Identification of a subgroup of patients at highest risk for complications after surgical cytoreduction and hyperthermic intraperitoneal chemotherapy.

OBJECTIVE: To assess the influence of parietal and visceral peritonectomy procedures on moderate/severe morbidity in patients undergoing surgical cytoreducion and hyperthermic intraperitoneal chemotherapy (HIPEC) and to identify subgroups of patients at highest operative risk. BACKGROUND: Cytoreducion with HIPEC is an effective but potentially morbid treatment option for peritoneal surface malignancies. Although complication rates have recently decreased with increasing experience, risk-factors for adverse operative outcome are still poorly understood. METHODS: A prospective database of 426 combined procedures was reviewed. Multivariate analysis tested the correlation between major morbidity and 6 peritonectomies (greater and lesser omentectomy, pelvic, parietal anterior, left and right diaphragmatic peritonectomy), 14 visceral resections, 5 other operative factors, and 12 clinical variables. The extent of peritoneal involvement was quantified by peritoneal cancer index (PCI). RESULTS: Mortality and major morbidity were 2.6% and 28.2%. PCI, number of visceral resections, poor performance status, and cisplatin dose more than 240 mg independently correlated to morbidity. The type and number of parietal peritonectomies and the type of visceral resections did not correlated to complications. Major morbidity rate was 65.7% in 35 (8.2%) patients with at least 2 of the following factors: PCI greater than 30, more than 5 visceral resections, poor performance status. Morbidity was 100% in 9 patients presenting all the risk factors. CONCLUSIONS: Acceptable morbidity and low mortality may be achieved in high-volume centers. Operative outcome is mainly affected by a complex interplay of tumor, patient, and treatment-related factors. Preoperative and early intraoperative assessment of operative risk may identify a subset of patients unlikely to tolerate aggressive management.

Pathophysiology and biology of peritoneal carcinomatosis.

Peritoneal carcinomatosis represents a devastating form of cancer progression with a very poor prognosis. Its complex pathogenesis is represented by a dynamic process comprising several steps. To the best of our knowledge pathogenesis can be partly explained by 3 major molecular pathways: (1) dissemination from the primary tumor; (2) primary tumor of peritoneum; and (3) independent origins of the primary tumor and peritoneal implants. These are not mutually exclusive and combinations of different mechanisms could occur inside a single case. There are still several aspects which need explanation by future studies. A comprehensive understanding of molecular events involved in peritoneal carcinomatosis is of paramount importance and should be systematically pursued not only to identify novel strategies for the prevention of the condition, but also to obtain therapeutic advances, through the identification of surrogate markers of prognosis and development of future molecular targeted therapies.

Early and long-term postoperative management following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Peritoneal surface malignancies have been traditionally regarded as end-stage conditions amenable to merely palliative options. The combination of aggressive cytoreductive surgery (CRS), involving peritonectomy procedures and multivisceral resections, with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC) and/or early postoperative intra-peritoneal chemotherapy (EPIC) to treat the microscopic residual tumor is a new concept. In recent years, promising results have been reported for peritoneal mesothelioma and carcinomatosis of gastrointestinal and gynaecologic origin treated by this combined protocol. However, CRS with HIPEC and/or EPIC is a complex procedure associated with high rates of potentially life-threatening complications. Furthermore, disease progression following comprehensive treatment is not uncommon and represents a relevant cause of treatment failure. The present paper reviews the available information on early postoperative management and long-term follow-up in patients treated with CRS and intraperitoneal chemotherapy. The peculiar clinical and biological alterations that can be expected during an uncomplicated postoperative course, as compared to standard digestive surgery, are discussed. Early recognition and appropriate management of the most common adverse events are addressed, in order to minimize the impact of treatment-related morbidity on survival and quality of life results. Since re-operative surgery with additional HIPEC, has proven to be useful in selected patients with recurrent disease, long-term surveillance aiming at early detection of postoperative disease progression has become a relevant issue. Current results on follow-up investigations are presented.

Experience with peritoneal mesothelioma at the Milan National Cancer Institute.

Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon and rapidly fatal tumor. Therapeutic options have traditionally been limited and ineffective. The biologic and molecular events correlated with poor responsiveness to therapy are still poorly understood. In recent years, an innovative treatment approach involving aggressive cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has reportedly resulted in improved outcome, as compared to historical controls. Since 1995, at the National Cancer Institute (NCI) of Milan (Italy), patients with DMPM have been treated with CRS and hyperthermic intra-peritoneal chemotherapy (HIPEC). In the present paper, clinical experiences and basic science investigations on DMPM at Milan NCI are reviewed. Peri-operative and long-term outcome results with CRS and HIPEC are presented. Clinico-pathological prognostic factors were investigated by multivariate analysis. The pathologic features and immunohistochemical markers related to DMPM biologic behavior were assessed in a large case-series uniformly treated at our institution. The prevalence and prognostic role of telomere maintenance mechanisms, which account for the limitless cell replicative potential of many malignancies, were studied. The dysregulation of the apoptotic pathways may play a role in the relative chemo-resistance of DMPM and a better understanding of apoptosis-related mechanisms could result in novel targeted therapeutic strategies. On this basis, the expression of survivin and other IAP family members (IAP-1, IAP-2, and X-IAP), the pro-apoptotic protein Smac/DIABLO, and antigens associated with cell proliferation (Ki-67) and apoptosis (caspase-cleaved cytokeratin-18) were analyzed. Finally, analyses of EGFR, PDGFRA and PDGFRB were performed to ascertain if deregulation of RTK could offer useful alternative therapeutic targets.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in a patient with peritoneal mesothelioma and HIV infection.

BACKGROUND: High rates of septic complications have been associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, which has been suggested as the treatment of choice for isolated peritoneal malignancies. Patients infected by the human immunodeficiency virus (HIV) are still considered at a high operative risk. METHOD: A 58-year-old man with HIV infection and diffuse peritoneal mesothelioma underwent optimal cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. RESULTS: The patient experienced a complete clinical response to therapy with no adverse effect on disease course or markers for HIV (CD4 count, beta2-microglobulin, neopterin, p24 antigen, and viral load). CONCLUSION: This report suggests that this innovative approach can be successfully performed also in this clinical setting. In selected patients who respond to all criteria, surgery is possible and is a safe and effective therapeutic option.

Peritoneal sarcomatosis: is there a subset of patients who may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy?

BACKGROUND: Unlike novel molecular-targeted therapies for metastatic gastrointestinal stromal tumors (GIST), conventional treatments for peritoneal sarcomatosis (PS) are mostly ineffective. As with carcinomatosis of epithelial origin, a rationale base supports an aggressive locoregional treatment of PS, but the use of CRS and HIPEC in this setting is still controversial. We assessed the outcome of clinically and pathologically homogeneous subsets of patients with PS uniformly treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A prospective database of 37 patients who underwent CRS and close-abdomen HIPEC with cisplatin and doxorubicin or mitomycin-C was reviewed. PS originated from GIST (pre-imatinib era) in 8 patients, uterine leiomyosarcoma (ULS) in 11, retroperitoneal liposarcoma (RPLP) in 13, and other sarcoma in 5. RESULTS: CRS was macroscopically complete in 28 patients (75.7%). Operative mortality was 3.7% and morbidity 21.6%. After median follow-up of 104 (range, 1-131) months, peritoneal disease progression occurred in 16 patients, distant metastases in 5, and both in 13. For all patients, median overall survival was 26.2 months; 7 patients were alive at 46-130 months (ULS, n = 4; RPLP, n = 2; GIST, n = 1). RPLP had the best overall survival (median, 34 months) but 100% peritoneal relapse; GIST had dismal overall, local-regional-free and distant-free survival; ULS had the higher proportion of long survivors and best local-regional-free survival. CONCLUSIONS: Overall, results of CRS and HIPEC did not compare favorably to those of conventional therapy. In a subgroup analysis, the combined approach did not change GIST and RPLS natural history. The interesting results with ULS may warrant further investigations.

Lymph node metastases in diffuse malignant peritoneal mesothelioma.

BACKGROUND: Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The significance of lymph node involvement in this disease is still poorly understood. METHODS: Prospectively collected clinical data on 83 consecutive patients with DMPM undergoing surgical cytoreduction and closed-abdomen HIPEC with cisplatin and doxorubicin were reviewed. Clinically suspicious lymph nodes were submitted to pathological examination. The impact of nodal involvement on survival was assessed by multivariate analysis; 14 clinicopathological control variables were tested. RESULTS: For the overall series, median follow-up was 52 months (range 1-126 months) and 5-year overall survival (OS) was 49.5%. Lymph nodes were submitted to pathological examination in 38 patients, being positive in 11 and negative in 27. Lymph nodes were not clinically suspicious and not sampled in 45 patients. Iliac (n = 7) and paracolic (n = 2) nodes were the most commonly involved nodes. OS was 18.0% for patients with pathologically positive nodes and 82.5% for those with pathologically negative nodes (P = 0.0024). On multivariate analysis, pathologically negative (versus positive/not assessed) nodes [hazard ratio (HR) = 2.81; 95% confidence interval (CI) = 1.12-7.05; P = 0.027], epithelial subtype (HR = 2.93; CI = 1.24-6.95; P = 0.015), mitotic count

Surgical technique of parietal and visceral peritonectomy for peritoneal surface malignancies.

Peritoneal surface malignancies have been traditionally regarded as rapidly fatal conditions. Encouraging survival results has been associated to an innovative strategy involving aggressive cytoreductive surgery with total peritonectomy and heated intraperitoneal chemotherapy. Many controversial issues still remain regarding the optimization of the cytoreductive surgical procedures. The present article critically analyzes the relevant modifications from the original technique emerged during a 15-year experience in a single center. Operative outcome results are presented.