Do Lymph Node Metastases Matter in Appendiceal Cancer with Peritoneal Carcinomatosis? A US HIPEC Collaborative Study.

BACKGROUND: Whether formal regional lymph node (LN) evaluation is necessary for patients with appendiceal adenocarcinoma (AA) who have peritoneal metastases is unclear. The aim of this study was to evaluate the prognostic value of LN metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: A retrospective analysis of the US HIPEC collaborative, a multi-institutional consortium comprising 12 high-volume centers, was performed to identify patients with AA who underwent CRS-HIPEC with adequate LN sampling (≥ 12 LNs). RESULTS: Two hundred-fifty patients with AA who underwent CRS-HIPEC were included. Outcomes were compared between LN - and LN + disease. Baseline patient characteristics between groups were similar, with most patients undergoing complete cytoreduction (0/1: 86.0% vs. 76.8%, p = 0.08), respectively. More adverse tumor factors were found in patients with LN + disease, including poor differentiation, signet ring cells, and lymphovascular invasion. Multivariate analysis of overall survival (OS) found LN + disease was independently associated with worse OS (HR: 2.82 95%CI: 1.25-6.34, p = 0.01), even after correction for receipt of systemic therapy. On Kaplan-Meier analysis, median OS was lower in patients with LN + disease (25.9 months vs. 91.4 months, p < 0.01). LN + disease remained associated with poor OS following propensity score matching (HR: 4.98 95%CI: 1.72-14.40, p < 0.01) and in patients with PCI ≥ 20 (HR: 3.68 95%CI: 1.54-8.80, p < 0.01). CONCLUSIONS: In this large multi-institutional study of patients with AA undergoing CRS-HIPEC, LN status remained associated with worse OS even in the setting of advanced peritoneal carcinomatosis. Formal LN evaluation should be performed for most patients with AA undergoing CRS-HIPEC.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for patients at High-Risk of Peritoneal Metastases.

BACKGROUND: Selection of patients for hyperthermic intraperitoneal chemotherapy (HIPEC) continues to evolve. We hypothesized that adjuvant HIPEC for patients at high-risk of peritoneal progression is safe and associated with favorable outcomes. METHODS: The institutional database of a high-volume center was queried for patients with high-risk disease undergoing HIPEC with a peritoneal carcinomatosis index (PCI) of 0. High-risk patients were defined as those with ruptured primary tumors or locally advanced (T4) disease. RESULTS: 37 patients underwent adjuvant HIPEC, with a median follow-up of 5.2 years. 54% had low-grade (LG) tumors while 46% had high-grade (HG) tumors. No patients underwent neoadjuvant chemotherapy, while eleven patients (32.4%) received adjuvant chemotherapy. There were no perioperative mortalities, and the overall complication rate was 43%. For the entire cohort, five year recurrence-free survival (RFS) and overall survival (OS) were 77% and 100%, respectively. Five year RFS and OS were 75% and 100% for LG patients and 81% and 100% for HG patients, respectively. CONCLUSIONS: Adjuvant HIPEC for patients at high-risk of peritoneal progression, with PCI 0, is safe and associated with favorable long-term survival. Additional prospective investigation is needed to identify patient populations who may benefit most from HIPEC.

Incidence and Long-term Outcomes of Patients Requiring Early Reoperation After HIPEC.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) remains a formidable operation associated with considerable morbidity. It is unclear how often these patients require reoperation for postoperative complications and if the need for reoperations leads to worse long-term outcomes. METHODS: The Peritoneal Surface Malignancy Database at a single center was retrospectively queried. Out of 149 entries, 141 HIPECs performed between 2012 and 2018 met inclusion criteria. Patients were categorized based on early reoperation (<60 d after HIPEC), and demographic and tumor factors were compared using univariate analyses. Recurrence was calculated for patients with complete cytoreduction and overall survival analyzed using the Kaplan-Meier method. RESULTS: There were 15 reoperations after 141 HIPECs (10.6%). Median duration between HIPEC and reoperation was 18 d. Indications for reoperation included intra-abdominal infection (n = 5), bowel obstruction (n = 4), wound infection (n = 3), bleeding (n = 2), and evisceration (n = 1). There were no identified patient- or tumor-related risk factors for reoperation. Reoperations were associated with longer hospital length of stay (19 versus 9 d, P = 0.005) and 30-d readmissions (46.7% versus 12.8%, P = 0.003). There was no significant difference in 3-year recurrence-free survival, but there was a significant association between reoperation and 3-year overall survival (38.0% versus 71.9%, P = 0.03). CONCLUSIONS: Complications requiring reoperation after HIPEC lead to increased short-term morbidity, longer hospital length of stay, and most importantly, reduced overall survival. Further studies investigating interventions to decrease complications and reduce reoperation rates are needed to improve outcomes after HIPEC.

Primary Tumor Sidedness is Predictive of Survival in Colon Cancer Patients Treated with Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy: A US HIPEC Collaborative Study.

INTRODUCTION: The clinical relevance of primary tumor sidedness is not fully understood in colon cancer patients with peritoneal metastasis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This was a retrospective cohort study of a multi-institutional database of patients with peritoneal surface malignancy at 12 participating high-volume academic centers from the US HIPEC Collaborative. RESULTS: Overall, 336 patients with colon primary tumors who underwent curative-intent CRS with or without HIPEC were identified; 179 (53.3%) patients had right-sided primary tumors and 157 (46.7%) had left-sided primary tumors. Patients with right-sided tumors were more likely to be older, male, have higher Peritoneal Cancer Index (PCI), and have a perforated primary tumor, but were less likely to have extraperitoneal disease. Patients with complete cytoreduction (CC-0/1) had a median disease-free survival (DFS) of 11.5 months (95% confidence interval [CI] 7.6-15.3) versus 13.1 months (95% CI 9.5-16.8) [p = 0.158] and median overall survival (OS) of 30 months (95% CI 23.5-36.6) versus 45.4 months (95% CI 35.9-54.8) [p = 0.028] for right- and left-sided tumors; respectively. Multivariate analysis revealed that right-sided primary tumor was an independent predictor of worse DFS (hazard ratio [HR] 1.75, 95% CI 1.19-2.56; p =0.004) and OS (HR 1.72, 95% CI 1.09-2.73; p = 0.020). CONCLUSION: Right-sided primary tumor was an independent predictor of worse DFS and OS. Relevant clinicopathologic criteria, such as tumor sidedness and PCI, should be considered in patient selection for CRS with or without HIPEC, and guide stratification for clinical trials.

Factors Associated with Readmission After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis.

PURPOSE: Cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for peritoneal carcinomatosis is a morbid endeavor. Despite improvement in perioperative management of these patients, there are subsets of patients requiring hospital readmission after discharge. We sought to identify variables associated with readmission rates for CRS/HIPEC. METHODS: We conducted a retrospective review of CRS/HIPEC cases at the University of Cincinnati between 1999 and 2014. Patient-, tumor-, and treatment-specific characteristics were evaluated. The association between patient- and outcome-specific variables for 30- and 90-day readmission were evaluated. RESULTS: Of 215 CRS/HIPEC patients, the 7-, 30-, and 90-day readmission rates were 9.8 % (n = 21), 14.9 % (n = 32), and 21.4 % (n = 46), respectively. The most common reasons for readmission within 90 days included abdominal pain (n = 14), intra-abdominal abscess (n = 9), malnutrition/failure to thrive (n = 8), and bowel obstruction (n = 7). The primary factor associated with readmission at all time points (7, 30, and 90 days) was the presence of an enterocutaneous fistula (p < 0.01). Six patients (2.8 %) had multiple readmissions; 3 of these had ECF. Factors not associated with higher admission rates included sex, age, race, operative blood loss, pancreatectomy or liver resection at the index operation, and postoperative complications of wound infection, line infection, and thromboembolic events. CONCLUSIONS: In patients undergoing CRS/HIPEC, readmission was primarily associated with poor pain control, malnutrition, and infectious complications. Patients with enterocutaneous fistula were also disproportionately readmitted multiple times. These data should inform clinicians about patients at high risk for readmission after CRS/HIPEC and encourage more comprehensive coordination of postdischarge planning and care for specific patient populations.

Predictors of survival in patients with high-grade peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Peritoneal metastases in patients with high-grade adenocarcinoma have been typically associated with a poor outcome. Recent literature has suggested that cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival. We examined this subset of patients in an effort to better delineate those factors which contribute to improved survival. METHODS: A retrospective review was performed looking at patients who had undergone CRS/HIPEC. Patients were identified as high-grade histology on the basis of pathology reports indicating their lesion as high grade, moderately, or poorly differentiated and/or associated with signet ring or goblet cell carcinoid features. Peritoneal cancer index and completeness of cytoreduction (CC) were used to define disease burden. Survival analysis was performed by the method of Kaplan-Meier with the log-rank test used to determine significance. RESULTS: Of the 250 patients who underwent CRS/HIPEC between 1999 and 2011, 36 (14%) were identified as having peritoneal metastases from a high-grade gastrointestinal primary. Actual overall survival from the time of diagnosis was 11.1% at 5 years. Median survival from time of surgery was 21.6 months. Survival advantage was conferred to those patients who underwent a CC0/CC1 resection, had a peritoneal cancer index score at time of surgery ≤20, appendiceal primary, or moderately differentiated histopathology. Receipt of neoadjuvant chemotherapy and nodal status was not significantly predictive of improved survival. Patients with signet ring cell histology had a particularly poor prognosis. CONCLUSION: For those patients with high-grade peritoneal metastases and historically a poor prognosis, prolonged survival may be achieved through CRS/HIPEC, optimally with a CC0/CC1 resection.

Technology for the delivery of hyperthermic intraoperative intraperitoneal chemotherapy: a survey of techniques.

Peritoneal metastases are common sequelae of gastrointestinal malignancy. The treatment of peritoneal metastases through use of aggressive surgical cytoreduction including peritonectomy coupled with HIPEC has now been reported in several large single-institution series. The available literature suggests that in experienced hands and with appropriate patient selection cytoreduction and HIPEC can be an effective therapy, particularly when all macroscopic tumor deposits are removed. Different techniques involving the administration of intraperitoneal chemotherapy have been reported, including the closed intraoperative technique, the open or coliseum technique, and the open technique using a PCE device. All techniques have been associated with mortality and morbidity that is significant, but generally consistent with other major surgical procedures. In theory, the coliseum and PCE techniques may have less associated morbidity because of improved heat distribution; however, this remains to be definitively proven in a controlled clinical trial. Such controlled studies are critical to defining the best techniques for HIPEC administration and the appropriate role for this treatment regimen in patients with peritoneal metastases. The development of a program in cytoreductive surgery and HIPEC requires a comprehensive patient care team led by appropriately trained surgeons. Such teams are best suited to provide the highest-quality care to patients with peritoneal surface malignancy.

Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020.

PURPOSE: To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. PATIENTS AND METHODS: Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. RESULTS: The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively). CONCLUSION: In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.

Reduced morbidity following cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion.

BACKGROUND: Cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (IPHC) are an aggressive treatment for patients with peritoneal based malignancies or those with peritoneal dissemination of select histology. Although promising, this therapeutic regimen has been associated with significant morbidity, long hospital stays, and, in some reports, moderate risk for perioperative mortality. Recent experience suggests that these outcomes may be improved. METHODS: Thirty-three patients underwent cytoreductive surgery and intraperitoneal hyperthermic perfusion during the period of December 1999 to July 2002. All patients underwent resection by a three-surgeon team, followed by IPHC with an open technique. Peritonectomy was performed with the goal of total gross excision of disease. RESULTS: Thirty-five procedures were performed in 33 patients (20 female) with a mean age of 49 years (range, 26-72). Complete cytoreduction was achieved in 22 cases (63%), and in 6 cases (17%) residual disease was <4 mm. There were nine major perioperative complications (27%) and no perioperative deaths. The median hospital stay was 11 days. CONCLUSIONS: These results demonstrate that cytoreductive surgery and IPHC can be performed with morbidity and mortality rates in line with those of other major oncologic operations. Employment of a three-surgeon approach, limited peritonectomy, and an open technique may help to reduce the morbidity from this aggressive treatment. Continued investigation of this promising treatment regimen is warranted.

Technology of intraperitoneal chemotherapy administration: a survey of techniques with a review of morbidity and mortality.

Peritoneal metastases are a common sequela of gastrointestinal malignancy. The treatment of peritoneal metastases through use of aggressive surgical cytoreduction including peritonectomy, coupled with IPHC has now been reported in several large single institution series. The available literature suggests that in experienced hands and with appropriate patient selection, cytoreduction, and IPHC can be an effective therapy, particularly when all macroscopic tumor deposits are removed. Different techniques involving the administration of intraperitoneal chemotherapy have been reported including early postoperative, closed intraoperative, the open or coliseum technique, and the open technique using a PCE device. All techniques have been associated with low mortality and morbidity that is significant, but generally consistent with other major surgical procedures. Commonly reported complications of IPHC include prolonged ileus, fistula, abscess, and thrombosis. In theory, the coliseum and PCE techniques may have less associated morbidity due to improved heat distribution, however, this remains to be definitively proven in a controlled clinical trial. Such controlled studies are critical to defining the best techniques of IPHC administration and the appropriate role for this treatment regimen in patients with peritoneal metastases.