Introduction

Peritoneal sarcomatosis may be defined as the spread of a soft tissue sarcoma throughout the abdomen, in the absence of any extra-abdominal dissemination, or at least other sites of disease of major clinical concern. This gives rise to presentations in which the abdominal spread of disease is the dominating clinical factor, thus the main therapeutic challenge. The perspective may be palliative or curative, the former situation being more frequent than latter.
Retroperitoneal soft tissue sarcomas are the most frequent sarcomas to give rise to disseminated abdominal disease. Indeed, the local regional risk of a retroperitoneal sarcoma may well be in the 70% range in the long term. Liposarcomas are especially at risk, given their inherent anatomic characteristics (average tumor size, multinodularity or even multifocality, etc.) and their tendency to remain confined to the abdomen in many cases throughout their natural history. Even pelvic tumors may result in peritoneal sarcomatosis, such as a uterine leiomyosarcoma relapsing with scattered tumor masses throughout the abdomen. Gastrointestinal stromal tumors (GIST) essentially metastatize to two sites, peritoneum and the liver, the former in the lack of the latter in a number of patients. Other rare mesenchymal entities may metastatize throughout the abdomen, such as the desmoplastic small round cell abdominal tumor of young adults or adolescents, typically spreading with multiple tumor nodules over the peritoneal surface.
All these tumors are rare. Their abdominal spread in the lack of lesions outside is even less frequent, though it may typically occur, indeed, in a number of patients. Finally, the prognosis of abdominal sarcomatosis is generally dismal, although, say, liposarcomas may run a slow course, and GIST are now amenable to effective medical therapies which at least prolong significantly survival.

Medical therapies

Disseminated disease spreading throughout the abdomen makes the patient metastatic, and thus a candidate for medical therapies by definition. At the moment, chemotherapy of adult soft tissue sarcomas is based on anthracyclines and Ifosfamide, given either alone or in combination (Type 1 ). The response rate is in the 20-40% range, and median survival is in the one-year range. Gemcitabine plus/minus Docetaxel may exert a palliative effect especially in leiomyosarcoma (Type 3). The new marine agent Trabectedin (ET-743) is active in liposarcoma and leiomyosarcoma, i.e. the two main retroperitoneal mesenchymal entities, with an exceedingly high activity in myxoid liposarcoma, which however is rare in the retroperitoneum (but an abdominal widespread extent of disease, even in the lack of lesions elsewhere, may occur following a primary tumor in a limb) (Type 3)). Imatinib is exceedingly effective in GIST, with a progression-free interval and an overall survival, respectively, in the 2-year and 5-year range if the disease is metastatic. Surgery of residual disease is often carried out following optimal response of GIST to Imatinib, though, possibly, peritoneal lesions may benefit less than liver metastases from such an approach, which in any case remains investigational. (Type R basis) Medical therapy is active, but generally of limited prognostic meaning, in desmoplastic small round cell abdominal tumor.
Therefore, medical therapies have some activity against peritoneal sarcomatosis, but always with an essentially palliative aim, major limitations, and variability across tumor entities. A huge distinction can be made between GIST and other adult soft tissue sarcomas, because the natural history of GIST has been deeply affected by the medical therapy, while this is still not the case for other sarcomas. Integrated approaches are often resorted to, often using surgery in the case of tumor response to medical therapies, and/or medical therapy in the case surgery is unfeasible. Surgery is obviously the treatment mainstay in most cases with a localized disease stage, but the surgeon is well aware of the risk of sarcomatosis, which may be inherent to the natural history of disease, and also a consequence of complications occurring during surgery (tumor rupture, etc.). Therefore, the value of adjuvant procedures has been long explored. Unfortunately, as of today, no adjuvant medical therapy has been proved of value in these diseases. Prospective trials on adjuvant Imatinib are ongoing in intermediate-high risk GIST patients. On the other hand, patients with adult soft tissue sarcomas are often offered adjuvant chemotherapy in several institutions across the world when the disease is high-risk, as is the case by definition in most cases of high-grade retroperitoneal, or pelvic, sarcomas. However, we lack any formal proof of efficacy thereof.
Local regional drug delivery systems can yield high intra-peritoneal concentrations of chemotherapeutic agents, while keeping low their systemic levels. As the intraperitoneal route cannot guarantee an adequate drug penetration into tumor deposits larger than 1-3 mm, cytoreductive surgery is the main prerequisite for any intraperitoneal chemotherapy. In addition, by entrapping cancer cells and preventing them from being reached by chemotherapeutic agents [6], early postoperative adhesions may limit the effect of intraperitoneal therapies when given postoperatively. This has led to place these therapies immediately after surgery (early postoperative intraperitoneal chemotherapy: EPIC). Furthermore, the notion that some antineoplastic drugs act synergistically with others, as well as with heat, led some authors to propose hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of locally advanced intra-abdominal malignancies ([7], [8]). So far, aggressive cytoreductive surgery combined with EPIC or HIPEC has been mainly considered for peritoneal carcinomatosis from gastrointestinal cancers, with encouraging results ([9], [10]). Based on the same rationale, studies have been performed also in patients with PS.

Intraperitoneal chemotherapy

The first published study investigating this therapeutic approach in patients with PS is attributed to Berthet and Sugarbaker [11]. These authors combined complete gross resection through a peritonectomy procedure with early peritoneal chemotherapy with or without hyperthermia. Only 16 out of 43 underwent HIPEC. Overall, the 43 patients achieved a median survival of 20 months. Only the completeness of cytoreductive surgery had a significant impact on survival. Eilber et al. used a similar aggressive surgical approach [12] for recurrent abdominal sarcoma, including first recurrence with/without sarcomatosis, but intraperitoneal chemotherapy was delayed (1-2 weeks after complete surgery) with the risk of postoperative adhesions preventing complete bathing of the peritoneal cavity. The 35 pts having intraperitoneal disease alone showed a median survival of 24 months. The median survival of patients treated in these two studies does not differ from that reported by Bilimoria, who treated 51 patients with sarcomatosis or GISTs at the MD Anderson Cancer Centre by means of surgery and conventional chemo/radiotherapy, thus obtaining a median survival of around 22 months [1]. Bonvalot et al. recently published a randomized trial on 19 patients with peritoneal sarcomatosis treated with surgery alone, versus 19 who underwent surgery followed by intraperitoneal chemotherapy with doxorubicin and cisplatin for five days [13]. After a median follow-up of 60 months, the local relapse-free, metastatic relapse-free and overall survival were similar in the two groups. So far, the most relevant experience reported with surgery combined with HIPEC is from the Italian Society for Locoregional Treatments in Oncology (SITILO) [14]. In a study, 60 patients affected by advanced (multifocal primary or locally recurrent) intraabdominal visceral or retroperitoneal soft tissue sarcomas underwent optimal cytoreductive surgery (tumor remnants diameter < 3 mm) followed by HIPEC with doxorubicin and cisplatin. The postoperative complication rate was 23%, locoregional toxicity 15%, and overall morbidity 33%. The median time to local disease progression and the median overall survival were 22 and 34 months, respectively. A multivariate analysis showed a significant advantage for patients who had undergone complete vs near-complete cytoreduction. Moreover, the importance of inherent tumor aggressiveness was underscored by the different prognosis of high vs low grade malignancies. Although in this group of patients an improved median overall survival was observed in comparison to other case series (34 vs 20-29 months), these results should be interpreted by considering: 1) heterogeneity of histological types across the case series; 2) different inclusion criteria; 3) different treatments (HIPEC end EPIC).  One possible explanation for these poor results in PS might lie in the natural history of sarcomas, which tend to spread across anatomical structures as nerves and vessels, which in the abdomen are retroperitoneal, and are therefore not accessible to peritoneal bathing.
It may be concluded that, at present, there is no sufficient evidence supporting the treatment of patients with peritoneal sarcomatosis with HIPEC or EPIC, even if the former may be slightly more effective. (Type 3) This treatment modality is highly demanding both for patients and health resources, and thus should be all the more considered investigational for patients with multiple peritoneum implants (true peritoneal sarcomatosis).

Perspectives

The rarity of these presentations makes it difficult to undertake formal clinical trials. However, only the joined efforts of several institutions might achieve the goal.
At the moment, medical therapy is the standard of care for these patients. The histological entity dictates which medical treatment to select, and/or clinical studies may be open in the various presentations. Following optimal tumor response, surgery is often resorted to in sarcomas, and may well be used also in these patients. Its combination with HIPEC should be considered investigational in retroperitoneal and/or pelvic sarcomas. The major benefit gained from Imatinib, and the availability of further second-line molecularly targeted agents, in the lack of any formal proof of efficacy of surgery for residual disease, makes it difficult, at the moment, to foresee that HIPEC may make any difference in advanced GIST patients, even when the disease is confined to the peritoneum.
A prospective study on the combination of aggressive cytoreductive surgery with HIPEC might be foreseen in principle, if a collaborative effort can be put in place. Eligible for such a trial could be patients with: 1) histologically proven multifocal peritoneal implants of non-GIST adult soft tissue sarcoma; 2) tumor remnants <3 mm following cytoreductive surgery; 3) absence of distant metastasis on CT / MR imaging. Patients’ selection should be based on an accurate preoperative work-up encompassing thoraco-abdominal CT scan. Intraoperative staging should include a peritoneal cancer index. Cytoreductive surgeryshould be performed according to the criteria by Sugarbaker[15]. HIPEC should be based on Doxorubucin and Cisplatin, according to the results of a previosly reported Phase I study [16]. In the event such a clinical trial provides interesting results, further investigations with randomized confirmatory studies and/or on new pharmacological regimens could be pursued.