is highly related to the histological subtype.

WDLPS are characterized by a relatively lower LR rate, negligible metastatic potential and a
favorable overall survival. These tumors however, still may recur locally even years after
the primary resection. Intermediate grade DDLPS are characterized by a strong tendency to
recur locally and low metastatic potential. High grade DDLPS has a high risk of both local
recurrence and distant metastasis. LMS are usually intermediate or high-grade tumors with a
strong tendency to develop distant metastasis; with an adequate resection, it is relatively
common to obtain a durable local control. Classic SFT usually fare well after surgery, with a
low rate of local recurrence and distant metastasis.

Historically, surgery emerged as the only potentially curative option in the localized
setting. In the last few years there has been lively debate as to how far should a surgeon
resect in order to obtain a margin that could be considerate adequate. This issue is
particularly challenging in this anatomical compartment where widening the surgical margins
means resecting adjacent organs.

Since 2002 an 'extended' surgical approach has been proposed for primary RPS patients. The
concept was that surgical margins could be improved by encompassing the tumor with en-bloc
resection of adjacent organs. The aim was to obtain reduced local recurrence and improved
survival. This approach has proven to be effective. In particular, this surgical approach has
been supported by an experimental model, retrospective comparisons, pathology studies
demonstrating adjacent organ involvement, and reports of high rates of residual tumor at
re-excision after conventional (non-extended) primary surgery. Finally, this approach has
been shown to be safe after both short and long term follow-up.

Radiotherapy is an option for RPS, especially in the preoperative setting, but currently the
best evidence for efficacy comes form retrospective, mainly single-center, small size series.
The results of such studies are controversial and high quality data are lacking. A randomized
prospective study led by EORTC (STRASS) is ongoing but results are not expected for several
years.

The role of chemotherapy in the localized disease is also still under investigation,
especially in high grade tumors. So far, there is no agreement on the optimal treatment
strategy, even within reference centers, regarding the use of both chemo- and radiotherapy.
In the recent years European and North-American centers joined the panel of expert and this
led to the formation of the TransAtlantic Retroperitoneal Sarcoma Working Group (TARPSWG),
which now consists of more than 50 representatives from sarcoma centers from all over the
world.

The aim of this collaboration is to expand the knowledge of the disease and formulate shared,
standardized principles of treatment. A retrospective study has been carried out and recently
published by the group to better define patients' outcome and prognostic factors after
surgical resection of primary tumors. Other retrospective studies have been published
focusing on post-relapse outcome, postsurgical morbidity and local recurrence treatment. This
collaboration has also just recently led to the development of consensus guidelines for the
treatment of primary and recurrent and metastatic RPS.

To take advantage of the group collaboration, TARPSWG promoted a prospective collection of
clinical, radiological and pathologic data for RPS.

This study is aimed to prospectively collect standardized clinical data and radiological and
pathological material from primary RPS patients treated with surgery at reference centers.
Patient outcome will be evaluated in terms of overall survival (OS), disease-free survival
(DFS), crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM).

STUDY DESIGN

This is a prospective, multicentric observational study under the supervision of TARPSWG
(TransAtlantic Retroperitoneal Sarcoma Working Group) aimed to prospectively collect clinical
data and prospectively store radiological and pathological material from patients affected by
primary RPS treated with surgery.

Patients with a diagnosis of primary RPS who meet the eligibility criteria will be invited to
participate to the current study.

Eligible patients will receive full information on the type of surgery proposed and on the
data and material (radiological and pathological) that will be collected. Eligible and
informed patients who give their consent to participate will be included in the Prospective
Cohort Study (PCS) and will be followed-up prospectively.

A data collection form including patient and tumor-related factors, treatment variables,
follow-up findings, development of and time to local recurrence and status at follow-up has
been constructed and shared among all the participating centers.

Each participating reference center will individually be able to have access to both cross
sectional imaging (CT or MRI images) and pathological material (a representative formalin
block of the tumor). Whenever possible patient identifiers will be removed and patient
confidentiality will be maintained. Any data shared between institutions will be deidentified
and all measures to conceal patient identifiers will be taken.

Each center will be responsible for data-entry and storage of its own patients' data,
radiological examinations and pathological samples. At the time of the analysis each center
is committed to provide the requested updated data to the group.

Follow-up will be based on clinical evaluation and on cross sectional imaging (CT scan of the
thorax and abdomen and/or contrast enhanced MRI of the abdomen) every 4 months for the first
2 years, every 6 months until the 5th year and yearly thereafter.

The overall duration of the project has not been fixed.

Sample size

The number of patients we plan to include in this prospective multicenter study will be 400
patients per year.

STATISTICAL CONSIDERATIONS Continuous variables will be summarized with appropriate summary
statistics such as the mean, median, standard deviation, minimum and maximum. Categorical
variables will be tabulated with frequencies and percentages. We will evaluate OS, DFS, CCI
of DM and LR and correlate this with clinicopathologic factors such as histology, grade, type
of surgery, etc.

DATA COLLECTION Data entry will be performed by every participating center. Data will be
collected in a standardized database, stored by every participating center, and shared with
the group at the time of future studies. Data shared between institutions will be
deidentified and whenever possible all measures to conceal patient identifiers and maintain
patient confidentiality will be taken.

ETHICS It is the responsibility of the investigator to have prospective approval of the trial
protocol, informed consent forms, and other relevant documents, from the IRB/IEC. All
correspondence with the IRB/IEC should be retained in the Investigator File.

Inclusion Criteria:

- primary RPS operated on in the participating center;

- age>18 years at the time of the first treatment (pediatric patients can not be
included)

- histological confirmed diagnosis according to the WHO criteria done on biopsy or
surgical specimen by dedicated sarcoma pathologist;

- radiological examinations performed (contrast enhanced abdominal CT scan and/or MRI)
prior to surgical resection;

- signed informed consent form;

- adequate compliance of the patients to the plan of follow-up

Exclusion Criteria:

- age<18 years;

- recurrent tumor;

- benign retroperitoneal tumors;

- serious psychiatric disease that precludes informed consent or limits compliance;

- impossibility to ensure adequate follow-up