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.

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.

Colobronchial fistula: an unusual complication after peritonectomy and hyperthermic intra-peritoneal chemotherapy (HIPEC).

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an innovative approach to peritoneal carcinomatosis. Due to the complexity of the combined procedure, high rates of potentially life-threatening complications have been reported. This is the first report of colobronchial fistula following CRS and HIPEC. CASE REPORT: A 70-year-old woman underwent CRS and HIPEC for papillary well-differentiated peritoneal mesothelioma. During the postoperative course, recurrent pneumonia occurred and bacteria of intestinal origin were isolated from expectorated sputum. Water-soluble contrast studies revealed direct communication between the left colon flexure and the bronchial tree. After appropriate medical and supportive therapies, the patient underwent resection of the splenic flexure and immediate anastomosis with complete recovery. CONCLUSION: Colobronchial fistula is a rare and potentially lethal complication of CRS and HIPEC. A suggestive clinical picture and contrast studies allow conclusive diagnosis to be made. Surgery is a safe and effective therapeutic option.

Role of explorative laparoscopy to evaluate optimal candidates for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal mesothelioma.

BACKGROUND: Prognosis of peritoneal mesothelioma (PM) treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is closely related to the completeness of the surgical cytoreduction. The reliability of explorative laparoscopy (EL) in selecting patients with PM amenable to optimal combined treatment has never been specifically assessed. PATIENTS AND METHODS: Thirty-three patients with PM underwent EL before CRS and closed-abdomen HIPEC with cisplatin and doxorubicin. EL effectiveness in predicting complete cytoreduction (residual tumour nodules < or = 2.5 mm) was analyzed. RESULTS: At EL, peritoneal involvement was considered amenable to complete CRS in 30 out of 33 patients (91%). In this group, cytoreduction was complete in 29 patients and incomplete in one. Three patients were judged not amenable to complete CRS and subsequently were not able to undergo complete cytoreduction. CONCLUSION: EL findings can integrate clinical and radiological information in the selection process of patients with PM for combined treatment.

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 < or =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.

Pseudomyxoma peritonei: clinical pathological and biological prognostic factors in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Surgical 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. METHODS: One hundred and four patients with PMP were operated on with the aim of performing adequate cytoreduction (residual tumor nodules < or =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. RESULTS: Adequate 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. CONCLUSIONS: Favorable 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.

Incidence of postoperative pancreatic fistula and hyperamylasemia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: The 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 METHODS: Two 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 25 mg/m2/L of perfusate)+mitomycin C (MMC 3.3 mg/m2/L of perfusate) or CDDP (43 mg/L of perfusate)+doxorubicin (Dx 15.25 mg/L of perfusate), at 42.5 degrees 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. RESULTS: POPF 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 >240 mg were proven to be independent risk factors for both G3-4 hyperamylasemia and POPF. CONCLUSIONS: CRS+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.

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

INTRODUCTION: The 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 METHODS: A 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/m(2)/l of perfusate)+mitomycin C (MMC 3.3 mg/m(2)/l perfusate) or CDDP (43 mg/l perfusate)+doxorubicin (Dx 15.25 mg/l perfusate) at 42.5 degrees 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. RESULTS: G3-5 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%. CONCLUSIONS: CRS+HIPEC presented acceptable systemic toxicity and PRM rates. Independent risk factors for systemic toxicity were the CDDP+Dx schedule and CDDP dose for HIPEC.

Prognostic value of circulating tumor markers in patients with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Encouraging 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. METHODS: Sixty-two patients with PMP were operated on at a single institution with the intent of performing adequate CRS (residual tumor nodules

Circulating CA125 in patients with peritoneal mesothelioma treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion.

BACKGROUND: Recent phase I/II trials report encouraging results in selected patients with peritoneal mesothelioma (PM) treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). Circulating tumor markers have never been extensively investigated in the management of PM. We assessed the clinical role of markers in a large series of patients with PM undergoing CRS and IPHP. METHODS: Clinical data on 60 patients with PM operated with the intention to perform adequate CRS (residual tumor nodules

Cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy (HIPEC) in the treatment of pseudomyxoma peritonei: ten years experience in a single center.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare and fatal disease for which no standard treatment has been established. Encouraging results have been recently reported with the combination of cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). PATIENTS AND METHODS: Seventy-five patients with PMP underwent CRS and closed abdomen HIPEC with mytomicin-C and cis-platinum over 10 years at a single institution. Potential clinicopathological prognostic variables were tested using multivariate analysis. RESULTS: Optimal cytoreduction (residual tumor nodules < or = 2.5 mm) was performed in 72 patients (96%). Operative mortality was 1%. Five-year overall (OS) and progression-free (PFS) survival were 78.3% and 31.1% in the overall series, respectively. Optimal CRS, no previous systemic chemotherapy and low histological aggressiveness were independent predictors of better OS and PFS using multivariate analysis. CONCLUSION: Favourable outcome after CRS and HIPEC can be expected in patients affected by PMP variants with low histological aggressiveness, undergoing optimal surgical cytoreduction and with no pre-operative systemic chemotherapy.