Cytoreductive Surgery with Intraperitoneal Hyperthermic Chemotherapy for Malignant Peritoneal Mesothelioma: Mitomycin Versus Cisplatin

Background  

Malignant peritoneal mesothelioma (MPM) is a rare, rapidly fatal disease. Because traditional treatments offer little benefit, there has been increasing interest in cytoreductive surgery (CS) with intraperitoneal hyperthermic chemotherapy (IPHC). The most efficacious chemotherapy regimen is not established. Herein we report clinical outcomes of MPM patients treated with CS and IPHC and contrast results using two chemoperfusates: mitomycin and cisplatin.     

The Role of Perioperative Systemic Chemotherapy in Diffuse Malignant Peritoneal Mesothelioma Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Background

The aim of this study was to evaluate the effects of perioperative systemic chemotherapy (CT) on short-term surgical and long-term oncologic results in diffuse malignant peritoneal mesothelioma (DMPM) patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Patients and Methods

We retrospectively analyzed data obtained from an institutional prospective database at NCI of Milan. The study group comprised 116 DMPM patients treated with CRS + HIPEC from August 1995 to October 2011. A total of 60 cases underwent preoperative CT (PRECT), 30 underwent postoperative CT (POSTCT), and 26 did not undergo any CT (NOCT). Also, 55 cases used the perioperative combination of platinum and pemetrexed. We tested whether covariates related to clinical, histologic, PRECT, and surgical treatment were correlated with completeness of cytoreduction (CC), postoperative G3-5 morbidity, and progression-free survival and overall survival (OS). Univariate and multivariate analyses were performed.

Results

Factors independently associated with CC were ECOG performance status (PF) of 0, and PCI <20. Factors independently associated with postoperative G3-5 morbidity were ECOG >1, bowel anastomosis, and number of peritonectomy procedures. Preoperative platelet count >400 × 103/mm³, histological subtype (biphasic and sarcomatoid vs epithelial), CC, and G3-5 morbidity were independent prognostic factors. PRECT was not associated with CC or G3-5 morbidity. There was no significant difference in terms of survival between the PRECT, POSTCT, and NOCT groups.

Conclusions

The CC, G3-5, and OS were not influenced by aspects related to perioperative CT. The present data warrants confirmation reconducting the comparative analysis in a larger multi-institutional series preferably using matching control techniques.     

Cytoreductive Surgery Combined With Intraoperative Hyperthermic Intrathoracic Chemotherapy for Stage I Malignant Pleural Mesothelioma

Background:Malignant pleural mesothelioma (MPM) is a disease mostly confined to the thoracic cavity. Untreated, the median survival is <1 year. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy is used to kill residual tumor cells on the surface of the thoracic cavity while having limited systemic side effects.Methods:From August 1998 to August 2001, 22 patients with stage I MPM were included in this study. Two patients were irresectable at operation because of extrathoracic tumor growth. Twenty procedures were performed. After cytoreduction, a perfusion was performed with cisplatin and doxorubicin at 40°C to 41°C for 90 minutes. Adjuvant radiotherapy was given to surgical scars and drainage tracts.Results:There was no perioperative mortality, but significant morbidity was seen in 13 patients (65%), including bronchopleural fistula, diaphragm rupture, wound dehiscence, persistent air leakage, and chylous effusion. No hair loss or leucopenia was noticed. The median follow-up was 14 months. The median survival (Kaplan-Meier) was 11 months, with a 1-year survival of 42%. A favorable pharmacokinetic ratio was observed for both cisplatin and doxorubicin.Conclusions:Cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy for stage I MPM is feasible. However, this treatment is accompanied by considerable morbidity. Survival data were less encouraging.     

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

Background Diffuse 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). Methods Forty-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. Results The 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. Conclusions Completeness 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.     

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Peritoneal Sarcomatosis

Background  

The prognosis of peritoneal sarcomatosis is generally poor and conventional treatments for this disease process are mostly ineffective. The use of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as an aggressive locoregional treatment option remains controversial.     

Peritoneal Mesothelioma Treated by Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy: Results of a Prospective Study

Background Peritoneal mesothelioma is a rare disease with few therapeutic options. Recently, the combination of cytoreductive surgery with intraperitoneal hyperthermic chemotherapy (HIPEC) has shown promising results. Methods Fifteen patients with peritoneal mesothelioma who were treated by cytoreductive surgery and HIPEC between 1989 and 2004 were identified from a prospective database. HIPEC was performed with cisplatin and mitomycin C for 90 minutes by using the closed-abdomen technique. Results All patients but one (multicystic) had malignant disease of the following pathologic types: 12 epithelial and 2 biphasic. After surgical resection, 11 patients were considered to have a CC-0 or CC-1 resection (macroscopic complete resection or diameter of residual nodules <2.5 mm). No postoperative death occurred, and six postoperative complications were recorded. All but one patient had resolution of ascites. The overall median survival for the 14 patients with malignant mesothelioma was 35.6 months. The median survival was 37.8 months for patients treated with a CC-0 or CC-1 resection, whereas it was 6.5 months for those treated with a CC-2 or CC-3 resection (diameter of residual nodules >2.5 mm; P < .001). In a univariate analysis, the only other significant prognostic factor was the carcinomatosis extent (P = .02). Conclusions A therapeutic strategy combining cytoreductive surgery with HIPEC seems to provide an adequate and efficient locoregional treatment for peritoneal mesothelioma. It is associated with acceptable morbidity when performed by an experienced surgical team. The completeness of cytoreduction is the major determinant of survival.     

Timing of Adjuvant Radioimmunotherapy after Cytoreductive Surgery in Experimental Peritoneal Carcinomatosis of Colorectal Origin

Background Treatment of patients with peritoneal carcinomatosis (PC) of colorectal cancer (CRC) includes cytoreductive surgery (CS) in combination with (hyperthermic) intraperitoneal chemotherapy (HIPEC), resulting in a limited survival benefit with high morbidity and mortality rates. Radioimmunotherapy (RIT) as adjuvant therapy after CS of CRC has been shown to prolong survival in preclinical studies. However, the optimal setting of RIT remains to be determined. Methods PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to exploratory laparotomy (Sham), CS only or CS + RIT at different time points after surgery. RIT consisted of 55 MBq lutetium-177-labelled anti-CC531 antibody MG1 (183 μg). The primary endpoint was survival. Results Cytoreductive surgery with or without RIT was well tolerated. Median survival of animals in the Sham and CS group was 29 days and 39 days, respectively (P < 0.04). Compared to CS alone, median survival of rats after adjuvant RIT was 77 days (P < 0.0001), 52 days (P < 0.0001) and 45 days (P < 0.0001) when given directly, 4 and 14 days after surgery, respectively. Conclusion The efficacy of adjuvant RIT after CS for the treatment of PC of colonic origin decreases when the administration of the radiolabelled MAbs is postponed. This study shows that adjuvant RIT should be given as early as possible after surgery.     

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 ≤ 2.5mm) and IPHP were prospectively collected. Marker levels were determined pre-operatively, post-operatively, and routinely during long-term follow-up. Baseline diagnostic sensitivity, accuracy in monitoring response to treatment or tumor progression and prognostic significance were determined. Results Baseline diagnostic sensitivity was 53.3% for CA125, 0 for CEA, 3.8% for CA19.9 and 48.5% for CA15.3. Forty-six patients underwent adequate cytoreduction and IPHP; gross residual tumor was left after the operation in fourteen. Postoperatively, CA125 became negative in 21/22 patients with elevated baseline levels undergoing adequate CRS and IPHP, while remained elevated in 9/9 patients with persistent macroscopic disease. CA125 became positive in 12/12 patients with elevated baseline levels developing disease progression after adequate CRS and IPHP. Baseline CA125 showed borderline prognostic significance only among patients not previously treated with systemic chemotherapy. Conclusions CA125 was elevated in the majority of patients with PM in the present series. Serial maker measurements paralleled tumor growth or regression after CRS and IPHP, suggesting the need of further studies to assess the role of CA125 in this clinical setting.     

Cytoreductive Surgery with Selective Versus Complete Parietal Peritonectomy Followed by Hyperthermic Intraperitoneal Chemotherapy in Patients with Diffuse Malignant Peritoneal Mesothelioma: A Controlled Study

Background  

Combined treatment involving peritonectomy procedures, multivisceral resections, and hyperthermic intraperitoneal chemotherapy (HIPEC) has reportedly resulted in survival benefit for peritoneal surface malignancies, including diffuse malignant peritoneal mesothelioma (DMPM). Many unanswered questions remain regarding the surgical options in the management of DMPM. The aim of this case–control study was to assess the impact of the type and extent of parietal peritonectomy on survival and operative outcomes.     

Cytoreductive Surgery and Continuous Hyperthermic Peritoneal Perfusion in Patients with Mesothelioma and Peritoneal Carcinomatosis: Hemodynamic, Metabolic, and Anesthetic Considerations

Cytoreductive surgery and continuous hyperthermic peritoneal perfusion (CHPP) involve the conduct of a complex surgical procedure and delivery of high-dose hyperthermic chemotherapy to the peritoneum. This therapeutic modality has been shown to benefit patients with peritoneal carcinomatosis resulting from gastrointestinal and ovarian tumors and mesothelioma. However, it is unknown whether the primary disease (mesothelioma versus peritoneal carcinomatosis) affects hemodynamic and metabolic perturbations during the course of CHPP with cisplatin. We examined the perioperative course of patients undergoing CHPP with cisplatin and evaluated the effect of primary diagnosis (mesothelioma versus peritoneal carcinomatosis) on hemodynamic and metabolic parameters in response to peritoneal perfusion. Sixty-nine mesothelioma and 100 peritoneal carcinomatosis patients underwent 169 consecutive cytoreduction and CHPP procedures with general anesthesia. During CHPP, patients from both groups developed significant increases in central venous pressure, and heart rate, decreases in mean arterial pressure (all P < 0.0001), metabolic acidosis with significant decreases in pH and bicarbonate (P < 0.0001), deterioration of gas exchange with significant increases in PaCO₂ and oxygen alveolar–arterial gradient (P < 0.0001), and significant increases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) and decreases in hematocrit and platelet counts (all P < 0.0001). However, patients with mesothelioma had lesser increases in temperature (P < 0.01) and heart rate (P < 0.0001) and lesser decreases in hematocrit (P = 0.0013) during CHPP and greater decreases in sodium bicarbonate (P = 0.0082) after completion of CHPP compared with patients with peritoneal carcinomatosis. We conclude that the transient hemodynamic and metabolic perturbations associated with cytoreductive surgery and CHPP with cisplatin can vary according to the primary diagnosis (mesothelioma versus peritoneal carcinomatosis) warranting this therapy.     

Primary Malignant Peritoneal Mesothelioma in an Incarcerated Groin Hernia: Report of a Case

Malignant peritoneal mesothelioma arising from the inguinal hernia sac is rare. We report the case of a 71-year-old man examined in our emergency department for a bilateral inguinoscrotal hernia, which was recurrent in the right groin, and primary and incarcerated in the left groin. An emergency exploratory operation revealed a firm mass, 10cm in diameter, in the left inguinal hernia sac. The remaining peritoneal surface appeared macroscopically normal. Therefore, we resected the mass and performed a Rutkow hernioplasty. The patient was discharged after a short, uneventful recovery, and was referred to the oncology department for adjuvant therapy. He is now well and asymptomatic with no evidence of ascites, 26 months after his operation. A mesothelioma of the hernial sac peritoneum was the final histological diagnosis.     

Cytoreductive Surgery and Intraperitoneal Chemohyperthermia for Recurrent Peritoneal Carcinomatosis from Ovarian Cancer

Aggressive surgical cytoreduction has been shown to have a positive impact on survival of patients with ovarian cancer. After first-line chemotherapy, 47% of patients relapse within 5 years, and median survival after second line chemotherapy is 10—15 months. Adding intraperitoneal chemohyperthermia (IPCH) to surgical cytoreduction could further control ceolomic spread of disease. The aim of this study was to determine morbidity and mortality, regional relapse-free survival and, preliminarily, overall survival after combining cytoreductive surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian epithelial cancer relapsed after prior chemotherapy. Thirty women affected with such a relapse were included. Patients underwent extensive cytoreductive surgery including tumor resections and peritonectomy, followed by intraoperative IPCH with cisplatin. Complete surgical cytoreduction down to nodules less than 2.5 mm (CC0—CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). We registered one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Kaplan-Meier estimates of median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively. Patients with CC0—CC1 had locoregional relapse-free and overall survival rates of 24.4 and 37.8 months, whereas the remainder had survival rates of 4.1 and 11.0 months. We concluded that cytoreductive surgery combined with IPCH is feasible with acceptable morbidity and mortality and seems to promise good results in selected patients affected with peritoneal carcinomatosis from ovarian cancer.     

Monitoring Health Outcomes Following Cytoreductive Surgery Plus Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Carcinomatosis

Background Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for peritoneal carcinomitosis (PC) is an aggressive treatment designed to alleviate symptoms and prolong life. It is associated with physical and psychological morbidity. The purpose of this study was to monitor health outcomes related to treatment. Methods Patients completed a questionnaire before and after surgery at 3, 6 and 12 months. The questionnaire consisted of basic demographic items as well as the Functional Assessment of Cancer Therapy–Colon Scale (FACT-C), SF-36 Medical Outcomes Study Health Survey, Center for Epidemiologic Studies–Depression Scale (CES-D), Brief Pain Inventory–Short Form, and ECOG Performance Status Rating. Time trends were assessed with mixed models (SAS PROC MIXED) so as to use all data and to account for missing data. Results Ninety-six patients (49% females, 9% African Americans) of an average age of 52.9 (SD = 12.5) years were assessed before surgery. PC originated in primary lesions of the appendix (n = 36); colon/rectum (n = 24); mesothelium (n = 9); ovary (n = 5); stomach (n = 4); and miscellaneous (n = 18). Quality of life (QOL) and pain scores improved from baseline to 12 months. Physical functioning changed over the 12-month study period with improvement recorded at 6 months. The percentage of patients reporting significant depressive symptom at each time point was; baseline= 32%; 3 months= 19%; 6 & 12 months= 24%. Conclusions Acceptable QOL, return of functional status, and reduced pain can be attained between 3 and 6 months following treatment although some deficits in general health remain. Depressive symptoms are common and should be monitored.