Early identification of DPAM in at-risk low-grade appendiceal mucinous neoplasm patients: a new approach to surveillance for peritoneal metastasis.

BACKGROUND: Disseminated peritoneal adenomucinosis (DPAM) patients often have a history of appendectomy with identification of an incidental mucinous neoplasm (low-grade appendiceal mucinous neoplasm (LAMN)). The rate of developing DPAM is not well established. METHODS: Twenty-two patients with incidental LAMN were identified and monitored with cancer markers and CT every 4-6 months. Laparoscopy with peritoneal washing was performed in patients either in the event of radiographic disease or after 12 months in absence of radiographic disease. The rate of detecting peritoneal metastasis was determined for CT scan and laparoscopy. RESULTS: Peritoneal metastasis was detected in 5 (23 %) patients. Occult disease was detected in four patients at laparoscopy without a detectable disease on CT scan. One patient developed radiographic progression at 6 months confirmed with laparoscopy. Four patients were treated with cytoreductive surgery (CRS)/HIPEC and one with CRS only. The 17 patients with negative laparoscopy remain disease free with a median follow-up of 50 months. CONCLUSIONS: The rate of peritoneal metastasis in incidental LAMN patients was 23 %. Laparoscopy was the primary screening tool identifying occult metastasis. The median PCI of 7 was low, and all the patients underwent R0/R1 resections. This study revealed 1 in every 4.4 patients with LAMN may develop PMP. Longer follow-up and further patient surveillance is warranted.

Gastrointestinal Cancers With Peritoneal Carcinomatosis: Surgery and Hyperthermic Intraperitoneal Chemotherapy.

This review focuses on the underlying rationale for the use of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS+HIPEC) in the treatment of patients with primary gastrointestinal tumors with metastatic peritoneal disease. It examines the advantages of CS+HIPEC in peritoneal cancers and explores the controversies surrounding this treatment. For low-grade cancers, such as pseudomyxoma peritonei, CS+HIPEC is standard of care. However, for more aggressive tumors, such as gastric cancers, the results with this approach are not as encouraging and patient selection is very important. Generally, the cost of HIPEC is not prohibitive and increases the cost of surgery by only a small percentage. Overall, the consensus is that HIPEC is probably beneficial for less aggressive cancers. We believe that CS+HIPEC should be standard of care for appendiceal and colorectal cancers with peritoneal disease. For other cancers, such as gastric, pancreatic, or small bowel cancers, further study is warranted.

Comparison of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with mitomycin or carboplatin for diffuse malignant peritoneal mesothelioma.

Diffuse malignant peritoneal mesothelioma is a rare, aggressive disease. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved outcomes where systemic chemotherapy has not succeeded. In this study, we compare outcomes of patients treated with mitomycin or carboplatin as perfusate. In this retrospective study, 47 procedures (CRS + HIPEC) were conducted on 44 patients between March 2003 and August 2010 with either mitomycin or carboplatin. χ(2) and Student's t test were used for comparison of clinicopathological variables and Kaplan-Meier curves and log rank test were used to compare overall survival. Median survival of the mitomycin group was 18 months with 1- and 5-year survivals of 72.3 and 27.3 per cent, respectively. Median survival of the carboplatin group was not reached and 1- and 5-year survivals were 89.7 and 62.5 per cent, respectively (P = 0.014). Mean hospital and intensive care unit length of stay was 18.9 and 8.7 days in the mitomycin group and 12.5 and 2.3 days in the carboplatin group (P = 0.0069). Mean number of packed red blood cell units transfused was higher in the mitomycin group compared with the carboplatin group (3.54 vs 0.83, P < 0.05). There was no postoperative mortality. HIPEC with carboplatin in diffuse malignant peritoneal mesothelioma is associated with improved overall survival and shorter hospital stay compared with HIPEC with mitomycin.

Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients.

BACKGROUND: Peritoneal dissemination of abdominal malignancy (carcinomatosis) has a clinical course marked by bowel obstruction and death; it traditionally does not respond well to systemic therapy and has been approached with nihilism. To treat carcinomatosis, we use cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A prospective database of patients has been maintained since 1992. Patients with biopsy-proven peritoneal surface disease were uniformly evaluated for, and treated with, CS and HIPEC. Patient demographics, performance status (Eastern Cooperative Oncology Group), resection status, and peritoneal surface disease were classified according to primary site. Univariate and multivariate analyses were performed. The experience was divided into quintiles and outcomes compared. RESULTS: Between 1991 and 2013, a total of 1,000 patients underwent 1,097 HIPEC procedures. Mean age was 52.9 years and 53.1% were female. Primary tumor site was appendix in 472 (47.2%), colorectal in 248 (24.8%), mesothelioma in 72 (7.2%), ovary in 69 (6.9%), gastric in 46 (4.6%), and other in 97 (9.7%). Thirty-day mortality rate was 3.8% and median hospital stay was 8 days. Median overall survival was 29.4 months, with a 5-year survival rate of 32.5%. Factors correlating with improved survival on univariate and multivariate analysis (p ≤ 0.0001 for each) were preoperative performance status, primary tumor type, resection status, and experience quintile (p = 0.04). For the 5 quintiles, the 1- and 5-year survival rates, as well as the complete cytoreduction score (R0, R1, R2a) have increased, and transfusions, stoma creations, and complications have all decreased significantly (p < .001 for all). CONCLUSIONS: This largest reported single-center experience with CS and HIPEC demonstrates that prognostic factors include primary site, performance status, completeness of resection, and institutional experience. The data show that outcomes have improved over time, with more complete cytoreduction and fewer serious complications, transfusions, and stomas. This was due to better patient selection and increased operative experience. Cytoreductive surgery with HIPEC represents a substantial improvement in outcomes compared with historical series, and shows that meaningful long-term survival is possible for selected carcinomatosis patients. Multi-institutional cooperative trials are needed to refine the use of CS and HIPEC.

Hyperthermic intraperitoneal chemotherapy in ovarian cancer: first report of the HYPER-O registry.

INTRODUCTION: An analysis of experience of surgical and gynecologic oncologists in the United States with the use of hyperthermic intraperitoneal chemotherapy for women with invasive epithelial ovarian cancer (EOC). METHODS: An Internet-based registry (HYPER-O) collected data from collaborating institutions. Eligibility included women with EOC treated with hyperthermic intraperitoneal chemotherapy. Borderline and nonepithelial cancers were excluded. RESULTS: As of July 1, 2008, 141 women were eligible for analysis treated at the following time points: frontline (n = 26), interval debulking (n = 19), consolidation (n = 12), and recurrence (n = 83). The mean perfusion temperatures were 38.5 to 43.6 degrees C (median, 41.9 degrees C) for inflow and 36.9 to 42.9 degrees C (median, 41 degrees C) for outflow for 30 to 120 minutes. Treatment was with a platinum agent (n = 72), mitomycin (n = 53), or a combination (n = 14). Median follow-up was 18 months (range, 0.3-140.5 months) and median overall survival 30.3 months (95% confidence interval, 23.0-37.6) with 2-, 5-, and 10-year overall survival probabilities of 49.1%, 25.4%, and 14.3%, respectively. Of the 141 patients, 110 (78%) experienced recurrence of ovarian cancer and 87 died, 3 (0.5%) dying within 30 days of surgery. In the multivariable analysis, the factors significant for increased survival were sensitivity to platinum response (P = 0.048), completeness of cytoreduction scores of 1 or 0 (P = 0.025), carboplatin alone or a combination of 2 or more chemotherapy agents used (P = 0.011), and duration of hospital stays of 10 days or less (P = 0.021). CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy is a viable additional treatment option for patients with invasive EOC and may extend life in selected groups. It warrants further study in randomized controlled trials.

Peritoneal surface disease from colorectal cancer: comparison with the hepatic metastases surgical paradigm in optimally resected patients.

BACKGROUND: Surgical resection is the treatment of choice for colorectal hepatic metastases (HM). In contrast, metastatic disease to the peritoneum is treated with systemic therapy. We examined our experience with cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal surface disease (PSD) compared with liver resection for HM. METHODS: A review of prospective databases of colorectal cancer patients undergoing surgery for metastatic disease to the peritoneum or liver (1992-2005) was carried out. RESULTS: One hundred and twenty-one patients underwent CS + IPHC and 101 patients underwent hepatic resection with median follow-up of 86 and 56 months, respectively. Fifty-five (45%) patients in the IPHC group had complete resection of all gross tumor. Ninety-five (94%) of the HM patients had negative surgical margins. Comparison of the R0/R1 PSD and margin-negative HM group demonstrated significant differences in age, performance status, and preoperative chemotherapy. The 1-, 3-, and 5-year overall survival for the R0/R1 PSD patients was 91, 48, and 26%; while it was 87, 59, and 34% for the HM patients (P = 0.32). Perioperative morbidity was 42% versus 34% (P = 0.38) and mortality was 5.5% versus 4.2% (P = 0.71) between the PSD and HM patients, respectively. CONCLUSION: R0/R1 resection during CS + IPHC compared with margin-negative hepatic resection demonstrated no significant difference in overall survival and for select patients should be considered a viable treatment option. Further studies to improve the resectability of PSD patients and define the role of neoadjuvant and adjuvant drug strategies are needed.

Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures.

BACKGROUND: Peritoneal dissemination of abdominal malignancy (PSD) has a clinical course marked by bowel obstruction and death. We have been using aggressive cytoreductive surgery with intraperitoneal hyperthermic chemotherapy (IPHC) to treat PSD. The purpose of this article was to review our experience with IPHC. STUDY DESIGN: A prospective database of patients undergoing IPHC has been maintained since 1991. Patients were uniformly evaluated and treated. Demographics, performance status, resection status, primary site, and experience quartile were compared with outcomes. Univariate and multivariate analyses were performed. RESULTS: A total of 460 patients underwent 501 IPHC procedures. Average age was 53.0 years, and 50.4% were women. The 30-day mortality rate was 4.8%, the complication rate was 43%, and median hospital stay was 9 days. Median followup was 55.4 months, median survival was 22.2 months, and 5-year survival rate was 27.8%. Factors correlating with improved survival were performance status (p=0.0001), primary tumor (p=0.0001), resection status (p=0.0001), complications (p=0.002), previous IPHC (p=0.006), and experience quartile (p=0.031). On multivariate analysis, primary tumor site, performance status, resection status, and development of complications (p < 0.001) predicted outcomes. CONCLUSIONS: Our experience demonstrated that preoperative criteria for better outcomes include primary tumor site and performance status. Completeness of resection and development of postoperative complications are also crucial, and outcomes have improved over time. Cytoreductive surgery and IPHC represent substantial improvements in outcomes compared with historic series and best-available systemic therapy. Longterm survival is possible for selected patients who undergo the procedure.

Appendiceal neoplasms with peritoneal dissemination: outcomes after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy.

BACKGROUND: Appendiceal neoplasms frequently present with peritoneal dissemination (PD) and have a clinical course marked by bowel obstruction and subsequent death. Few data have correlated outcome with appendiceal histology after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC). We have reviewed our experience with cytoreductive surgery and IPHC for PD from the appendix. METHODS: A total of 110 cases of PD from proven appendiceal neoplasms treated with IPHC were identified from a prospectively managed database. Tumor samples were classified on pathologic review as disseminated peritoneal adenomucinosis (n = 55), peritoneal mucinous carcinomatosis (PMCA) with intermediate features (n = 18), PMCA (n = 29), or high-grade nonmucinous lesions (n = 8). A retrospective review was performed with long-term survival as the primary outcome measure. RESULTS: A total of 116 IPHCs were performed on 110 patients for appendiceal PD between 1993 and 2004. The 1-, 3-, and 5-year survival rates for all cases were 79.9% +/- 4.1%, 59.0% +/- 5.7%, and 53.4% +/- 6.5%, respectively. When stratified by histology, disseminated peritoneal adenomucinosis and intermediate tumors had better 3-year survival rates (77% +/- 7% and 81% +/- 10%) than PMCA and high-grade nonmucinous lesions (35% +/- 10% and 15% +/- 14%; P = .0032 for test of differences between groups). Age at presentation (P = .0134), performance status (P < .0001), time between diagnosis and IPHC (P = .0011), resection status (P = .0044), and length of hyperthermic chemoperfusion (P = .0193) were independently associated with survival. CONCLUSIONS: The data show that long-term survival is anticipated in most patients who are treated with cytoreduction and IPHC for appendiceal PD. The findings presented herein underscore the important prognostic characteristics that predict outcome after IPHC in patients with PD. In all, this work establishes a framework for the consideration of IPHC in future trials for appendiceal PD.

Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for advanced gastric cancer.

Peritoneal carcinomatosis is a common and universally fatal sequelae of gastric carcinoma. Treatment of peritoneal carcinomatosis from appendiceal and colorectal sources with intraperitoneal hyperthermic chemotherapy (IPHC) combined with aggressive cytoreductive surgery has been shown to be effective. There are few data on this treatment modality for carcinoma of the stomach. This study evaluates cytoreductive surgery and IPHC with peritoneal carcinomatosis from gastric carcinoma. Thirty-four patients with peritoneal carcinomatosis due to gastric carcinoma underwent gastric resection with cytoreductive surgery followed by IPHC with mitomycin C. A control group consisting of 40 contemporaneous patients, who underwent radical gastrectomy without extended nodal resection, was identified through the tumor registry. Despite more advanced disease in the IPHC group compared to the control group (P < 0.001), overall survival in the two groups was similar. Proportional-hazards regression analysis shows that only resection status is significantly correlated with improved survival (P=0.0068). Within the IPHC group, patients who underwent an R0/R1 resection had increased survival times (11.2 vs. 3.3 months, P=0.015) vs. those who underwent R2 resection. The group who had an R0/R1 resection had 1- and 2-year survival rates of 45% and 45% compared to 16% and 8%, respectively, in the R2 group. Cytoreductive surgery and IPHC is a modality with limited potential for the treatment of peritoneal carcinomatosis from gastric carcinoma. Careful patient selection for this procedure is imperative, and patients in whom an R0/R1 resection can be achieved are the best candidates.

Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy with mitomycin C for peritoneal carcinomatosis from nonappendiceal colorectal carcinoma.

BACKGROUND: Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) are efficacious in patients with disseminated mucinous tumors of the appendix. We reviewed our experience using this approach for nonappendiceal colorectal cancer (NACC). METHODS: We performed a retrospective chart review of a prospective database for patients undergoing CS and IPHC with mitomycin C for peritoneal carcinomatosis from colorectal primary lesions between December 1991 and April 2002. RESULTS: There were 77 patients, with a median age of 54 years. Peritoneal carcinomatosis was synchronous and metachronous in 27% and 73% patients, respectively. Seventy-five percent of patients (n = 58) had received chemotherapy prior to IPHC. Complete resection of all gross disease was accomplished in 37 patients (48%). The mean carcinoembryonic antigen level decreased from a preoperative value of 31.2 to a postoperative value of 6.9 (P <.0001). Overall survival (OS) at 1, 3, and 5 years was 56%, 25%, and 17%, respectively. With a median follow-up of 15 months, the median OS was 16 months. Perioperative morbidity and mortality were 30% and 12%, respectively. Hematologic toxicity occurred in 15 patients (19%). Cox regression analysis identified poor performance status (P =.018), bowel obstruction (P =.001), malignant ascites (P =.001), and incomplete resection of gross disease (P =.011) as independent predictors of decreased survival. Patients with complete resection of all gross disease had a 5-year OS of 34%, with a median OS of 28 months. CONCLUSIONS: CS and IPHC with mitomycin C can improve outcomes for select patients with peritoneal spread from NACC. One third of patients who undergo complete resection of gross disease have long-term survival.

Long-term survivorship and quality of life after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy with mitomycin C for peritoneal carcinomatosis is used as a palliative treatment for a variety of malignancies. The purpose of this study was to measure the quality of life (QOL) of survivors (>3 years) after treatment. METHODS: Patients were interviewed by telephone with the following tools: (1) the Functional Assessment of Cancer Therapy-Colon (FACT-C), (2) the Short Form of the Medical Outcomes Study Questionnaire, (3) the Center for Epidemiologic Studies-Depression scale, (4) the Life Appreciation scale, (5) the Psychosocial Concerns Questionnaire, and (6) performance status rating. RESULTS: Seventeen (10 appendix, 5 large intestine, 1 ovarian, and 1 peritoneum) of 109 patients were interviewed from 3.1 to 8.0 years after treatment. Ten patients (62.5%) described their health as excellent or very good. No limitations on moderate activity were reported in 94% of cases. Paired t-tests were used to compare 10 patients who had baseline QOL data. FACT mean difference scores and P values (positive difference scores indicate improved QOL) were functional well-being: 4.9, P =.01; physical well-being: 3.3, P =.05; and FACT total: 14.3, P =.02. CONCLUSIONS: Long-term survival with good QOL is possible for selected patients with peritoneal carcinomatosis after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy.

Factors predicting survival after intraperitoneal hyperthermic chemotherapy with mitomycin C after cytoreductive surgery for patients with peritoneal carcinomatosis.

HYPOTHESIS: Certain clinicopathologic factors predict improved survival after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. DESIGN: Prospective clinical trial. SETTING: Surgical oncology service at a university academic hospital. PATIENTS: A population of 109 consecutive patients with peritoneal carcinomatosis treated between December 1991 and November 1997. INTERVENTION: All patients underwent resection of gross disease followed by 2-hour intraoperative perfusion of mitomycin C (20-40 mg) into the peritoneal cavity at a temperature of 40.5 degrees C. MAIN OUTCOME MEASURES: Clinicopathologic factors that independently predicted improved overall survival rates. RESULTS: Overall survival at 1 and 3 years was 61% and 33%, respectively. With median follow-up of 52 months, median overall survival was 16 months. Four factors were significant independent predictors of improved survival by multivariate analysis: nonadenocarcinoma histologic features (P =.001), the appendix as a primary site (P =.003), the absence of hepatic parenchymal metastases (P =.01), and complete resection of all gross disease (R1/0 resection) (P<.001). Patients with an R1/0 resection vs an incomplete resection of gross disease (R2 resection) had 3-year overall survival of 68% vs 21% (P<.001). CONCLUSIONS: Patients with peritoneal carcinomatosis have a uniformly poor prognosis. However, in select patients, the natural history of this disease condition may be altered by using the multimodality approach of cytoreductive surgery and intraperitoneal hyperthermic chemotherapy. These results require confirmation in prospective randomized studies.

Clinical significance of a NAD(P)H: quinone oxidoreductase 1 polymorphism in patients with disseminated peritoneal cancer receiving intraperitoneal hyperthermic chemotherapy with mitomycin C.

Recent data indicate that NAD(P)H: quinone oxidoreductase 1 (NQO1) is important in the activation of mitomycin C. A polymorphism in human NQO1 (609C>T) is associated with diminished NQO1 activity. The purpose of our study was to determine the effect of the 609C>T polymorphism on tumor NQO1 activity and overall survival in patients with disseminated peritoneal cancer receiving intraperitoneal mitomycin C therapy. Patients with disseminated peritoneal cancer of gastrointestinal or other origin were eligible. Following aggressive surgical debulking, patients were administered a 2-h heated (40.5 degrees C) intraperitoneal perfusion with mitomycin C. NQO1 activity was determined in tumor tissue obtained during surgery and patients were genotyped for the NQO1 C609T polymorphism using a polymerase chain reaction-based method. The major response variable monitored during the trial was overall survival. Of the 117 patients genotyped for the NQO1 609C>T polymorphism, 67% were wild-type (WT), 31% were heterozygous (HE), and 2% were homozygous mutant (HM). In tumor tissue, the mean NQO1 activities from WT (n = 14) and HE (n = 5) patients were 794 +/- 603 and 70 +/- 133.1 nmol/min/mg protein respectively (P = 0.006). Significant differences in survival between WT versus HE/HM genotypes were noted in optimally debulked patients (R0/R1) (43.6+ months, median not yet reached versus 23 months respectively, P = 0.037) and in patients with peritoneal carcinomatosis of colonic origin (18.2 versus 11.5 months respectively, P = 0.050). These data indicate that the NQO1 609C>T polymorphism results in significantly reduced tumor NQO1 activity and reduced survival in subsets of patients receiving intraperitoneal hyperthermic mitomycin C therapy.