Indications and outcomes for repeat cytoreductive surgery and heated intra-peritoneal chemotherapy in peritoneal surface malignancy.

INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is offered in specialist centres as a treatment for peritoneal surface tumours. Despite its demonstrated efficacy, intra-abdominal recurrence occurs in 31-57% of patients. The aim of this study is to review the early and long-term outcomes in patients who undergo repeat CRS/HIPEC. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database of patients who had undergone repeat CRS/HIPEC for appendiceal neoplasms and colorectal peritoneal metastases (CRPM) from 2003 to 2019 was performed at a single specialist centre. Data pertaining to both short term outcomes and survival were evaluated. RESULTS: Of 1259 patients who had undergone CRS/HIPEC, 84(6.7%) underwent repeat surgery: 45(53.6%) had pseudomyxoma peritonei (PMP) secondary to low grade appendiceal mucinous neoplasms (LAMN), 21(25.0%) had appendix carcinoma and 18(21.4%) had CRPM. Demographics, intra-operative findings and short-term outcomes were comparable across tumour types and between procedures. Median (95% CI) interval between procedures was 22.7(18.9-26.6) months and was comparable between tumour types. Median (95%CI) overall survival was not reached for the cohort overall or for those with PMP, but was 61.0(32.6-89.4) months for those with appendix cancer and 76.9(47.4-106.4) months for CRPM (p=<0.001). Survival was favourable in the PMP group (HR [95%CI] 0.044 [0.008-0.262]; p = 0.000) and unfavourable in the CC2-3 at index CRS procedure group (HR [95%CI] 25.612 [2.703-242.703]; p = 0.005). CONCLUSION: Our findings demonstrate that repeat cytoredutive surgery with HIPEC can result in favourable survival, especially for patients with PMP when complete cytoreduction is achieved at index operation. We recommend that detailed patient assessment is performed through an expert multidisciplinary team meeting (MDT).

Comparative effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for resected low-grade appendiceal mucinous neoplasm (LAMN): A protocol for systematic review and network meta-analysis.

BACKGROUND: Whether prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) offers long-term survival benefit to patients with low-grade appendiceal mucinous neoplasms (LAMNs) after resection surgery is still under heated debate. The aim of the present meta-analysis is to investigate the comparative effectiveness and safety of prophylactic HIPEC regimens in LAMNs METHODS:: A systematic search of MEDLINE, EMBASE, PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and controlledtrials.com will be performed. All published RCTs and quasi-RCTs through July 20, 2020 with language restricted in English will be included in this review study. Two reviewers will independently conduct the procedures of study identification, data collection, and methodological quality assessment. The primary outcomes are overall survival (OS) and disease-free survival (DFS). The secondary outcomes consist of peritonitis and sepsis, colonic fistula, chemotherapy-associated adverse events, and adhesive intestinal obstruction. The pooled odds ratios (ORs) or hazard ratios (HRs) and relative 95% confident intervals (CIs) of each outcome measurement will be calculated. EndNote X9 software will be applied to manage all citations. The Stata software version 14.0 and R x64 software version 3.5.1 will be employed for main statistical analyses. DISCUSSION: This study will employ a network meta-analysis to summarize direct and indirect evidence in the specific area to provide detailed individualized guidance on surgical management for LAMNs. REGISTRATION: This protocol was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on 25 July 2020 (registration number INPLASY202070112).

Management and prognostic prediction of appendiceal mucinous adenocarcinoma with peritoneal metastasis: a single center study in China.

BACKGROUND: To investigate the clinical and pathological characteristics of appendiceal mucinous adenocarcinoma with peritoneal metastasis and analyze the prognostic factors. METHODS: A retrospective analyses of clinicopathological features of 50 patients with appendiceal mucinous adenocarcinoma with peritoneal metastasis from January, 2013 to December, 2017 in Aerospace Central Hospital, Beijing, China. Survival data calculation and comparison were respectively performed with the Kaplan-Meier method and the log-rank test. The Cox proportional hazards regression method was used for multivariate survival analyses. RESULTS: Cytoreduction for appendiceal mucinous adenocarcinoma was conducted on 50 patients (24 males and 26 females), with a median age of 52.5 years at the time of surgery (range 31-71 years). The median overall survival (OS) time was 24 months, with 2-,3- and 5-year survival rates of 53, 24 and 8%, respectively. At the last follow-up in December 2018, 13 patients were still alive. Multivariate analysis revealed that patients who had low Ki-67 expression (less than 50%) and CCR (completeness of cytoreduction) 0/1/2 score had significantly better OS rate than their respective counterparts. CONCLUSIONS: Ki-67 expression statue and CCR score could be employed as the prognosis prediction in patients with appendiceal mucinous adenocarcinoma.

Improved Survival with Experience: A 10-Year Learning Curve in Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an aggressive locoregional treatment for peritoneal carcinomatosis (PC). Studies demonstrate improved perioperative and oncologic outcomes at high-volume centers. METHODS: This study retrospectively analyzed all patients with PC from various malignancies who underwent attempted CRS/HIPEC at the authors' institution from 2007 to 2017. Clinicopathologic, perioperative, and oncologic outcomes of early (2007-2012) and late (2012-2017) experience were compared, and multivariate analyses for factors predictive of perioperative and oncologic outcomes were performed. RESULTS: The study enrolled 388 patients (157 early and 231 late). The late experience contained more appendiceal low-grade mucinous neoplasms (LGMNs; 21% vs 9%) and had a lower Peritoneal Cancer Index (PCI; 10 vs 16). Moreover, achieving a similar rate of CC-0/1 required fewer organ resections, involved shorter operations (298 vs 347 min), and had lower estimated blood loss (EBL) (400 vs 200 ml) (p < 0.05). More procedures were aborted (20% vs 3%; p < 0.01). The late experience had fewer ICU admissions (13% vs. 55%) and a lower perioperative mortality rate (0% vs 3%) (p < 0.05). In the multivariate analyses, PCI and number of organ resections were independent predictors of multiple perioperative outcomes [EBL, operating room time, intensive care unit (ICU) admission, ICU length of stay (LOS), overall LOS]. Survival was significantly longer in the late cohort (median overall survival: NR vs 31 months; progression-free survival: 22 vs 11 months; p < 0.01), even after control for tumor histology. CONCLUSIONS: At the authors' high-volume center, with increased surgeon and institutional experience over time, perioperative and oncologic outcomes have improved significantly for patients undergoing CRS/HIPEC for PC.

Systemic chemotherapy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in patients with high-grade mucinous carcinoma peritonei of appendiceal origin.

BACKGROUND: The role of systemic chemotherapy (SC) before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in appendiceal high-grade mucinous carcinoma peritonei (HGMCP) is controversial. We analyzed the effect of SC prior to CRS/HIPEC in HGMCP. METHODS: A prospective database of CRS/HIPEC procedures for HGMCP without signet ring cells and with signet ring cells (HGMCP-S) from 1998 to 2017 was reviewed. Exclusion criteria was prior surgery >5 regions or >2 regimens of prior SC. Perioperative variables were analyzed. RESULTS: There were 140 HGMCP/HGMCP-S identified: 64 with prior SC (preSC) and 76 without (noSC). Groups were balanced for lymph node status, complete cytoreduction rate, disease burden, complications, and postoperative SC. PreSC had more HGMCP-S, moderately/poorly differentiated histology, and longer time-to-surgery (median: 6 vs 2 months, p < 0.001). Median overall survival (mOS) was 40 vs 86 and median progression-free survival (mPFS) was 19 vs 43 months for preSC vs noSC, respectively (p = 0.006 and p = 0.007). In HGMCP-S subanalysis, mOS was 25 vs 39 and mPFS 16 vs 29 months for preSC vs noSC, respectively (p = 0.188 and p = 0.063). In moderately/poorly differentiated histology subanalysis, mOS was 38 vs 56 and mPFS 18 vs 29 months in preSC vs noSC, respectively (p = 0.199 and 0.082). Prior SC was not linked to improved OS or PFS in non-signet ring HGMCP or well-differentiated histology subanalysis. CONCLUSION: Prior SC was not associated with less disease burden, better cytoreduction rates, or improved clinical outcomes in HGMCP, regardless of histopathologic subtype. Traditional SC agents may not be effective in HGMCP in the neoadjuvant setting.

Selection and Characteristics of Patients with Peritoneal Dissemination from Appendiceal Cancer with Exceptional/Poor Survival After CRS/HIPEC.

BACKGROUND: Survival in peritoneal dissemination from appendiceal cancer after complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) varies within each histopathologic subtype. Analyzing patients with unique responses may uncover the mechanisms behind their extreme outcomes. We proposed a method to identify retrospectively and to characterize patients who responded exceptionally well or very poorly within each histopathologic subtype. METHODS: Retrospective review of patients with low-grade mucinous carcinoma peritonei (LGMCP), high-grade MCP (HGMCP), and HGMCP with signet ring cells (HGMCP-S) with complete CRS/HIPEC (CC-0/1) was performed. Patients were divided by recurrence status. Median follow-up was calculated for each. Exceptional responders (ExR) were defined as alive without recurrence after median follow-up of the nonrecurrent group. Poor responders (PoR) were defined as disease recurrence before median follow-up of the recurrent group. Perioperative characteristics were analyzed. RESULTS: LGMCP, HGMCP, and HGMCP-S had 48 (41%), 19 (23%), and 7 (14%) ExR and 11 (10%), 20 (24%), and 20 (39%) PoR, respectively. All ExR had lower median PCI (26 vs. 36 [p = 0.004]; 13 vs. 33.5 [p < 0.001]; 3 vs. 29.5 [p = 0.001]). Fewer LGMCP and HGMCP ExR had abnormal tumor markers (36% vs. 90% [p = 0.003]; 22% vs. 74% [p = 0.003]). More HGMCP and HGMCP-S ExR had CC-0 (vs. CC-1) cytoreductions (84% vs. 50%, p = 0.041; 100% vs. 40%, p = 0.008). CONCLUSIONS: Stratifying patients by recurrence status and follow-up time successfully selects ExR and PoR within each histopathologic subtype. Perioperative characteristics of ExR versus PoR differ across histopathologic subtypes, except for disease burden. Genetic analysis may further elucidate differences and aid in the development of novel targeted therapies.

Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

BACKGROUND: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR. METHODS: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-ß, and PI3K). RESULTS: Mutation of genes within the WNT, P53, RTK-RAS, TGF-ß, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-ß pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-ß pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-ß pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-ß pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation. CONCLUSIONS: Mutation in genes within TGF-ß pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.

Discrimination of low- and high-grade appendiceal mucinous neoplasms by targeted sequencing of cancer-related variants.

DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). There were significantly more damaging variants in high-grade versus low-grade tumor cohorts. Both cohorts contained damaging, heterozygous germline variants (catenin ß1; notch receptor 1 and 4) in pathways associated with cell-lineage specification (WNT, NOTCH). Damaging, somatic KRAS proto-oncogene, GTPase mutations were present in both cohorts, while somatic GNAS complex locus mutations were confined to low-grade neoplasms. Variants predominantly affected transcription factors, kinases, and stem cell signaling molecules in canonical pathways including epithelial to mesenchymal transition, stem cell pluripotency, p53, PTEN, and NF-қB signaling pathways. High-grade tumors demonstrated MYC proto-oncogene, bHLH transcription factor (MYC) and death domain associated protein (DAXX) amplification and damaging somatic variants in tumor protein p53 (TP53), likely to amplify an aggressive phenotype. Damaging APC, WNT signaling pathway regulator (APC) deletions were identified in metastatic tissue of both cohorts suggesting a role in invasive disease. Our data suggest that germline dysregulation of WNT and/or NOTCH pathways predisposes patients toward a secretory cell phenotype (i.e., goblet-like cells) upon acquisition of somatic KRAS mutations. Additional somatically acquired variants activating oncogenes MYC and DAXX and inhibiting the critical tumor suppressor, tumor protein TP53, were consistent with manifestation of a high-grade phenotype. These additional changes within the epithelial to mesenchymal transition signaling network (WNT, NOTCH, RAS/ERK/PI3K, PTEN, NF-қB), produce aggressive high-grade tumor characteristics by actively driving cells towards dedifferentiation, proliferation, and migration.

Long term survival analysis after hyperthermic intraperitoneal chemotherapy with oxaliplatin as a treatment for appendiceal peritoneal carcinomatosis.

BACKGROUND AND OBJECTIVES: Complete cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) have been proven to lengthen survival in appendiceal peritoneal carcinomatosis (PC-A). The aim of this study was to analyze survival results of this therapy in our institution over the last 10 years. METHODS: Data was retrospectively reviewed and analyzed. Treatment consisted of CRS plus HIPEC with oxaliplatin. Ronnett's histologic classification was used (peritoneal mucinous carcinomatosis (PMCA), PMCA with intermediate features (PMCA-I) and disseminated peritoneal adenomucinosis (DPAM)). Overall survival (OS) and disease-free survival (DFS) estimates were calculated using Kaplan-Meier survival curves. RESULTS: 109 patients with PC-A underwent laparotomy with curative intent. Of those, 92 underwent CRS plus HIPEC. Median follow-up was 42 months. The 5 and 10-year OS rates for the HIPEC group were 82.2% and 76.5%. The 5 and 10-year OS estimates for DPAM and PMCA-I subgroups were 100% and 100%, 78.1% and 72.9%, respectively. For the PMCA subgroup, the 3 and 5-year OS were 61.4% and 40.1%, respectively. The 5 and 10-year DFS estimates were 71.9% and 42.7%. CONCLUSION: CRS plus HIPEC with oxaliplatin represent an effective therapeutic approach for PC-A. Long term OS estimates for patients treated at our institution are encouraging.

Outcomes of Low-Grade Appendiceal Mucinous Neoplasms with Remote Acellular Mucinous Peritoneal Deposits.

BACKGROUND: Occasionally, low-grade appendiceal mucinous neoplasms (LAMN) present with mucinous peritoneal deposits (MPD) localized to periappendiceal tissue or diffused throughout the peritoneum. OBJECTIVE: This study was aimed at evaluating the relevance of mucin cellularity for predicting outcomes of LAMN with remote MPD. METHODS: The records of patients with LAMN and remote MPD who underwent initial assessment at a comprehensive cancer center from 1990 to 2015 were reviewed, and diagnostic procedures, treatments, and outcomes were analyzed. RESULTS: Of 48 patients included in the analysis, 19 had cellular MPD (CMPD) and 29 had acellular MPD. Of 33 patients who underwent cytoreductive surgery, 30 had a complete cytoreduction; the 3 patients with an incomplete cytoreduction had CMPD. In the follow-up period (median, 4 years), 6 patients died of the disease, all of whom had CMPD. Of 11 patients who had progression of disease, 10 had CMPD. CONCLUSION: Cellularity of remote MPD is an important determinant of disease outcome in LAMN. Approaches such as active surveillance may have a role in selected patients with LAMN and AMPD.

Long-term Survival and Propensity Score Matched Outcomes of Bilateral vs. Unilateral Diaphragm Interventions in Cytoreductive Surgery plus Intra-peritoneal Chemotherapy.

BACKGROUND/AIM: To assess the impact of short- and long-term outcomes of bilateral vs. unilateral diaphragm interventions in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC). PATIENTS AND METHODS: A total of 652 CRS/IPC procedures, between 1996 and 2018, required diaphragm interventions. Among these, 388 underwent bilateral intervention. Preoperative heterogeneity was assessed in 6 parameters and addressed with propensity score matching. The association of each respective analysis was assessed with 11 outcomes. Overall survival was assessed based on histology. RESULTS: CRS/IPC requiring bilateral diaphragmatic interventions illustrated significantly increased operative hours (9.6 vs. 8.6 hours, p<0.001). Postoperatively, there was significantly increased red blood cell (RBC) transfusion (6.37 units vs. 4.47 units, p=0.007) and grade III and IV complications (57.3% vs. 40.6%, p=0.004). No difference was noted in ICU stay, total length of stay, hospital death and return to OT. In terms of respiratory complications, an increased incidence of pneumothorax (16.5% vs. 6.2%, p<0.001) was noted whilst pleural effusions and pneumonia occurrences were non-significant. Overall survival, revealed bilateral interventions in low-grade appendiceal mucinous neoplasm conferred an increased relative risk (p=0.037, RR=2.230, 95%CI=1.052-4.730). They did not have an effect on OS in colorectal cancer and mesothelioma. CONCLUSION: Despite the increase in short-term morbidity, bilateral diaphragm interventions resulted in similar long-term survival to unilateral interventions.

Outcomes of Surgical and Chemotherapeutic Treatments of Goblet Cell Carcinoid Tumors of the Appendix.

BACKGROUND: Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a population-based cohort. METHODS: Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. RESULTS: Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). CONCLUSIONS: In this population-based cohort, we demonstrate excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.

Metachronous Peritoneal Metastases After Adjuvant Chemotherapy are Associated with Poor Outcome After Cytoreduction and HIPEC.

INTRODUCTION: Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve the survival of colorectal cancer (CRC) patients with peritoneal metastases. Patient selection is key since this treatment is associated with high morbidity. Patients with peritoneal recurrence within 1 year after previous adjuvant chemotherapy are thought to benefit less from HIPEC treatment; however, no published data are available to assist in clinical decision making. This study assessed whether peritoneal recurrence within 1 year after adjuvant chemotherapy was associated with survival after HIPEC treatment. METHODS: Peritoneal recurrence within 1 year after adjuvant chemotherapy, as well as other potentially prognostic clinical and pathological variables, were tested in univariate and multivariate analysis for correlation with primary outcomes, i.e. overall survival (OS) and disease-free survival (DFS). Two prospectively collected databases from the VU University Medical Center Amsterdam and Catherina Hospital Eindhoven containing 345 CRC patients treated with the intent of HIPEC were utilized. RESULTS: High Peritoneal Cancer Index (PCI) scores were associated with worse DFS [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00-1.08, p = 0.040] and OS (HR 1.11, 95% CI 1.07-1.15, p < 0.001) in multivariate analysis. Furthermore, patients with peritoneal recurrence within 1 year following adjuvant chemotherapy had worse DFS (HR 2.13, 95% CI 1.26-3.61, p = 0.005) and OS (HR 2.76, 95% CI 1.45-5.27, p = 0.002) than patients who did not receive adjuvant chemotherapy or patients with peritoneal recurrence after 1 year. CONCLUSION: Peritoneal recurrence within 1 year after previous adjuvant chemotherapy, as well as high PCI scores, are associated with poor survival after cytoreduction and HIPEC. These factors should be considered in order to avoid high-morbidity treatment in patients who might not benefit from such treatment.

Predictive value of peritoneal cancer index for survival in patients with mucinous peritoneal malignancies treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a single centre experience.

OBJECTIVES: This study investigated the correlation between the peritoneal carcinomatosis index (PCI) and patient outcome depending on the tumour type. BACKGROUND: Peritoneal surface malignancy (PSM) treatment depends on tumour type. Mucinous PSM (m-PSM) is associated with a better prognosis than non-mucinous PSM (nm-PSM). The PCI's predictive ability has not yet been evaluated. METHODS: We analysed 123 patients with PSM treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) between 2008 and 2015. The m-PSM group (n = 75) included patients with appendiceal cancer (n = 15), colorectal cancer (n = 21), or low-grade appendiceal mucinous neoplasm (n = 39); the nm-PSM group (n = 48) included patients with gastric (n = 18) or colorectal (n = 30) cancer. The PCI's predictive ability was evaluated by multiple Cox-proportional hazard regression analysis and Kaplan-Meier curves. RESULTS: The 5-year survival and PCI were higher in m-PSM patients (67.0%; 20.5 ± 12.1) than in nm-PSM patients (32.6%; p = 0.013; 8.9 ± 6.0; p < 0.001). Colorectal nm-PSM patients with PCI ≥16 had a worse 2-year survival (25.0%) vs. patients with PCI <16 (79.1%; log rank = 0.009), but no significant effect was observed in patients with m-PSM (66.7% vs. 68.1%; p = 0.935). Underlying disease (HR 5.666-16.240), BMI (HR 1.109), and PCI (HR 1.068) significantly influenced overall survival in all patients. CONCLUSIONS: PCI is prognostic in nm-PSM, but not in m-PSM. CRS and HIPEC may benefit not only patients with low PCI, but also those with high PCI and m-PSM.

Histologic Predictors of Recurrence in Mucinous Appendiceal Tumors with Peritoneal Dissemination after HIPEC.

BACKGROUND: Mucinous appendiceal tumors (MAT) are rare neoplasms that can metastasize to the peritoneum and often are treated with cytoreductive surgery (CRS) and HIPEC. Pathologic classification and outcomes vary, but standardized histologic definitions are emerging. We sought to evaluate outcomes in this disease after CRS/HIPEC using standardized pathologic criteria. METHOD: Outcomes of MAT with peritoneal metastases (PM) after CRS/HIPEC from 2007 to 2015 were reviewed at our institution. Standardized histologic categories per WHO and consensus definitions were used: low-grade appendiceal mucinous neoplasm (LAMN), low-grade adenocarcinoma (LGAC), or high-grade adenocarcinoma (HGAC) primary tumors; and acellular mucin (AM), low-grade mucinous carcinoma peritonei (LGMCP), or high-grade mucinous carcinoma peritonei (HGMCP) peritoneal metastases. Cox proportional hazards model was used identify predictors of progression-free survival (PFS) by univariate and multivariate analyses. RESULTS: A total of 183 patients undergoing 197 CRS/HIPECs were included. Among 75 patients with primary histology review, there were 33 (44.0%) LAMNs, 28 (37.3%) LGACs, and 14 (18.7%) HGACs. Peritoneal histology was benign in 6 (3.0%), AM in 33 (16.8%), LGMCP in 114 (57.9%), and HGMCP in 44 (22.3%). PFS was not reached for AM, 34.3 months for LGMCP, and 16.8 months for HGMCP (p < 0.001). Peritoneal histology predicted PFS on multivariate analysis (hazard ratio 9.82 and 24.60 for LGMCP and HGMCP, respectively, vs. AM, p < 0.001). Among the LGMCP group, CEA and completeness of cytoreduction (CC score) predicted PFS on multivariate analysis. CONCLUSIONS: Standardized peritoneal histology in patients with PM from MAT predicts PFS and patients with low-grade histology can be further discriminated by CEA and CC score.

CA 19-9 to peritoneal carcinomatosis index (PCI) ratio is prognostic in patients with epithelial appendiceal mucinous neoplasms and peritoneal dissemination undergoing cytoreduction surgery and intraperitoneal chemotherapy: A retrospective cohort study.

BACKGROUND: Serum tumour levels have been shown to be prognostic in patients with epithelial appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei (PMP)). A singular index which incorporates both tumour activity (as depicted by serum tumour marker levels) and tumour volume (as depicted by peritoneal carcinomatosis index (PCI)), may give a more precise surrogate of tumour biological behaviour. The prognostic implication of this index has not yet been reported. METHODS: A retrospective cohort study of all patients with PMP managed from 1996 to 2016 with cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) was performed by analysing the survival effect of the ratio of preoperative serum CEA, CA19.9 and CA125 to PCI. RESULTS: Three hundred and eighty-six patients were included. In patients with low-grade PMP, elevated CA19-9/PCI ratio resulted in poorer median overall survival times (104 months vs NR, 95%CI 83 - NR, log-rank p < 0.001) and was an independent predictor of reduced overall survival on multivariable analysis (adjusted HR 5.60, 95%CI 1.60-19.68, p = 0.007). In patients with high-grade PMP, no statistically significant difference in survival was recognised. CONCLUSION: CA19-9/PCI ratio is an independent prognostic factor for overall survival in patients with low-grade PMP undergoing CRS and IPC. By accounting for both tumour activity and tumour volume simultaneously, this novel index behaves as a surrogate of tumour biology and provides a useful adjunct for decisions regarding treatment allocation in this patient group.

Perioperative systemic chemotherapy for peritoneal mucinous appendiceal carcinomas treated with cytoreductive surgery & HIPEC.

PURPOSE: To identify the role of systemic chemotherapy in the management of appendiceal malignancies. METHODS: Over a 10-year period (2005 -2014), 52 patients with appendiceal neoplasms were treated at our Peritoneal Surface Malignancy Unit [14 (26.9%) disseminated peritoneal adenomucinosis (DPAM), 30 (57.7%) peritoneal mucinous carcinomatosis of appendiceal origin (PMCA) and 8 (15.4%) PMCA-I]. All patients (100%) underwent cytoreductive surgery (CRS) & hyperthermic intraperitoneal chemotherapy (HIPEC), while 20 (38.5%) of them also received perioperative systemic chemotherapy. RESULTS: Mean peritoneal cancer index (PCI) was 23.6. Completeness of cytoreduction score (CC-S) was: CC-0 in 26 patients (50%), CC-1 in 20 patients (38.5%) and CC-2 in 6 patients (11.5%). High grade malignancy was reported in 27 patients (51.9%) and low grade malignancy in 25 patients (48.1%). More than half of the patients developed recurrence (n=36, 69.2%), while death was reported in 40.4% (n=21). Median overall survival (OS) in all histologic groups was 24 months for patients who received perioperative systemic chemotherapy and 14 months for patients who did not (p=0.048). Median disease free survival (DFS) in all histologic groups was 19 months for patients who received perioperative systemic chemotherapy and 10 months for patients who did not (p=0.034). CONCLUSION: We suggest that perioperative systemic chemotherapy serves as a helpful therapeutic tool in the management of peritoneal mucinous appendiceal carcinomas treated with cytoreductive surgery & HIPEC.

Histological Subtype Remains a Significant Prognostic Factor for Survival Outcomes in Patients With Appendiceal Mucinous Neoplasm With Peritoneal Dissemination.

BACKGROUND: It has been increasingly recognized that appendiceal mucinous neoplasm with peritoneal dissemination is not a homogenous disease. OBJECTIVE: This study aimed to examine the impact of different histological subtypes on survival of a large cohort of patients with appendiceal mucinous neoplasms uniformly treated by cytoreductive surgery and intraperitoneal chemotherapy. DESIGN: This was a retrospective study of prospectively collected data of patients with peritoneal dissemination of appendiceal neoplasm who underwent cytoreductive surgery and intraperitoneal chemotherapy. SETTING: The study was conducted by 1 surgical team at St. George Hospital. PATIENTS: A total of 444 patients formed the cohort of this study. MAIN OUTCOME MEASURES: Histological diagnoses were categorized based on Carr criteria to include acellular mucin, disseminated peritoneal adenomucinosis, peritoneal mucinous neoplasms without signet ring cells, and peritoneal mucinous carcinomatosis with signet cells. RESULTS: Patients with low-grade appendiceal mucinous neoplasms with neoplastic epithelium absent tended to have lower CEA, CA19-9, and CA125 levels preoperatively (p = 0.109, 0.008, and 0.034). Factor analysis showed that histological diagnosis was an independent prognostic factor for survival outcomes (HR = 3.13 (95% CI, 2.34-4.39); p < 0.001), adjusted for peritoneal cancer index >20, completeness of cytoreductive score ≥2, use of early postoperative intraperitoneal chemotherapy, transfusion units, CEA >7.0 mg/L, CA19-9 >24.0 U/mL, and CA125 >24 U/mL. LIMITATIONS: This study was limited by its retrospective nature, lack of uniform classifications of appendiceal mucinous neoplasms in early years, and the heterogeneity of this study cohort given the long study period. CONCLUSIONS: Histological subtype remains a significant prognostic factor for survival outcomes in patients with appendiceal mucinous neoplasms. It should be taken into account when selecting patients for cytoreductive surgery, tailoring appropriate adjuvant therapies and follow-up surveillance plan.

Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Patients with High-Grade, High-Volume Disseminated Mucinous Appendiceal Neoplasms.

BACKGROUND: High-grade (HG) mucinous appendiceal neoplasms (MAN) have a worse prognosis than low-grade histology. Our objective was to assess the safety and efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) in patients with high-grade, high-volume (HG-HV) peritoneal metastases in whom the utility of this aggressive approach is controversial. METHODS: Prospectively collected perioperative data were compared between patients with peritoneal metastases from HG-HV MAN, defined as simplified peritoneal cancer index (SPCI) ≥12, and those with high-grade, low-volume (HG-LV; SPCI <12) disease. Kaplan-Meier curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes. RESULTS: Overall, 54 patients with HG-HV and 43 with HG-LV peritoneal metastases underwent CRS/HIPEC. The HG-HV group had longer operative time, increased blood loss/transfusion, and increased intensive care unit length of stay (p < 0.05). Incomplete macroscopic cytoreduction (CC-1/2/3) was higher in the HG-HV group compared with the HG-LV group (68.5 vs. 32.6 %; p = 0.005). Patients with HG-HV disease demonstrated worse survival than those with HG-LV disease (overall survival [OS] 17 vs. 42 m, p = 0.009; time to progression (TTP) 10 vs. 14 m, p = 0.024). However, when complete macroscopic resection (CC-0) was achieved, the OS and progression-free survival of patients with HG-HV disease were comparable with HG-LV disease (OS 56 vs. 52 m, p = 0.728; TTP 20 vs. 19 m, p = 0.393). In a multivariate Cox proportional hazard regression model, CC-0 resection was the only significant predictor of improved survival for patients with HG-HV disease. CONCLUSIONS: Although patients with HG-HV peritoneal metastases from MAN have worse prognosis compared with patients with HG-LV disease, their survival is comparable when complete macroscopic cytoreduction is achieved.

Hyperthermic intraperitoneal chemotherapy + early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved survival for colorectal and high-grade appendiceal carcinomatosis. We compared the overall and recurrence-free survival (OS and RFS) of patients treated with HIPEC with mitomycin c and early postoperative intraperitoneal chemotherapy (EPIC) with fluorouracil versus HIPEC alone using oxaliplatin and simultaneous IV infusion of fluorouracil. METHODS: Ninety-three patients with colorectal or high-grade appendiceal carcinomatosis were treated with CRS and HIPEC + EPIC or HIPEC alone. OS and RFS were analyzed using Kaplan-Meier curves and log-rank testing. RESULTS: Survival did not differ between HIPEC regimens. The 3-year OS and RFS rates were 50% and 21% for HIPEC + EPIC and 46% and 6% for HIPEC alone (P = .72 and P = .89, respectively). HIPEC + EPIC patients experienced more grade III/IV complications (43.2% vs 19.6%, P = .01). CONCLUSIONS: There was no difference in OS and RFS between colorectal and high-grade appendiceal adenocarcinoma patients treated with CRS and HIPEC + EPIC versus HIPEC alone. However, HIPEC + EPIC patients suffered greater morbidity, making HIPEC alone the preferable regimen.