Shigeki Kusamura

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: Multi-Institutional Experience

PURPOSE This multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM). PATIENTS AND METHODS A multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival. RESULTS Follow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002). CONCLUSION The data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.

Peritonectomy and Intraperitoneal Hyperthermic Perfusion (IPHP): A Strategy That Has Confirmed its Efficacy in Patients with Pseudomyxoma Peritonei

Background: Pseudomyxoma peritonei (PMP) is a rare disease with a poor prognosis characterized by a complete redistribution of mucin within the peritoneal cavity. The aim of this multicentric study was to evaluate the survival, morbidity, toxicity, and mortality of patients with PMP treated by cytoreductive surgery (CRS) with intraperitoneal hyperthermic perfusion (IPHP).Methods: Thirty-three patients with PMP (21 males and 12 females) were enrolled in a phase II clinical trial. One patient underwent surgery twice because of disease recurrence. CRS was performed with peritonectomy procedures. The closed abdomen technique was employed for IPHP with use of cisplatin (25 mg/m2/L) plus mitomycin-C (3.3 mg/m2/L) for 60 minutes under hyperthermic conditions (42.5°C).Results: Thirty-one patients (92%) were optimally cytoreduced. Five-year overall survival, progression-free survival, and locoregional progression-free survival rates were 97%, 43%, and 59%, respectively. Grade II and grade III morbidity was observed in 5 patient (15%) and 6 patients (18%), respectively. There was one treatment-related death (3%), 21 days after treatment.Conclusions: CRS associated with IPHP permitted complete tumor removal with an acceptable morbidity and mortality for patients with PMP. This study confirms the efficacy of the combined treatment in terms of long-term survival and local disease control.

Consensus statement on the loco regional treatment of colorectal cancer with peritoneal dissemination

Medical management with combinations of cytotoxic chemotherapy, and/or biological agents, has resulted in an unprecedented median survival >20 months in patients with Stage IV colorectal cancer. The management of disease limited to the peritoneal cavity has been controversial and at the present time, there is no published data that outlines the impact of these new therapeutic regimens when given to patients with colorectal cancer with metastatic disease confined to the peritoneum. Over the last 5 years, an increasing number of international treatment centers have published their prospective results using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of peritoneal surface malignancies of colorectal origin and have shown that good long‐term results can be achieved with a complete cytoreduction and HIPEC. However, most of the surgical data comes from Phase II studies from single institutions and there is a wide range on inclusion/exclusion criteria, drugs, temperatures and methods of delivering the heated chemotherapy. This manuscript will analyze and discuss the results of a group of health care providers trying to achieve a consensus statement in the management of this group of patients. J. Surg. Oncol. 2008;98:263–267.

Prognostic Analysis of Clinicopathologic Factors in 49 Patients With Diffuse Malignant Peritoneal Mesothelioma Treated With Cytoreductive Surgery and Intraperitoneal Hyperthermic Perfusion

BackgroundDiffuse malignant peritoneal mesothelioma (DMPM) is a subset of peritoneal mesothelioma with a poor clinical outcome. We performed a prognostic analysis in a cohort of DMPM patients treated homogeneously by cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP).MethodsForty-nine DMPM patients who underwent 52 consecutive procedures were enrolled onto the study. Cytoreductive surgery was performed according to the peritonectomy technique, and the IPHP was performed with cisplatin plus doxorubicin or cisplatin plus mitomycin C. We assessed the correlation of the clinicopathologic variables (previous surgical score, age, sex, performance status, previous systemic chemotherapy, carcinomatosis extension, completeness of cytoreduction, IPHP drug schedule, mitotic count [MC], nuclear grade, and biological markers [epidermal growth factor receptor, p16, matrix metalloproteinase 2 and matrix metalloproteinase 9]) with overall and progression-free survival.ResultsThe mean age was 52 years (range, 22–74 years). The mean follow-up was 20.3 months (range, 1–89 months). Regarding the biological markers, the rates of immunoreactivity of epidermal growth factor receptor, p16, matrix metalloproteinase 2, and matrix metalloproteinase 9 were 94%, 60%, 100%, and 85%, respectively. The strongest factors influencing overall survival were completeness of cytoreduction and MC, whereas those for progression-free survival were performance status and MC. No biological markers were shown to be of prognostic value.ConclusionsCompleteness of cytoreduction, performance status, and MC seem to be the best determinants of outcome. These data warrant confirmation by a further prospective formal trial. No biological markers presented a significant correlation with the outcome. The overexpression of epidermal growth factor receptor, matrix metalloproteinase 2, and matrix metalloproteinase 9 and absent or reduced expression of p16 might be related to the underlining tumor kinetics of DMPM and warrant further investigation with other methods.

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.

Consensus statement on the loco-regional treatment of appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei)

Pseudomyxoma peritonei (PMP) is a rare condition mostly originating from low malignant potential mucinous tumours of the appendix. Although this disease process is minimally invasive and rarely causes haematogenous or lymphatic metastases, expectation of long‐term survival are limited with no prospect of cure. Recently, the combined approach of cytoreductive surgery (CRS) and perioperative loco‐regional chemotherapy (PLC) has been proposed as the standard of treatment for the disease. The present paper summarizes the available literature data and the main features of the comprehensive loco‐regional treatment of PMP. The controversial issues concerning the indications and technical methodology in PMP management were discussed through a web‐based voting system by internationally known experts. Results were presented for further evaluation during a dedicated session of “The Fifth International Workshop on Peritoneal Surface Malignancy (Milan, Italy, December 4–6, 2006)”. The experts agreed that multiple prospective trials support a benefit of the procedure in terms of improved survival, as compared with historical controls. Concerning the main controversial methodological questions, there was an high grade of consistency among the experts and agreement with the findings of the literature. J. Surg. Oncol. 2008;98:277–282.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: Multi-institutional phase-II trial

OBJECTIVE The primary end-point of this multi-institutional phase-II trial was to assess results in terms of overall survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment-naive epithelial ovarian cancer (EOC) with advanced peritoneal involvement. Secondary end-points were treatment morbi-mortality and outcome effects of time to subsequent adjuvant systemic chemotherapy (TTC). METHODS Twenty-six women with stage III-IV EOC were prospectively enrolled in 4 Italian centers to undergo CRS and closed-abdomen HIPEC with cisplatin and doxorubicin. Then they received systemic chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m(2)) for 6 cycles. RESULTS Macroscopically complete cytoreduction was achieved in 15 patients; only minimal residual disease (≤2.5 mm) remained in 11. Major complications occurred in four patients and postoperative death in one. After a median follow-up of 25 months, 5-year overall survival was 60.7% and 5-year progression-free survival 15.2% (median 30 months). Excluding operative death, all the patients underwent systemic chemotherapy at a median of 46 days from combined treatment (range: 29-75). The median number of cycles per patient was 6 (range: 1-8). The time to chemotherapy did not affect the OS or PFS. CONCLUSIONS In selected patients with advanced stage EOC, upfront CRS and HIPEC provided promising results in terms of outcome. Morbidity was comparable to aggressive cytoreduction without HIPEC. Postoperative recovery delayed the initiation of adjuvant systemic chemotherapy but not sufficiently to impact negatively on survival. These data warrant further evaluation in a randomized clinical trial.

Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study.

Aims and Background The optimal salvage therapy for recurrent ovarian carcinoma has not been clearly established. Response to second-line chemotherapy is low, with a short median survival (8.8-15 months). We investigated the effect of an aggressive approach consisting of surgery followed by intraperitoneal drug delivery and local hyperthermia. Patients and Methods In a phase II clinical study, 27 patients with advanced/recurrent ovarian carcinoma were treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Median patient age was 53 years (range, 30-67) and mean follow-up was 17.4 months (range, 0.3-36.0). Patients had been surgically staged and heavily pretreated with cisplatin-based, taxol-based or taxol/platinum-containing regimens. Nineteen (70%) patients were cytoreduced to minimal residual disease <2.5 mm. The intraperitoneal hyperthermic perfusion was performed with the closed abdomen technique, using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) + mitomycin C (3.3 mg/m2/L) through a heart-lung pump (mean flow of 700 mL/min) for 60 min in the hyperthermic phase (42.5 °C). Results Two-year overall survival was 55%. Median times to overall progression and local progression were 16 months and 21.8 months, respectively. Variables that affected the overall survival or time to progression were as follows: residual disease (P = 0.00025), patient age (P = 0.04), and lag time between diagnosis and cytoreductive surgery + intraperitoneal hyperthermic perfusion (P = 0.04). Treatment-related morbidity, mortality and acute toxicity (grade II-III) rates were 11%, 4% and 11%, respectively. Eight (89%) of 9 patients had ascites resolution. Conclusion Our results suggest that cytoreductive surgery + intraperitoneal hyperthermic perfusion is a well-tolerated, feasible and promising alternative in the management of selected patients with recurrent ovarian cancer, but further randomized controlled studies are needed in order to confirm our findings.

Hyperthermic intraperitoneal chemotherapy: Nomenclature and modalities of perfusion

Following international consensus, HIPEC should be the acronym used in the scientific literature to refer to the hyperthermic intraperitoneal chemotherapy. Several modalities of perfusion are used to deliver HIPEC: open abdominal technique (Coliseum), closed abdominal technique, peritoneal cavity expander, semi‐opened abdominal technique. There is no sufficient evidence in literature confirming the superiority of one technique over the others in terms of outcome, morbidity and safety to the personnel of the operating theatre. Each option has its own operational advantages and disadvantages and future prospective studies must be conducted to establish which one is the best alternative. Today, the best technique is the one which is routinely used and improved into each specialized institution involved in the management of peritoneal surface malignancy. J. Surg. Oncol. 2008;98:242–246.

Morbidity, toxicity, and mortality classification systems in the local regional treatment of peritoneal surface malignancy

To reach a consensus for reporting complications related to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reporting the adverse events related to CRS + HIPEC is not standardized yet. Post‐operative complications can be divided in two categories: the effects of surgical manipulation per se and the toxic effects of the heated intraoperative chemotherapy. Additive and/or synergistic effects also exist. Different centers have published their experience with regard to the complications associated with the procedure. Various classification systems have been used which makes a temptative comparison of the different techniques and results almost impossible. An effort was made here to review the existing major classification systems: The Bozzetti classification, the Clavien classification (and two proposed modifications from Feldman et al. and Elias et al.) and the Common terminology criteria for adverse events (CTCAE) version 3.0 of the National Institute of Health (NIH) criteria. A related document was sent to an international panel of experts. The CTCAE was adopted by the panel of experts as the unique classification system to be used for reporting complications related to CRS + HIPEC. J. Surg. Oncol. 2008;98:253–257.