Barbara Laterza

Pseudomyxoma Peritonei: Clinical Pathological and Biological Prognostic Factors in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

BackgroundSurgical cytoreduction combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been recently advocated as the standard of care for pseudomyxoma peritonei (PMP). We reviewed our 10-year monoinstitutional case series to identify selection factors predicting postoperative outcome.MethodsOne hundred and four patients with PMP were operated on with the aim of performing adequate cytoreduction (residual tumor nodules ≤2.5 mm) and closed-abdomen HIPEC with mytomicin-C and cisplatin. Previously, 26 patients had systemic chemotherapy. PMP was histologically classified into disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and intermediate/discordant group (ID). Immunohistochemical stains were performed for cytokeratin (CK)-7, CK-20, CDX-2, MUC-2, MUC-5AC, CD-44s. The significance of 22 potential clinical, pathological, and biological prognostic variables was assessed by multivariate analysis.ResultsAdequate cytoreduction was performed in 89 patients, suboptimal cytoreduction in six, palliative surgery in nine. Operative mortality was 1%. Seventy-eight patients were diagnosed with DPAM, 26 with PMCA, and none with ID. Median follow-up was 37 months (range, 1–110) for the overall series. Five-year overall survival (OS) and progression-free survival (PFS) were 78.3% and 31.1%, respectively. At multivariate analysis, adequate cytoreduction, no previous systemic chemotherapy, and DPAM correlated to better OS and PFS, elevated serum CA19.9 correlated only to better PFS. In most cases, CK20, CDX-2, and MUC-2 were diffusely positive, while CK-7, MUC-5AC, and CD44s were variably expressed. CK20 expression correlated to prognosis at univariate analysis.ConclusionsFavorable outcome after comprehensive treatment can be expected in patients with DPAM, not treated with preoperative systemic chemotherapy and amenable to adequate cytoreduction. MUC-2, CK-20, and CD44s expression may be related to PMP unique biologic behavior.

Impact of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on systemic toxicity.

IntroductionThe purpose of this study was to analyze the postoperative systemic toxicity and procedure-related mortality (PRM) of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSMs).Patients and methodsA total of 242 (84 males/158 females) patients with PSM underwent 247 consecutive procedures. The mean age was 52 years (range 22–79). CRS was performed using peritonectomy procedures. The HIPEC technique through the closed abdomen was conducted with cisplatin (CDDP 25 mg/m2/l of perfusate)+mitomycin C (MMC 3.3 mg/m2/l perfusate) or CDDP (43 mg/l perfusate)+doxorubicin (Dx 15.25 mg/l perfusate) at 42.5°C. These dosages were reduced by 30% when the patient had received systemic chemotherapy before the CRS+HIPEC. Systemic toxicities were graded according to the NCI CTCAE v3 criteria.ResultsG3-5 systemic toxicity rate was 11.7 % and adverse events were bone marrow suppression, 13; nephrotoxicity, 14; neutropenic infection, 2 and pulmonary toxicity, 1. Independent risk factors for G3-5 systemic toxicity after multivariate analysis were a dose of CDDP for HIPEC of 240 mg or more (OR 2.78, CI 95% 1.20–6.45) and CDDP+Dx schedule for HIPEC (OR 2.36, CI 95% 1.02–5.45). PRM was 1.2%.ConclusionsCRS+HIPEC presented acceptable systemic toxicity and PRM rates. Independent risk factors for systemic toxicity were the CDDP+Dx schedule and CDDP dose for HIPEC.

Pseudomyxoma peritonei: biological features are the dominant prognostic determinants after complete cytoreduction and hyperthermic intraperitoneal chemotherapy.

Objective:To investigate outcome and prognostic factors in patients with pesudomyxoma peritonei (PMP) treated by complete cytoreduction and hyperthermic intraperitoneal chemotherapy. Background:After comprehensive treatment, prognosis of PMP is predominantly dependent on the completeness of cytoreduction. Once complete cytoreduction is achieved, additional factors predicting long-term outcome are still poorly understood. Methods:From a prospective database, we selected 102 patients undergoing complete cytoreduction (residual tumor nodules ≤2.5 mm) and closed-abdomen hyperthermic intraperitoneal chemotherapy with mitomycin-C and cisplatin. Previously, 22 patients had systemic chemotherapy. PMP was histologically classified into disseminated peritoneal adenomucinosis, peritoneal mucinous carcinomatosis (PMCA), and intermediate/discordant group. Twenty-one patient-, tumor-, and treatment-related variables were assessed by multivariate analysis with respect to overall (OS) and progression-free (PFS) survival. The following immunohistochemical markers were tested: cytokeratin (CK)-7, CK-20, CDX-2, MUC-2, and MUC-5AC. Results:Operative mortality was 1%. Seventy-eight patients were diagnosed with disseminated peritoneal adenomucinosis, 24 with PMCA, none with intermediate/discordant group. For the overall series, median follow-up, 5-year OS, and PFS were 45 months (range 1–110), 84.4%, and 48.3%, respectively. In most cases, CK20, CDX-2, and MUC-2 were diffusely positive, whereas CK-7 and MUC-5AC were variably expressed. At multivariate analysis, previous systemic chemotherapy and PMCA correlated to both worse OS and PFS, elevated serum CA125 only to worse PFS. CK20, CDX-2, and MUC-2 expression correlated to prognosis at univariate analysis. Conclusions:After complete cytoreduction and hyperthermic intraperitoneal chemotherapy, prognosis of PMP is primarily dependent on pathologic and biologic features. MUC-2, CK-20, and CDX-2 may be related to the disease biology. Understanding PMP molecular basis may facilitate personalized treatment.

Prognostic Value of Circulating Tumor Markers in Patients with Pseudomyxoma Peritonei Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BackgroundEncouraging results have been recently reported in selected patients affected by pseudomyxoma peritonei (PMP) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The selection factors predicting clinical outcome are still a matter of clinical investigation. We assessed the prognostic reliability of serum tumor markers in a large series of patients with PMP undergoing CRS and HIPEC.MethodsSixty-two patients with PMP were operated on at a single institution with the intent of performing adequate CRS (residual tumor nodules ≤2.5mm) and HIPEC. Baseline and serial marker measurements were prospectively collected and tested by multivariate analysis with respect to adequate cytoreduction, overall (OS) and progression-free (PFS) survival, along with the following variables: age, sex, performance status, prior surgical score, histological subtype, prior systemic chemotherapy, disease extent, completeness of cytoreduction.ResultsBaseline diagnostic sensitivity was 72.6% for CEA, 58.1% for CA19.9, 58.7% for CA125, 36.1% for CA15.3. Fifty-three patients underwent adequate CRS and HIPEC; gross residual tumor was left after surgery in nine. Adequate CRS was performed in 19/27 patients with elevated and in 19/19 with normal baseline CA125 (P = .0140). The other markers were unable to predict the completeness of CRS by univariate analysis. Baseline elevated CA19.9 was an independent predictor of reduced PFS; inadequate CRS and aggressive histology were independent prognostic factors for both reduced OS and PFS.ConclusionNormal CA125 correlated to the likelihood to achieve adequate CRS, which is a significant prognostic factor for PMP. Increased baseline CA19.9 was an independent predictor of worse PFS after CRS and HIPEC.

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. J. Surg. Oncol. 2009;100:321–328.

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.

Incidence of Postoperative Pancreatic Fistula and Hyperamylasemia after Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy

IntroductionThe purpose of this study was to analyze the postoperative pancreatic morbidity of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal surface malignancies (PSM).Patients and methodsTwo hundred and sixty five patients (87M/178F) with PSM underwent 270 consecutive procedures. The mean age was 52 years (range: 22–79 years). CRS was performed using peritonectomy procedures. HIPEC through the closed abdomen technique was conducted using cisplatin (CDDP 25mg/m2/L of perfusate)+mitomycin C (MMC 3.3 mg/m2/L of perfusate) or CDDP (43mg/L of perfusate)+doxorubicin (Dx 15.25 mg/L of perfusate), at 42.5°C. Diagnosis and classification of postoperative pancreatic fistula (POPF) were performed according to the international study group on pancreatic fistula criteria. Serum amylase alterations were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v3.ResultsPOPF was observed in 13 (4.8%) cases. Three cases were classified as major (grade C). Two cases presented postoperative pancreatitis. G3-4 alteration of amylase was observed in 12.3% of the cases. Performing splenectomy and CDDP dosage for HIPEC >240mg were proven to be independent risk factors for both G3-4 hyperamylasemia and POPF.ConclusionsCRS+HIPEC presented an acceptable rate of pancreatic morbidity which did not contribute to the mortality related to the procedure. Most of the POPF were mild and/or easily controlled by conservative measures. Although not specific a normal amylasemia could be a useful marker of pancreatic integrity after CRS+HIPEC.