REtroperitoneal SArcoma Registry (RESAR): prospective collection of primary retroperitoneal sarcoma patient’s data, radiological and pathological material for the TransAtlantic Retroperitoneal Sarcoma Working Group.
1.1 Disease Background
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. Indeed, RPS typically reach a large size before being detected, usually because of vague abdominal symptoms or incidental palpation of an abdominal mass.
Although any histological subtype of RPS can arise in the retroperitoneum, 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. At a closer look, the outcome of primary RPS is in fact, highly related to the histological subtype.
WDLPS are characterized by a relatively lower LR rate, negligible metastatic potential and a favorable overall survival compared to other histological subtypes. 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 while 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 as well as distant metastasis.
Since the first published series of RPS, surgery emerged as the only potentially curative option in the localized setting. Although it is agreed that surgery is the mainstay of treatment, 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 hope was that this would translate into reduced local recurrence and improved survival. After years of studies, this approach has proven to be effective. In particular, this surgical approach has been supported by an experimental model, retrospective comparisons, pathology studies demonstrationing 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.
In 2012 a panel of experts standardized the principles of the extended surgery to RPS and these technical considerations were also adopted by the latest ESMO guidelines. The keypoints described in the position paper were the removal of the whole tumor avoiding tumor rupture in the surgical field and taking the tumor out surrounded by a cuff of healthy tissue, in order to obtain negative microscopic surgical margins all around. In other words, where barriers exist, surgeons should proceed beyond the safe tissues leaving the tumor covered by the barriers; where anatomic barriers do not exist, surgeons should try to use adjacent organs as a new barrier if their sacrifice is acceptable in terms of short- and long-term morbidity.
In retroperitoneal sarcoma, nonsurgical therapies include radiation therapy and chemotherapy.
Radiotherapy is an option, 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 20 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. This group meets at least bi-annually.
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 are ongoing 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 RPS.
To take advantage of the group collaboration, the next logical step is to begin a prospective collection of clinical, radiological and pathologic data for RPS.
1.2 Rationale supporting the proposed study
Surgery is currently the only potentially curative treatment modality for localized RPS. Available studies regarding oncologic outcomes after surgery have been carried out, but are mainly retrospective in nature. Moreover, due to the rarity of the disease, current published data are often hampered by small patient populations. All of these limitations are reflected in the relative paucity of established guidelines and consensus statements for RPS, compared to more common malignances.
In addition, the biologic behavior, response to treatment, and clinical outcomes of RPS vary by histologic subtype and subgroup analysis are even more difficult to conduct.
Therefore, prospective analysis of high quality data is a top priority. From this perspective, building a standardized multicentric database and storing radiological and pathological material would lead to the creation of a high quality dataset available for comparisons with previously published data and for future studies. Findings from work done using this database will help further understanding of RPS and ultimately may help to guide appropriate treatment for patients afflicted by this challenging disease.
- STUDY OBJECTIVE
2.1 Primary Objectives
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).
2.2 Secondary Objectives
– to estimate the efficacy and safety of surgical treatment, including extended surgical approach to primary RPS;
– to prospectively evaluate the impact of multimodality therapy, including radiation therapy and chemotherapy;
– to identify clinical, radiological and pathological characteristics that may influence the oncological outcome or may be used as predictors of LR/DM/OS. These may be important biomarkers of disease;
– to utilize collected pathological material for research collaborations.
- STUDY DESIGN
3.1 Overview of 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.
This study does not currently aim to change the current practice in the treatment of RPS patients but to create a platform of high quality prospectively collected data for outcome comparison and future studies.
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. Patients will also be reassured that enrolling in the study will not affect or influence their current treatment. 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. Currently, radiological and pathological materials will not be centralized.
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.