A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.

BACKGROUND: Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. METHODS: Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. FINDINGS: Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. CONCLUSION: Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

Health-Related Quality of Life After Cytoreductive Surgery/HIPEC for Mucinous Appendiceal Cancer: Results of a Multicenter Randomized Trial Comparing Oxaliplatin and Mitomycin.

BACKGROUND: This study evaluated health-related quality of life (HRQOL) using patient-reported outcomes in subjects with mucinous appendiceal neoplasms who underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as part of a randomized trial comparing mitomycin with oxaliplatin. METHODS: In this prospective multicenter study, 121 mucinous appendiceal cancer patients, with evidence of peritoneal dissemination who underwent CRS, were randomized to receive mitomycin (divided 40 mg) or oxaliplatin (200 mg/m2) for HIPEC. The Functional Assessment of Cancer Therapy Neurotoxicity (FACT-G/NTX) questionnaire was utilized to assess HRQOL. The Trial Outcome Index (TOI) is a summary index responsive to changes in physical/functional outcomes. Repeated measures mixed models with an unstructured variance matrix were applied to assess changes in HRQOL longitudinally. RESULTS: Baseline questionnaire compliance was 95.9%. Baseline physical well-being (PWB) was independently associated with overall survival (hazard ratio 0.79, 95% confidence interval 0.66-0.96; p = 0.017). The TOI was significantly lower in the mitomycin group compared with the oxaliplatin arm at 12 weeks (p = 0.044; score difference 6.35) and 24 weeks after surgery (p = 0.049; score difference 5.61). At 12 weeks after surgery, declines from baseline were significant in the TOI (p = 0.004; score decline 8.99), PWB (p < 0.001; score decline 2.83), and FWB (p < 0.001; score decline 3.42) in the mitomycin group but not the oxaliplatin group. CONCLUSIONS: Compared with mitomycin, HIPEC perfusion with oxaliplatin results in significantly better physical and functional outcomes. With similar survival outcomes and complication rates, oxaliplatin should be considered as the chemoperfusion agent of choice in mucinous appendiceal cancer patients undergoing CRS/HIPEC.

P.R.O.P.S. - A novel Pre-Operative Predictive Score for unresectability in patients with colorectal peritoneal metastases being considered for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Twenty to thirty percent of planned cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC) procedures are abandoned intra-operatively. Pre-operative factors associated with unresectability identified previously were used to develop a Pre-Operative Predictive Score (PROPS), which was compared with current selection criteria-Peritoneal Surface Disease Severity Score (PSDSS), Verwaal's Prognostic Score (PS) and Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), to determine which score provides the best prediction for unresectability. METHODS: Fifty-six patients with peritoneal metastases of colorectal origin were included. Beta-coefficient values of significant variables (p < 0.05) were determined from multivariate analysis to develop PROPS. PROPS, PSDSS, PS and COMPASS were compared using a receiver operating characteristic curve to calculate its accuracy, sensitivity and specificity. RESULTS: PROPS consisted of nine patient and tumour factors which were categorised into three groups: (i) poor tumour biology: previous inadequate resection, underwent multiple lines of chemotherapy and poorly differentiated or signet cell histology; (ii) heavy tumour burden: abdominal distension, palpable abdominal mass and computed tomography findings of ascites, small bowel disease and/or omental thickening; and (iii) active tumour proliferation: elevated tumour markers. Overall, PROPS achieved 86% accuracy with 100% sensitivity and 68% specificity, PSDSS achieved 85% accuracy with 100% sensitivity and 63% specificity, PS achieved 73% accuracy with 100% sensitivity and 68% specificity and COMPASS achieved 61% accuracy with 27% sensitivity and 100% specificity. CONCLUSIONS: PROPS is more effective in predicting unresectability as compared to PSDSS, PS and COMPASS, and has the added advantage of using solely pre-operative factors.

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 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.

Can low grade PMP be divided into prognostically distinct subgroups based on histological features? A retrospective study and the importance of using the appropriate classification.

INTRODUCTION: The pathological classification of PMP of appendiceal origin has prognostic and treatment implications. Our goals were to • Classify low grade mucinous carcinoma peritonei (LGMCP) into prognostically distinct subgroups based on histological features. • Compare the reproducibility of the WHO and the PSOGI classifications for both PMP and the appendiceal primary tumor. PATIENTS AND METHODS: A retrospective analysis of patients undergoing CRS and HIPEC or debulking surgery was done. All the tumors were re-classified according to the PSOGI classification. LGMCP was further classified into three histological subgroups and the impact on survival was evaluated. RESULTS: From Jun 2011 to June 2016, 101 patients underwent CRS with HIPEC (n = 89) or debulking surgery (n=12). The median PCI was 28 (3-39) and 74.1% patients had CC-0/1 resections. Of the 76.2% patients who had LGMCP, 4 patients (5.1%) were classified as group 1, 54 (70.1%) as group 2 and 19 patients (24.6%) as group 3. At a median follow up of 21 months, the disease free survival was not reached, 30 months and 14 months for groups 1, 2 and 3 respectively (p = 0.09). There was no difference in overall survival. Using the WHO classification, there was a discordance in the grade of the primary tumor and the peritoneal lesions in 19.8% and conflicting terminology was used in 62% of patients. CONCLUSIONS: The subgroups of LGMCP described here are prognostically different though this needs further prospective evaluation in larger series. The PSOGI classification is more uniformly reproducible and should be preferred to the WHO classification.

Impact of ovarian metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancy originating from appendiceal and colorectal cancer.

AIM: Ovarian metastases from gastrointestinal tract malignancies have been considered an ominous finding with poor prognosis. The aim of this project was to determine the impact on survival, and potential cure, when cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal malignancy in women with Krukenberg tumours. METHOD: A retrospective analysis of prospectively collected data between January 2010 and July 2015. Female patients undergoing complete CRS (macroscopic tumour removal) and HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin, or colorectal peritoneal metastases (CPM) were included. Survival was estimated using the Kaplan-Meier method and survival rates compared using the log-rank test. RESULTS: In total, 889 patients underwent surgery for peritoneal malignancy, of whom 551 were female. Of these, 504/551 (91%) underwent complete CRS and HIPEC. Overall, 405/504 (80%) had at least one involved ovary removed either during CRS and HIPEC or at their index prereferral operation. Three hundred and fifty-two patients (87%) had an appendiceal tumour and 53 (13%) had CPM. At a median follow up of 40 months, overall survival (OS) did not differ significantly between patients with or without ovarian involvement in women with a primary low-grade appendiceal tumour or CPM. In women with high-grade primary appendiceal pathology, OS was significantly lower in patients with ovarian metastases compared with those without ovarian involvement. CONCLUSION: Women with ovarian metastases from low-grade appendiceal tumours or colorectal cancer treated with CRS and HIPEC have similar survival rates to patients without ovarian metastases. Long-term survival and cure is feasible in patients amenable to complete tumour removal.

Risk Factors for Peritoneal Recurrence in Stage II to III Colon Cancer.

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil-based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

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.

Validation of the Recent PSOGI Pathological Classification of Pseudomyxoma Peritonei in a Single-Center Series of 265 Patients Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Controversies still persist regarding the terminology and pathologic classification of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei (PMP). We assessed reproducibility and prognostic significance of the classification recently proposed by the Peritoneal Surface Oncology Group International (PSOGI). METHODS: A prospective database of 265 PMP patients uniformly treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) from 1995 to 2017 was reviewed. According to the PSOGI, peritoneal disease was retrospectively classified into three categories: low-grade (LG-PMP), high-grade (HG-PMP), and signet-ring cells (SRC-PMP). Acellular mucin (AC) was classified separately. The extent of peritoneal involvement was quantified by the peritoneal cancer index (PCI). RESULTS: Twenty-six patients were diagnosed with AC (9.8%), 197 with LG-PMP (74.4%), 38 with HG-PMP (14.3%), and 4 with SRC-PMP (1.5%). In the overall series, median follow-up was 65.5 months (95% confidence interval 53.7-78.8) and 10-year overall survival was 62.9% (median 148.7 months). Operative death occurred in 10 patients (3.8%) and major complications occurred in 89 patients (33.6%). Ten-year survival was 89.6% for AC, 63.2% for LG-PMP, 40.1% for HG-PMP, and 0 for SRC-PMP. In a multivariate model, the World Health Organization (WHO) pathological classification independently correlated with survival (p = 0.028). In a separate model, the PSOGI classification did not reach statistical significance (p = 0.149). Completeness of cytoreduction and PCI > 22 correlated with prognosis in both models. CONCLUSIONS: AC and SRC-PMP pathological categories of the PSOGI classification identified two subsets of patients with favorable and exceedingly dismal prognosis, respectively. It remains unclear whether the PSOGI classification might provide better prognostic stratification than the current WHO classification. Further studies in larger prospective series are needed.

External Validation of the Prognostic Nomogram (COMPASS) for Patients with Peritoneal Carcinomatosis of Colorectal Cancer.

BACKGROUND: To optimize outcome, selection of patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is critical. Recently, Simkens et al.7 evaluated the peritoneal surface disease severity score (PSDSS) and suggested a new prognostic nomogram, the colorectal peritoneal metastases prognostic surgical score (COMPASS) based on age, peritoneal carcinomatosis index score, locoregional lymph node status, and signet ring cell histology. This COMPASS nomogram had better discriminative ability according to the Harrell c-index than PSDSS (c = 0.72 vs. 0.62). This study aimed to validate the COMPASS nomogram externally. METHODS: Data were retrieved from a prospectively maintained database, and all patients who underwent surgery between May 2005 and May 2016 were included in the study. For each patient, the PSDSS and COMPASS were calculated and then divided into subgroups. The discriminative ability of both scores for overall survival were quantified using Harrell c indices. RESULTS: A total of 153 patients underwent CRS + HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. The median overall survival (OS) was 46 months, and the mean PSDSS was 7.8 ± 3.7. When the PSDSS was divided into subgroups, the c index was 0.67. The mean COMPASS was 55.5 ± 25.6. When the patients were divided into four groups according to cutpoints of Simkens et al.7 a c index of 0.72 was obtained, showing its significant superiority over the discriminative ability of the PSDSS (p = 0.016). CONCLUSION: External validation of the COMPASS confirms its moderate to good discriminative ability and its superiority over the PSDSS. Nevertheless, discrimination with the COMPASS score remains suboptimal, and further research on prognostic variables is essential for optimal patient selection.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Moderately and Poorly Differentiated Appendiceal Adenocarcinoma: Survival Outcomes and Patient Selection.

BACKGROUND: Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death. METHODS: Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes. RESULTS: Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011). CONCLUSIONS: In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.

Risk of Ovarian Involvement in Advanced Colorectal or Appendiceal Tumors Involving the Peritoneum.

BACKGROUND: Ovarian metastases of GI tumors grow rapidly and are relatively resistant to systemic chemotherapy. They may be unilateral or bilateral and macroscopic or occult. The risk of macroscopic ovarian involvement or occult involvement of macroscopically normal ovaries is unquantified. OBJECTIVE: This study aims to quantify the risks of ovarian involvement in patients with peritoneal malignancy undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. DESIGN: This was a retrospective analysis of a dedicated prospective malignancy database. SETTINGS: This study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Female patients with at least 1 remaining ovary, undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal tumors or colorectal peritoneal metastases between January 2010 and March 2015 were included. OUTCOME MEASURES: Data regarding ovarian involvement was extracted from surgical and histological records. RESULTS: Two hundred fifty-eight female patients with at least 1 ovary underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy during the study period. In total, 141 of 258 (54.7%) patients had ovarian tumor involvement, and 80% with at least 1 macroscopically abnormal ovary had bilateral involvement. Of 40 patients with 1 macroscopic ovarian metastasis, microscopic involvement of the contralateral ovary was found in 18 of 40 (45.0%). Of 141 patients in whom both ovaries were macroscopically normal, 24 of 141 (17.0%) patients had microscopic ovarian involvement. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Occult malignancy was present in 17% when both ovaries looked macroscopically normal and in 45% of contralateral normal-looking ovaries if the other ovary was macroscopically involved. These results help to inform preoperative consent and intraoperative decision making in patients with advanced appendiceal and colorectal malignancy, and are of benefit in managing advanced lower GI tract malignancy.

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.

External Validation of the Simplified Preoperative Assessment for Low-Grade Mucinous Adenocarcinoma of the Appendix.

BACKGROUND: MD Anderson Cancer Center developed a computed tomography (CT)-based preoperative assessment tool simplified preoperative assessment for appendix tumor (SPAAT) for predicting incomplete cytoreduction (IC) in low-grade mucinous adenocarcinoma (LGMA) of the appendix, based on preoperative CT scans. This study independently evaluates the tool's performance. METHODS: Seventy-six preoperative CT scans of LGMA patients were evaluated by two surgeons unfamiliar with the patients' medical history. Scores were assigned based on SPAAT criteria, with a SPAAT ≥3 predictive of IC. Binary regression analyses and area under the receiver operating characteristic (AUROC) curve analyses were performed. Patients with splenic resection were excluded due to the structure of the SPAAT assessment tool. RESULTS: Seventy-six LGMA patients underwent attempted cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Of 68 patients, 58 had complete cytoreduction and 10 had IC; 8 patients were ineligible due to prior splenectomy. The mean SPAAT score was 0.8, with six patients having SPAAT scores ≥3. SPAAT scores ≥3 were predictive of IC, with a hazard ratio (HR) of 19 (95% confidence interval 2.8-124.1) (p = 0.002). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were 40, 97, 50, and 90%, respectively. A SPAAT score ≥3 was not associated with worse survival prognosis. Median follow-up was 2.4 years and AUROC curve was 71%. SPAAT components with respective HR and p-values were foreshortening of the bowel mesentery (29.5; p = 0.004), and scalloping of the pancreas (9; p = 0.008), spleen (4.3; p = 0.04), portal vein (3.1; p = 0.4), and liver (2.1; p = 0.3). CONCLUSION: A SPAAT score ≥3 predicted IC based on a binary regression model. The clinical value of this score is controversial due to low sensitivity and PPV.

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

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

Adverse Events Postoperatively Had No Impact on Long-Term Survival of Patients Treated with Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy for Appendiceal Cancer with Peritoneal Metastases.

BACKGROUND: Appendiceal cancer most commonly metastasizes to the peritoneum. Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) is the standard of care for appendiceal cancer with peritoneal metastases. Adverse events postoperatively have been associated with reduced survival. We analyzed clinical outcomes, including complications after CRS and HIPEC in patients with appendiceal cancer, in a recent cohort of patients to identify prognostic factors. METHODS: Patients undergoing CRS with HIPEC for appendix cancer with peritoneal metastases between January 2007 and December 2009 were identified. Prospectively collected data were analyzed, including preoperative, intraoperative, and postoperative variables, and multivariate Cox regression models were developed to identify factors independently predicting overall survival (OS). RESULTS: A total of 133 consecutive patients with a median age of 51 years were analyzed; 53.4 % were female. Pre-, intra-, and postoperative clinical variables analyzed for their impact on survival included sex, age, prior surgical score, Peritoneal Cancer Index, completeness of cytoreduction score, histology, lymph node metastases, operative time, blood transfusion, fresh frozen plasma transfusion, perioperative chemotherapy, postoperative complications, length of hospitalization, and disease recurrence. OS at 5 years was 74.4 %, and 5-year recurrence-free survival (RFS) of patients with a complete cytoreduction (CC ≤ 1) was 65.5 %. Factors independently predicting shorter survival included peritoneal mucinous adenocarcinoma (PMCA) histology (hazard ratio [HR] 15.2, 95 % confidence interval [CI] 3.38-69.0), lymph node metastasis (HR 3.82, 95 % CI 1.13-12.8), and incomplete cytoreduction [CC3; HR 13.7, 95 % CI 3.18-59.1). An incomplete cytoreduction was associated with the PMCA variant (p < 0.001). Postoperative complications grade I/II (p = 0.113) and grade III/IV (p = 0.669) had no impact on OS in multivariate analysis. CONCLUSION: CRS with HIPEC can achieve long-term survival for patients with appendix cancer with peritoneal metastases. Histologic subtype, lymph node metastasis, and incomplete cytoreduction are the significant predictors of OS. Postoperative adverse events had no impact on survival.

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.