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.

Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial. Objective: To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA. Design, Setting, and Participants: This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria. Interventions: Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2). Main Outcomes and Measures: The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review. Results: From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2. Conclusions and Relevance: This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT02562716.

Surgical Outcome Results From SWOG S1505: A Randomized Clinical Trial of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for Perioperative Treatment of Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear. METHODS: S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity. RESULTS: Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA. CONCLUSIONS: We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.

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.

Does radiologic response correlate to pathologic response in patients undergoing neoadjuvant therapy for borderline resectable pancreatic malignancy?

BACKGROUND AND OBJECTIVES: In patients with borderline resectable pancreas cancers, clinicians frequently consider radiographic response as the primary driver of whether patients should be offered surgical intervention following neoadjuvant therapy (NT). We sought to determine any correlation between radiographic and pathologic response rates following NT. METHODS: Between 2005 and 2015, 38 patients at a tertiary care referral center underwent NT followed by pancreaticoduodenectomy for borderline resectable pancreas cancer. Radiographic response after the completion of NT and pathologic response after surgery were graded according to RECIST and Evans' criteria, respectively. RESULTS: Preoperatively, 50% of patients underwent chemotherapy alone and 50% underwent chemotherapy and chemoradiation. Radiographically, one patient demonstrated a complete radiologic response, 68.4% (n = 26) of patients had stable disease (SD), 26.3% (n = 10) demonstrated a partial response, and one patient had progressive. Among patients without radiographic response, 77.7% (n = 21) achieved a R0 resection. Of patients with SD on imaging, 26.9% (n = 7) had Evans grade IIB or greater pathologic response. CONCLUSIONS: Our data indicate that approximately one-fourth of patients who did not have a radiologic response had a grade IIB or greater pathologic response. In the absence of metastatic progression, lack of radiographic down-staging following NT should not preclude surgery.

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.

Feasibility of a randomized trial of extended lymphadenectomy for pancreatic cancer.

HYPOTHESIS: The required sample size of a prospective randomized trial comparing standard pancreaticoduodenectomy with pancreaticoduodenectomy plus extended lymphadenectomy for pancreatic adenocarcinoma is prohibitively large, making such a trial infeasible. DESIGN: Retrospective cohort study. SETTING: Comprehensive cancer center. PATIENTS: We identified 158 patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma with separate pathologic analysis of second-echelon lymph nodes, defined as lymph nodes along the proximal hepatic artery and/or the great vessels. MAIN OUTCOME MEASURES: To estimate the sample size required for a randomized trial, we devised a biostatistical model with the following assumptions: extended lymphadenectomy can benefit only patients who (1) actually have disease removed from second-echelon nodes, (2) have microscopically negative (R0) primary tumor resection margins, and (3) do not have visceral metastatic (M0) disease. RESULTS: Seventy-six patients (48.1%) had negative first- and second-echelon lymph nodes, 65 (41.1%) had positive first-echelon and negative second-echelon lymph nodes, and 17 (10.8%) had positive first- and second-echelon lymph nodes. Patients with positive second-echelon lymph nodes had an R0 resection rate of 47.1%. At a median follow-up of 65.1 months, 4 patients with positive second-echelon lymph nodes were alive, but 3 had recurrent disease. This implies that only 1 patient (5.9%) with positive second-echelon lymph nodes may have had true M0 disease. Therefore, only 0.3% of patients (10.8% with positive second-echelon lymph nodes x 47.1% with R0 resection x 5.9% with M0 disease) may achieve a survival benefit from extended lymphadenectomy. A randomized trial of standard pancreaticoduodenectomy vs pancreaticoduodenectomy with extended lymphadenectomy would require 202 000 patients in each study arm to detect such a small difference. CONCLUSIONS: Definitive evaluation of the potential benefits of extended lymphadenectomy would require a prohibitively large sample size. Adequately powered randomized trials to address the potential benefit of extended lymphadenectomy are infeasible.

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.

Angiogenesis and antiangiogenic therapy of colon cancer liver metastasis.

The fact that tumor growth and metastatic spread relies on angiogenesis has been widely proven and accepted. The understanding of cancer biology and metastasis formation has led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of proangiogenic and antiangiogenic factors that favor angiogenesis. Colorectal cancer is one of the leading cancer deaths worldwide. Angiogenesis has been associated with colon cancer progression and metastatic spread, thereby significantly affecting patient survival. New experimental approaches that inhibit angiogenic processes have demonstrated promising antineoplastic effects on metastatic colorectal cancer and are partially being investigated in clinical trials. This review focuses on angiogenesis in colorectal cancer metastasis formation as a target for antiangiogenic therapy, describing the experience from experimental studies and current clinical trials.