Konstantinos I. Votanopoulos

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.

Rates and patterns of recurrence after curative intent resection for gastric cancer: a United States multi-institutional analysis.

BACKGROUND Reports on recurrence and outcomes of US patients with gastric cancer are scarce. The aim of this study was to determine incidence and pattern of recurrence after curative intent surgery for gastric cancer. STUDY DESIGN Using the multi-institutional US Gastric Cancer Collaborative database, we identified 817 patients undergoing curative intent resection for gastric cancer between 2000 and 2012. Patterns and rates of recurrence along with associated risk factors were identified using adjusted regression analysis. Recurrences were classified as locoregional, peritoneal, or hematogenous. RESULTS Median patient age was 65.8 years (interquartile range [IQR] 56.4, 74.7); the majority of patients were male (n = 462, 56.6%) and white (n = 511, 62.5%). At the time of surgery, the majority of patients underwent a partial gastrectomy (n = 481, 59.2%) with a complete R0 resection achieved in 91.6% (n = 748) of patients. At the time of last follow-up, 244 (29.9%) of 817 patients developed a recurrence; 163 (66.8%) patients had recurrence at only a single site; the remaining 81 (33.2%) had multiple sites of initial recurrence. Among patients who recurred at a single site, recurrence was most common at a distant location and included hematogenous (n = 57, 23.4%) or peritoneal (n = 47, 19.3%) only metastasis. Tumors at the gastroesophageal junction (odds ratio [OR] 3.18, 95% CI 1.08 to 9.40; p = 0.04) were associated with higher risk of locoregional recurrence, while the presence of multiple lesions (OR 10.82, 95% CI 3.56 to 32.85; p < 0.001) remained associated with an increased risk of distant hematogenous recurrence after adjusted analysis. Recurrence was associated with worse survival, with a median recurrence-free survival of 10.8 months (IQR 8.9, 12.8) among those who experienced a recurrence. CONCLUSIONS Nearly one-third of patients experienced recurrence after gastric cancer surgery. The most common site of recurrence was distant.

Outcomes of repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal surface malignancy.

BACKGROUND Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the survival of patients with peritoneal surface malignancy. On recurrence, a repeat CRS/HIPEC is a treatment option. STUDY DESIGN A retrospective analysis of 868 CRS/HIPEC procedures was performed. Type of primary, functional status, completion of resection, hospitalization, morbidity, mortality, and survival were reviewed. RESULTS Sixty-two patients (7.7%) underwent a second CRS/HIPEC, including 33 patients with appendiceal primaries, 8 ovarian, 7 mesotheliomas, 4 colon cancers, and 10 various malignancies. Median follow-up was 60.8 months. Median overall survival in months was 85.3 for appendiceal cancer, 52.9 for mesothelioma, 60.1 for ovarian, and 137.4 for colon cancer. R1 resection was achieved in 43.5% after both procedures. Median survival after the second cytoreduction was 52.1 months for appendiceal cancer, 21.8 for mesothelioma, 53.9 for ovarian, and 55.7 for colon cancer. Median survival was 55.7 months for R1 resection, 20.3 months for R2a resection, and 15.5 months for R2b-R2c. Median ICU and hospital stay was 1 and 7.5 days, respectively. The 30-day morbidity after the second CRS/HIPEC was 48.4% and mortality was 3.2%. In multivariate analysis, the R status of the second CRS/HIPEC (p = 0.013) and the interval between the 2 procedures (p = 0.009) were significant in predicting improved survival. CONCLUSIONS In experienced tertiary centers and for selected patients, a repeat CRS/HIPEC procedure has morbidity and mortality similar to the initial cytoreduction. Survival depends primarily on the completion of the repeat cytoreduction and favorable biology of the tumor.

A comparison of hematologic toxicity profiles after heated intraperitoneal chemotherapy with oxaliplatin and mitomycin C

BACKGROUND Although peritoneal carcinomatosis (PC) from colorectal and appendiceal tumors is consistent with metastatic disease, complete cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) using mitomycin C (MMC) can improve survival. A recent phase I study by our group using hyperthermic intraperitoneal oxaliplatin has demonstrated its safety and appropriate dose. Our goal in this study is to present a single institutions experience with the hematologic toxicities of the two agents. METHODS We performed a retrospective review of 187 patients with PC of colorectal or appendiceal origin who underwent HIPEC with MMC or oxaliplatin between October 2006 and September 2009. Hematologic toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0. RESULTS Of the 187 patients, 55 had oxaliplatin-based HIPEC while 132 patients received MMC. Splenectomy was performed in 95 patients (50.8%) due to disease involvement. When comparing hematologic toxicity for MMC and oxaliplatin among the cohort of patients who underwent splenectomy, a statistically significant difference was noted in the incidence of platelet (P = .02) and neutrophil (P = .05) toxicity, with oxaliplatin having a higher incidence of grade 3 and grade 4 platelet and neutrophil toxicity respectively. However, no statistically significant difference in hematologic toxicity was noted between the two agents in patients who did not undergo splenectomy during cytoreductive surgery. CONCLUSIONS Oxaliplatin-based HIPEC for PC of colorectal and appendiceal origin is associated with similar white blood cell toxicity and higher platelet and neutrophil toxicity compared to MMC-based HIPEC.

Outcomes with cytoreductive surgery and HIPEC for peritoneal metastasis.

Peritoneal metastasis (PM) has traditionally been approached with therapeutic nihilism. The evolution of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) over the last two decades, however, has caused a paradigm shift in treatment for PM. This modality is rapidly gaining acceptance as standard of care for PM from various cancers. This article reviews the current literature regarding the use of CRS/HIPEC for PM from the most common intra‐abdominal malignancies. J. Surg. Oncol. 2014 110:575–584.

Prognostic Performance of Different Lymph Node Staging Systems After Curative Intent Resection for Gastric Adenocarcinoma

Objective: To compare the prognostic performance of American Joint Committee on Cancer/International Union Against Cancer seventh N stage relative to lymph node ratio (LNR), log odds of metastatic lymph nodes (LODDS), and N score in gastric adenocarcinoma. Background: Metastatic disease to the regional LN basin is a strong predictor of worse long-term outcome following curative intent resection of gastric adenocarcinoma. Methods: A total of 804 patients who underwent surgical resection of gastric adenocarcinoma were identified from a multi-institutional database. The relative discriminative abilities of the different LN staging/scoring systems were assessed using the Akaikes Information Criterion (AIC) and the Harrells concordance index (c statistic). Results: Of the 804 patients, 333 (41.4%) had no lymph node metastasis, whereas 471 (58.6%) had lymph node metastasis. Patients with ≥N1 disease had an increased risk of death (hazards ratio = 2.09, 95% confidence interval: 1.68–2.61; P < 0.001]. When assessed using categorical cutoff values, LNR had a somewhat better prognostic performance (C index: 0.630; AIC: 4321.9) than the American Joint Committee on Cancer seventh edition (C index: 0.615; AIC: 4341.9), LODDS (C index: 0.615; AIC: 4323.4), or N score (C index: 0.620; AIC: 4324.6). When LN status was modeled as a continuous variable, the LODDS staging system (C index: 0.636; AIC: 4304.0) outperformed other staging/scoring systems including the N score (C index: 0.632; AIC: 4308.4) and LNR (C index: 0.631; AIC: 4225.8). Among patients with LNR scores of 0 or 1, there was a residual heterogeneity of outcomes that was better stratified and characterized by the LODDS. Conclusions: When assessed as a categorical variable, LNR was the most powerful manner to stratify patients on the basis of LN status. LODDS was a better predicator of survival when LN status was modeled as a continuous variable, especially among those patients with either very low or high LNR.

Effect of Perioperative Transfusion on Recurrence and Survival after Gastric Cancer Resection: A 7-Institution Analysis of 765 Patients from the US Gastric Cancer Collaborative

BACKGROUND The prognostic effect of perioperative blood transfusion on recurrence and survival in patients undergoing resection of gastric adenocarcinoma (GAC) remains controversial. STUDY DESIGN All patients who underwent resection for GAC from 2000 to 2012 at the 7 institutions of the US Gastric Cancer Collaborative were identified. The effect of transfusion on recurrence-free (RFS) and overall survival (OS) in the context of adverse clinicopathologic variables was examined by univariate and multivariate regression analyses. RESULTS Of 965 patients, 765 underwent curative intent R0 resection. Median follow-up was 44 months; 30-day mortalities were excluded. Median estimated blood loss (EBL) was 200 mL, and 168 patients (22%) received perioperative allogeneic blood transfusions. Transfused patients were less likely to receive adjuvant therapy (44% vs 56%; p = 0.01). Transfusion was associated with significantly decreased median RFS (13.5 vs 37.2 months, p < 0.001). Median OS was similarly decreased in patients receiving transfusions (18.6 vs 49.8 months, p < 0.001). On multivariate analysis, transfusion remained an independent risk factor for decreased RFS (hazard ratio [HR] 1.63; 95% CI 1.13 to 2.37; p = 0.010) and decreased OS (HR 1.79; 95% CI 1.21 to 2.67; p = 0.004), regardless of EBL or need for splenectomy. Timing (intraoperative vs postoperative) and volume of transfusion did not alter the negative prognostic effect of transfusion on survival. CONCLUSIONS Perioperative allogeneic blood transfusion is associated with decreased RFS and OS after resection of gastric cancer, independent of adverse clinicopathologic factors. This supports the judicious use of perioperative transfusion during resection of gastric cancer.

A nomogram to predict overall survival and disease-free survival after curative resection of gastric adenocarcinoma.

AbstractBackgroundThe American Cancer Society projects there will be over 22,000 new cases, resulting in nearly 11,000 deaths, related to gastric adenocarcinoma in the US in 2014. The aim of the current study was to find clinicopathologic variables associated with disease-free survival (DFS) and overall survival (OS) following curative resection of gastric adenocarcinoma, and create a nomogram for individual risk prediction.Methods A nomogram to predict DFS and OS following surgical resection of gastric adenocarcinoma was constructed using a multi-institutional cohort of patients who underwent surgery for primary gastric adenocarcinoma at seven major institutions in the US between January 2000 and August 2013. Discrimination and calibration of the nomogram were tested by C-statistic, Kaplan–Meier curves, and calibration plots.ResultsA total of 719 patients who underwent surgery for primary gastric adenocarcinoma were included in the study. Using the backward selection of clinically relevant variables with Akaike information criteria, age, sex, tumor site, depth of invasion, and lymph node ratio (LNR) were selected as factors predictive of OS, while age, tumor site, depth of invasion, and LNR were incorporated in the prediction of DFS. A nomogram was constructed to predict OS and DFS using these variables. Discrimination and calibration of the nomogram revealed good predictive abilities (C-index, DFS 0.711; OS 0.702).Conclusion Independent predictors of recurrence and death following surgery for primary gastric adenocarcinoma were used to create a nomogram to predict DFS and OS. The nomogram was able to stratify patients into prognostic groups, and performed well on internal validation.

Perioperative systemic chemotherapy for appendiceal mucinous carcinoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

The role of systemic chemotherapy (SC) in conjunction with cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in appendiceal mucinous carcinoma peritonei (MCP) is unknown.

Factors Associated With Recurrence and Survival in Lymph Node-negative Gastric Adenocarcinoma: A 7-Institution Study of the US Gastric Cancer Collaborative.

Objectives: To determine pathologic features associated with recurrence and survival in patients with lymph node–negative gastric adenocarcinoma. Study Design: Multi-institutional retrospective analysis. Background: Lymph node status is among the most important predictors of recurrence after gastrectomy for gastric adenocarcinoma. Pathologic features predictive of recurrence in patients with node-negative disease are less well established. Methods: Patients who underwent curative resection for gastric adenocarcinoma between 2000 and 2012 from 7 institutions of the US Gastric Cancer Collaborative were analyzed, excluding 30-day mortalities and stage IV disease. Competing risks regression and multivariate Cox regression were used to determine pathologic features associated with time to recurrence and overall survival. Differences in cumulative incidence of recurrence were assessed using the Gray method (for univariate nonparametric analyses) and the Fine and Gray method (for multivariate analyses) and shown as subhazard ratios (SHRs) and adjusted subhazard ratios (aSHRs), respectively. Results: Of 805 patients who met inclusion criteria, 317 (39%) had node-negative disease, of which 54 (17%) recurred. By 2 and 5 years, 66% and 88% of patients, respectively, experienced recurrence. On multivariate competing risks regression, only T-stage 3 or higher was associated with shorter time to recurrence [aSHR = 2.7; 95% confidence interval (CI), 1.5–5.2]. Multivariate Cox regression showed T-stage 3 or higher [hazard ratio (HR) = 1.8; 95% CI, 1.2–2.8], lymphovascular invasion (HR = 2.2; 95% CI, 1.4–3.4), and signet ring histology (HR = 2.1; 95% CI, 1.2–3.6) to be associated with decreased overall survival. Conclusions: Despite absence of lymph node involvement, patients with T-stage 3 or higher have a significantly shorter time to recurrence. These patients may benefit from more aggressive adjuvant therapy and postoperative surveillance regimens.