Volume 3, Issue 1 -

Treatment choices for colorectal peritoneal carcinomatosis/metastases include systemic therapy and increasingly cytoreductive surgery with intraperitoneal chemotherapy delivery. These options are best considered as complementary and not exclusive alternatives. Two prospective randomized trials support use of peritonectomy procedures and intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis. This overview examines efficacy, limitations and landscape of systemic therapy focusing on colorectal peritoneal carcinomatosis. Observations from literature support notions that (1) systemic therapy provides survival benefit for all prototypical patients with mCRC irrespective of metastatic disease site; (2) the magnitude of this benefit is considerably reduced among patients with peritoneal metastases who consequently experience significantly shorter overall survival; (3) efficacy of systemic therapy improved over time but at a slower pace for those with carcinomatosis; (4) this therapeutic difference has not diminished with introduction of targeted therapy, but perhaps widened; (5) further research of cytoreductive surgery and/or intraperitoneal regional therapies is thus a multidisciplinary responsibility of the entire oncology community; (6) peritonectomy procedures with intraperitoneal regional therapy are not scientifically supported in absence of systemic therapies.

Peritoneal response to various kinds of injury involves loss of peritoneal mesothelial cells (PMC), danger signalling, epithelial-mesenchymal transition and mesothelial-mesenchymal transition (MMT). Encapsulating peritoneal sclerosis (EPS), endometriosis (EM) and peritoneal metastasis (PM) are all characterized by hypoxia and formation of a vascularized connective tissue stroma mediated by vascular endothelial growth factor (VEGF). Transforming growth factor-β1 (TGF-β1) is constitutively expressed by the PMC and plays a major role in the maintenance of a transformed, inflammatory micro-environment in PM, but also in EPS and EM. Persistently high levels of TGF-β1 or stimulation by inflammatory cytokines (interleukin-6 (IL-6)) induce peritoneal MMT, adhesion formation and fibrosis. TGF-β1 enhances hypoxia inducible factor-1α expression, which drives cell growth, extracellular matrix production and cell migration. Disruption of the peritoneal glycocalyx and exposure of the basement membrane release low molecular weight hyaluronan, which initiates a cascade of pro-inflammatory mediators, including peritoneal cytokines (TNF-α, IL-1, IL-6, prostaglandins), growth factors (TGF-α, TGF-β, platelet-derived growth factor, VEGF, epidermal growth factor) and the fibrin/coagulation cascade (thrombin, Tissue factor, plasminogen activator inhibitor [PAI]-1/2). Chronic inflammation and cellular transformation are mediated by damage-associated molecular patterns, pattern recognition receptors, AGE-RAGE, extracellular lactate, pro-inflammatory cytokines, reactive oxygen species, increased glycolysis, metabolomic reprogramming and cancer-associated fibroblasts. The pathogenesis of EPS, EM and PM shows similarities to the cellular transformation and stromal recruitment of wound healing.

Background The aim of this systematic review was to investigate the accuracy of additional staging laparoscopy (SL) in advanced epithelial ovarian cancer (AEOC) to predict futile laparotomy (FL). Methods Systematic review according to preferred reporting items for systematic reviews and meta-analyses statement (PRISMA) criteria. Clinical studies investigating the role of SL in selecting women with AEOC for primary debulking surgery (PDS) were included. Index test: SL. Reference test: laparotomy. Target condition: incomplete cytoreduction (CR) with remaining disease<1 cm. Results Nine prospective and retrospective studies reporting on eight cohorts totalizing 778 LS were included. Reference test was completed in 76 % cases. PPV for FL was between 0.69 and 1.0. In three studies examining the value of a predictive index value (PIV) for predicting FL, sensitivity of the index test (LS with PIV ≥8) was between 46 % and 70 %, and specificity between 89 % and 100 %. The proportion of patients that received CR during PDS differed widely between studies (from 50 to 91). Using a PIV did not increase the sensitivity and might result in more patients receiving FL. In the only randomized trial, FL occurred in 10 (10 %) of 102 patients in the LS group versus 39 (39 %) of 99 patients in the primary PDS group (relative risk, 0.25; 95 % CI, 0.13–0.47; p<0.001). Port-site recurrences occurred in 2%–6 % patients. Overall costs of with or without SL were comparable. Conclusions The evidence available from this systematic review supports the inclusion of an additional LS to the conventional initial diagnostic workup in women with AEOC.

Background Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is a treatment option for patients with peritoneal metastases shown to provide improved overall survival for appropriately selected patients. However, the availability and utilization of this treatment remains limited. The aim of this survey-based study was to evaluate factors influencing physician treatment choices for peritoneal metastases. Methods Surveys were mailed to medical oncologists and surgeons in Virginia, Maryland, and Washington, D.C. Survey questions evaluated access to HIPEC centers, prior experience with referral to HIPEC centers, opinions regarding efficacy, and knowledge regarding outcomes of CRS and HIPEC. Results Surveys were mailed to 2279 physicians; 116 eligible surveys were returned. Seventy-five percent of respondents would consider referral to a HIPEC center for appendiceal peritoneal metastasis, while only 50% would consider it for colon cancer and peritoneal mesothelioma. The most common reason for never referring a patient to a HIPEC center was lack of access to a HIPEC specialist (47%) followed by perceived lack of evidence for the treatment modality (31%). Five-year survival after CRS and HIPEC was underestimated while 30-day mortality was overestimated by more than half of respondents. Conclusions Referral to HIPEC centers is underutilized among community physicians in practice. Limited access to HIPEC experts is the most common cause for lack of referral, followed by a perception of insufficient evidence for this treatment approach. Lack of familiarity with data regarding outcomes impacts referral patterns and treatment choices. Possible actions to increase awareness and appropriate utilization of CRS and HIPEC are suggested.