Metronomic Capecitabine With Cyclophosphamide Regimen in Unresectable or Relapsed Pseudomyxoma Peritonei.

BACKGROUND: No standard treatment for advanced unresectable pseudomyxoma peritonei (PMP) has been defined so far. PMP is traditionally considered chemoresistant but nonrandomized series showed promising results with regimens for gastrointestinal tumors. PATIENTS AND METHODS: We conducted a single-center prospective single-arm trial. Inclusion criteria were histologically confirmed PMP, unresectable or progressive to surgery/previous treatments. Patients received a continuous metronomic regimen with capecitabine (625 mg/m2 twice per day) with cyclophosphamide (50 mg/d) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was progression-free survival (PFS); secondary end points were disease control rate (DCR), overall survival (OS), and safety. Exploratory analyses were the variation of circulating tumor biomarkers and neutrophil to lymphocyte ratio (NLR). RESULTS: Twenty-three consecutive patients were enrolled from April 2015 to October 2017. At a median follow up of 22.4 months, median PFS was 9.5 months and 1-year OS rate was 73.7%. Overall, DCR was 87% and 6 (27%) patients achieved disease control ≥12 months. The safety profile was manageable: 26% of patients reported Grade 3 drug-related adverse events and none Grade 4/5. NLR baseline < 3 versus ≥ 3 was associated with prolonged PFS (12.6 vs. 3.4 months; P = .0001). CONCLUSION: Metronomic capecitabine with cyclophosphamide is a well tolerated regimen in unresectable/recurrent PMP, and its safety profile favorably compares with previously investigated regimens.

Impact of Cellularity on Oncologic Outcomes Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Pseudomyxoma Peritonei.

BACKGROUND: The Peritoneal Surface Oncology Group International (PSOGI) recommends pathologic reporting of tumor cellularity in patients with pseudomyxoma peritonei (PMP) undergoing cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC). We investigated the prognostic significance of PMP cellularity, or lack thereof (acellular mucin), following CRS-HIPEC. METHODS: We reviewed clinical data for 310 CRS-HIPEC procedures in low-grade (American Joint Committee on Cancer grade G1) PMP with acellular mucin (n = 19), scant cellularity (n = 30), or moderate cellularity (n = 242). Kaplan-Meier survival curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes. RESULTS: Compared with patients with acellular mucin, those with scant and moderate cellularity had higher PCI and less-frequent complete macroscopic resection. After an estimated median follow-up of 49 months, 4 patients (14%) with scant cellularity and 127 patients (56%) with moderate cellularity progressed, while none of the patients with acellular mucin progressed. While the median progression-free survival (PFS) was not reached for patients with acellular mucin or scant cellularity (estimated 5-year PFS probability of 100 and 83%, respectively), patients with moderate cellularity demonstrated a median PFS of 32 months (estimated 5-year PFS probability of 27%). In a multivariate model, degree of disease cellularity, or lack thereof (acellular mucin), was an independent predictor of PFS but not overall survival. CONCLUSIONS: Early disease progression is unlikely in patients with acellular mucin undergoing CRS-HIPEC, as opposed to a 14% recurrence rate with scant cellularity. Thorough pathologic assessment for cellularity, or lack thereof (acellular mucin), is vital for accurate prognostication of disease progression for patients with low-grade PMP undergoing CRS-HIPEC.

Advanced Pseudomyxoma Peritonei Requiring Gastrectomy to Achieve Complete Cytoreduction Results in Good Long-Term Oncologic Outcomes.

BACKGROUND: Optimal outcomes in pseudomyxoma peritonei (PMP) require complete macroscopic tumor removal by cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Partial or complete gastrectomy may be required with ongoing debate as to the risks and benefits of gastrectomy in what is often a low-grade malignancy. METHODS: Retrospective single-center analysis of 1014 patients undergoing CRS and HIPEC for PMP of appendiceal origin. Complications and survival were compared in patients who had gastrectomy versus the nongastrectomy cohort. RESULTS: Of 1014 patients, 747 (74 %) had CRS and HIPEC with complete cytoreduction. Overall, 86 (12 %) of 747 had partial (n = 80) or total (n = 6) gastrectomy. Median age was 55 years for gastrectomy patients and 56 for nongastrectomy patients (p = 0.591). Preoperative tumor markers [carcinoembryonic antigen, carbohydrate antigen (CA) 125 and CA19-9] were elevated more frequently in the gastrectomy group compared to the nongastrectomy group [81, 61 and 81 % compared to 41 % (p = 0.001), 20 % (p = 0.001) and 39 % (p = 0.001), respectively]. The proportion of high-grade histology was similar in the two groups (gastrectomy 19 % vs. nongastrectomy 18 %, p = 0.882). Postoperative complications (Clavien-Dindo III-IV) were 31 % for the gastrectomy group and 13 % for the nongastrectomy group (p = 0.001). The 30-day postoperative mortality was 3 (0.5 %) of 661 for the nongastrectomy group and 1 (1.2 %) of 86 for the gastrectomy group (p = 0.387). Three- and 5-year overall survival were 96 and 88 % in the nongastrectomy group and 87 and 77 % in the gastrectomy group (p = 0.018). Three- and 5-year disease-free survival were 89 and 77 % in the nongastrectomy group versus 66 and 48 % in the gastrectomy group (p = 0.001). CONCLUSIONS: Gastrectomy is an essential component of complete cytoreduction in advanced PMP and was required in 12 % of patients with good long-term survival.

The role of baseline inflammatory-based scores and serum tumor markers to risk stratify pseudomyxoma peritonei patients treated with cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

AIMS: Inflammation-based scores such as neutrophil-lymphocyte ratio (NLR) and Onodera nutritional index (ONI) have been identified as new prognosticators in several tumors. We conducted a prognostic analysis of these markers and performed a risk stratification of PMP patients submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: 226 patients from two peritoneal surface malignancies centers participated in this study. Cox proportional modeling was used to select predictors of overall survival (OS) among baseline inflammation-based scores, serum tumor markers, clinical and surgical variables. Risk stratification was done using conditional inference tree model. RESULTS: One hundred eighty-two cases had diffuse peritoneal adenomucinosis subtype. Fifty-four cases had received previous systemic chemotherapy. The means of ONI and NLR were 51.4 (SD = 9.8) and 3.2 (SD = 2.3), respectively. Two hundred ten cases were optimally cytoreduced. Cox analysis identified completeness of cytoreduction, histological subtype, previous systemic chemotherapy, NLR, and CA 19-9 as independent prognosticators. Conditional inference tree method identified two poor prognostic subsets: NLR ≤2.7 and CA 19-9>336 (5yr-OS = 15%) and NLR >2.7 and ONI ≤42 (5yr-OS = 30%). CONCLUSIONS: NLR, ONI, and CA 19-9 are new prognosticators that contributed to improve prediction of OS in PMP patients treated by CRS and HIPEC. These markers allowed a risk stratification that could optimize therapeutic management of PMP patients.

Elevated tumour markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumour removal.

AIM: Elevation of the preoperative tumour markers in pseudomyxoma peritonei (PMP) is common and is a risk factor for recurrence. There has, however, been no documentation of the effect of complete tumour removal on tumour markers levels after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of the study was to compare the tumour markers 7 days after surgery in patients with elevated preoperative levels. METHOD: This was an observational prospective study of patients with PMP of appendiceal origin treated in one of the UK National Referral Centres for this condition. Thirty patients [median age = 61 (range: 31-74) years; six men] with an elevated preoperative level of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and/or carbohydrate antigen 19-9 (CA19-9) underwent repeated estimation, 7 days after CRS and HIPEC for PMP. RESULTS: The median preoperative CEA level of 12 µg/l fell to 0.75 µg/l postoperatively (P < 0.0001), CA-125 fell from 45 to 31 kU/l (P = 0.183) and CA19-9 fell from 134 to 37 kU/l (P = 0.003). The CEA was raised in 22 (73%) of 30 patients preoperatively and in two (7%) of 30 patients 7 days after surgery (P < 0.0001). The corresponding data for CA-125 were 18 (60%) and 13 (43%) (P = 0.196) and for CA19-9 they were 24 (80%) and 16 (53%) (P = 0.028). CONCLUSION: This is the first documentation of a reduction or normalization of CEA 7 days after CRS, but not for CA19-9 or CA-125. This may indicate completeness of surgical resection and could aid selection for adjuvant therapy and predict prognosis. Long-term follow-up is, however, necessary to determine the significance of this observation.

Female patients with pseudomyxoma peritonei: a single-institution clinicopathologic study of 35 cases.

PURPOSE: To explore clinicopathologic/prognostic aspects of pseudomyxoma peritonei (PMP). METHODS: We reviewed records of 35 female patients with PMP treated at a single institution. RESULTS: Patients' median age was 57.0 years (range 35.0-71.0 years). Their median pre-surgery level of carbohydrate antigen 19-9 (CA-199) was 80.95 U/ml (range 0.00-1,562.10 U/ml); of carbohydrate antigen 12-5 (CA-125), 44.00 U/ml (range 0.90-231.20 U/ml); and of carcinoembryonic antigen (CEA), 17.20 ng/ml (range 2.04-211.60 ng/ml). Of the 35 patients, 23 (65.7 %) underwent cytoreductive surgery (CRS) by gynecological oncologists and 12 (34.3 %) underwent non-CRS surgeries by general gynecologists or surgeons, including one patient who refused surgical treatment beyond a diagnostic laparoscopy. After surgery, 18 patients (51.4 %) had residual lesions, 11 (31.4 %) had complete lesion removal and 6 (17.1 %)had insufficient information on residual lesion; 21 (60.0 %) had appendiceal-based tumors and 12 (34.3 %) had ovarian-based tumors. Median follow-up time was 37 months (range 1-148 months), during which 28 patients (80.0 %) had relapsed. By the end of the study, 12 patients (34.3 %) died of PMP, 16 (45.7 %) survived with disease, and 7 (20 %) survived without disease. Median progress-free survival (PFS) was 12 months (range 0.5-114.0 months). Median overall survival time was 42 months (range 5-150 months). Ovarian tumor origin, post-surgery residual lesions, preoperative CA199 > 258.9 U/ml and CA125 > 70.6 U/ml were independent predictors of PFS. CONCLUSIONS: PMP is rare in women, and has a poor long-term survival rate. Multi-center cooperation to gather more cases is needed to explore its behavior and proper treatment.

Circulating tumor markers: predictors of incomplete cytoreduction and powerful determinants of outcome in pseudomyxoma peritonei.

BACKGROUND: Incomplete cytoreduction (IC) is one of the main prognostic factor in pseudomyxoma peritonei (PMP). We evaluated the ability of preoperative Ca125, CEA, and Ca19-9 to predict IC and prognosis in PMP. METHODS: One hundred fifty-six cases elected candidate to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from 1996 to 2011 were included in the study. We assessed the: (1) optimal cut-off values for circulating Tumor markers (CTM) in predicting IC (residual disease >2.5 mm) using receiver-operating characteristics (ROC); (2) discriminant power of CTM and risk prediction models for IC by calculating the area under ROC curve (AUC-ROC); (3) prognostic factors using Cox proportional-hazard model. RESULTS: Optimal cut-offs were 125 U/ml for Ca125, 18 ng/ml for CEA, and 89 U/ml for Ca19-9. The AUCs-ROC were 0.76, 0.68, and 0.69 for Ca125, CEA, and Ca19-9, respectively. The addition of CTM to risk prediction model that considered preoperative clinicopathological factors increased marginally the AUC-ROC (0.80-0.84). Ca125 > 125 U/ml, Ca19-9 > 89 U/ml independently affected overall survival. CONCLUSIONS: Preoperative CTMs were reasonable but not perfect discriminators of IC. Moreover, Ca125 and Ca19-9, using new cut-off values, were proven to be new strong prognostic factors that overcome the value of disease extension and histological subtype.

Preoperative carcinoembryonic antigen level predicts prognosis in patients with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Even though management of pseudomyxoma peritonei (PMP) was improved with cytoreductive surgery (CRS) and hyperthermic chemotherapy (HIPEC), several aspects of PMP still need to be optimized, including patient selection for surgery and prognostic factors. We assessed the role of preoperative carcinoembryonic antigen (CEA) levels in PMP patients treated with CRS and HIPEC. METHODS: A total of 449 PMP patients with documented preoperative CEA levels referred to our center between 2005 and 2011 underwent CRS and HIPEC. The association between CEA levels and characteristics of patients with PMP was assessed with χ (2) test, linear correlation, and logistic regression analyses. Survival analysis was performed with Cox proportional hazard model. RESULTS: Median age was 55 (range 19-84) years. There were 245 (54.5 %) females and 204 (45.5 %) males. Preoperative CEA levels were elevated in 328 (73 %, sensitivity) patients with PMP. Preoperative CEA levels were also related to peritoneal cancer index (P < 0.0001), cytoreductive surgery scores (P < 0.0001), progress free survival (P < 0.001) and overall survival (P < 0.001) in patients with PMP. CONCLUSIONS: Our results indicated that preoperative CEA levels are useful in predicting the extent of disease and surgical success as well as progress-free and overall survival in patients with PMP treated with cytoreductive surgery and HIPEC.

Inflammatory markers in blood and serum tumor markers predict survival in patients with epithelial appendiceal neoplasms undergoing surgical cytoreduction and intraperitoneal chemotherapy.

BACKGROUND: The study examines the role inflammatory and tumor markers as biomarkers to preoperatively predict outcome in patients with epithelial appendiceal neoplasm undergoing cytoreduction and intraperitoneal chemotherapy. METHODS: Associations between baseline variables, tumor markers [CEA (carcinoembyronic antigen], CA125, CA199), inflammatory markers including neutrophils-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and C-reactive protein (CRP) with progression-free survival (PFS) and overall survival (OS) were examined in patients undergoing surgical cytoreduction and intraperitoneal chemotherapy for epithelial appendiceal neoplasm. RESULTS: A total of 174 patients with epithelial appendiceal neoplasm (low-grade pseudomyxoma, n = 117; appendiceal cancer, n = 57) underwent cytoreduction. On univariate analysis, all 3 inflammatory and tumor markers predicted for both PFS and OS, respectively; NLR ≤ 2.6 (P = 0.01, P = 0.002), PLR ≤ 166 (P = 0.006, P = 0.016), CRP ≤ 12.5 (P = 0.001, P = 0.008), CEA (P < 0.001, P = 0.001), CA125 (P = 0.004, P < 0.001), CA199 (P < 0.001, P < 0.001). On multivariate analysis, there were no independent predictors of OS. PFS was independently associated with the presence of lymph node metastasis (P = 0.02), CA199 > 37 (P = 0.003), and a CRP > 12.5 (P = 0.013). A higher peritoneal cancer index (PCI > 24) was associated with elevation in CEA > 12, CA125 > 39, CA199 > 37, PLR > 166 and CRP > 12. The tumor histologic subtype was associated with CA 199 levels. CONCLUSIONS: The results from this investigation suggest that preoperative inflammatory markers in blood and serologic tumor markers may predict outcomes and are associated with tumor biology in patients with epithelial appendiceal neoplasm undergoing cytoreduction and intraperitoneal chemotherapy treatment.

Early recurrence of pseudomyxoma peritonei following treatment failure of cytoreductive surgery and perioperative intraperitoneal chemotherapy is indicative of a poor survival outcome.

BACKGROUND: The aim of this study was to identify predictors of early recurrence to optimize outcomes. METHODS: A comparison of clinicopathological factors between patients who developed early recurrence (≤12 months) and late recurrence (>12 months) was performed to identify predictors of treatment failure through univariate and multivariate analyses. Survival parameters were estimated using the Kaplan-Meier method. RESULTS: A total of 113 patients with a median PCI of 24 (range, 2-39) underwent cytoreductive surgery. The median progression-free and overall survival was 48 and 104 months, respectively. Multivariate analysis identified prior operations >1, ≥10 units of fresh frozen plasma (FFP) transfusion, incomplete cytoreduction and not undergoing definitive cytoreductive surgery within 12 months of diagnosis as predictors for disease recurrence. Twenty of 41 patients (49%) developed early recurrence. The median overall survival of patients who developed early recurrence was 38 months and in patients who did not develop early recurrence was 97 months (P = 0.002). Subgroup analysis of patients with recurrence identified the male gender (P = 0.028), elevated CA 125 (P = 0.037), having elevated carcinoembryonic antigen (CEA), CA 125 and CA 19-9 (P = 0.029), peritoneal cancer index >25 (P = 0.020), incomplete cytoreduction (P = 0.020), >6 units of blood transfusion (P = 0.020) and >10 units of FFP transfusion (P = 0.009) as factors associated with early recurrence. CONCLUSION: Early recurrence of pseudomyxoma peritonei occurs despite achieving high rates of oncologically optimal cytoreduction. The clinicopathologic factors associated with early recurrence identified in this study may inform us about patients at greatest risk of treatment failure during the post cytoreduction follow-up.

Mucinous cystadenocarcinoma arising in mature cystic teratoma ovary and associated pseudomyxoma peritonei: report of a case.

Pseudomyxoma peritonei (PMP) is most commonly associated with intra-abdominal spread of an appendiceal mucinous neoplasm and very rarely seen in cases of primary ovarian tumours. Mucinous adenocarcinoma arising in a mature cystic teratoma giving rise to PMP is even rarer. Extensive medlar search has revealed only nine cases; we are reporting tenth such case.

Prognostic value of circulating tumor markers in patients with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Encouraging results have been recently reported in selected patients affected by pseudomyxoma peritonei (PMP) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The selection factors predicting clinical outcome are still a matter of clinical investigation. We assessed the prognostic reliability of serum tumor markers in a large series of patients with PMP undergoing CRS and HIPEC. METHODS: Sixty-two patients with PMP were operated on at a single institution with the intent of performing adequate CRS (residual tumor nodules

Elevated tumour markers prior to complete tumour removal in patients with pseudomyxoma peritonei predict early recurrence.

OBJECTIVE: To assess the potential value of pre-operative CEA, CA 125 and CA 19-9 in identifying Pseudomyxoma peritonei (PMP) patients at risk of recurrence following complete cytoreductive surgery and intraperitoneal chemotherapy. METHOD: Between March 1996 and October 2001, 35 patients, with documented pre-operative tumour marker measurements, underwent complete cytoreduction. Outcome in the 32 survivors was recorded. RESULTS: Median age was 53 years (range: 32-74). There were 17[53%] females. In 9/32[28%] all tumour markers were normal. The most common abnormality was elevated CEA level in 14/32[44%]. Median follow up was 23 months (range: 11-74). Recurrence was detected in 8/32[25%]. The 2-year recurrence free interval was 53% in those with elevated CEA compared with 94% with normal CEA. The 2-year disease free intervals were 100% in 9 patients with normal preop markers compared with 66% for the group with at least one abnormal marker. CONCLUSION: PMP patients with elevated CEA, or more than one abnormal serum tumour maker, are at risk of developing recurrent disease.

Pseudomyxoma peritonei with high serum CA19-9: report of three cases.

Pseudomyxoma peritonei (PMP) is an unusual form of intraabdominal neoplasm that produces a large amount of extracellular mucin. It is often associated with mucinous tumors of gastrointestinal tract or ovary. Herein, we report 3 patients with pseudomyxoma peritonei with high serum carbohydrate antigen 19-9 (CA19-9) levels. The first patient, who had a CA19-9 level of 1132 U/ml, had well-differentiated rectal cancer and died of chemotherapy complications, pneumonia and septic shock; one month after admission. The other 2 cases with CA19-9 levels of 2520 U/ml and 679 U/ml had tumors of unknown origins and had survived more than 1 year and 3 months after treatment, respectively. Usually, elevated serum CA19-9 levels are found in patients with pancreatic, biliary, colorectal, gastric or liver cancers. However, many studies have shown high serum CA19-9 levels are associated with mucinous carcinoma. Immunochemical studies also showed positive staining of CA19-9 in mucinous tumors. PMP is composed of large amounts of mucin, therefore, we suggest that serum and ascites CA19-9 levels should be routinely checked in patients with PMP.

A clinical study on pseudomyxoma peritonei.

To elucidate the clinical entity of pseudomyxoma peritonei, nine patients (male: female = 6:3) who had been treated in Chang Gung Memorial Hospital in the past 13 years were reviewed. The male patients with original appendiceal tumour were older than the male patients with original colon cancer or indefinite tumour (70, 67 and 67 years vs 42, 27 and 50 years). In addition, the former group survived in a disease-free status for 28 months on average, while the latter group died within 2 years. Echogenic ascites and diffuse low-attenuation intra-abdominal masses with scalloping on the surface of liver detected by ultrasonography and by computerized tomography, respectively, were found in most of the patients. Elevation of the serum carcinoembryonic antigen (CEA) during recurrence of the disease was also noted. This series suggested that: (i) the pre-operative diagnosis could be made with careful physical examination in conjunction with sonography or computerized tomography; (ii) the prognosis was better in patients with tumour of appendiceal origin; and (iii) serum CEA might be valuable for early detection of recurrence.