Article

Intraoperative macroscopic tumour consistency is associated with overall survival after cytoreductive surgery and intraperitoneal chemotherapy for appendiceal adenocarcinoma with peritoneal metastases: A retrospective observational study

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Abstract

Background: This study examines the impact of intraoperative macroscopic tumour consistency on short-term and long-term outcomes after cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) for appendiceal adenocarcinoma with peritoneal metastases. Methods: Macroscopic intraoperative tumour consistency was classified in three groups as soft (jelly-like geltatinous tumours), hard (hard tumour nodules without gelatinous features) and intermediate (both soft and hard features). In-hospital mortality, major morbidity, intensive care unit (ICU), high dependency unit (HDU) and total hospital stay, disease-free survival (DFS) and overall survival (OS) were compared. Results: The three groups had similar perioperative short-term outcomes. Patients with soft, intermediate and hard tumours revealed differences in OS (p < 0.001) and DFS (p = 0.03). Multivariable analysis revealed a shorter OS for patients with hard versus soft tumours (HR for hard tumours = 4.43, 95%CI 2.19-9.00). Conclusions: Intraoperative macroscopic tumour consistency may be used as a prognostic marker for survival in patients with appendiceal adenocarcinoma with peritoneal metastases.

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... The rationale of EPIC is to target microscopic disease post-CRS and maximise exposure to cytotoxic agents prior to the development of postoperative adhesions [3][4][5]. This is achieved with cell-cycle specific cytotoxic agents such as 5-fluorouracil or paclitaxel delivered into the peritoneum 23 hours a day for 5 days [1,6]. ...
... In their study of macroscopic tumours in appendiceal adenocarcinoma, patients with hard tumours had a significant decrease in survival. This was explained by the higher presence of signet cells in hard tumours which alters mucin production and structure leading to increased tumour resistance to chemotherapy [6]. This is similar to the findings of our study, where there were worse survival outcomes in signet cell cancers despite response to EPIC. ...
... This is similar to the findings of our study, where there were worse survival outcomes in signet cell cancers despite response to EPIC. In Huang et al.'s study, soft lesions such as mucinous tumours appeared to be more susceptible to 5-FU and EPIC due to their gelatinous nature allowing penetration of chemotherapy [4,6,12]. Mucinous tumours were the second most likely to respond in this study, and this is reflective of previous reports on EPIC efficacy [12]. ...
... The rationale of EPIC is to target microscopic disease post-CRS and maximise exposure to cytotoxic agents prior to the development of postoperative adhesions [3][4][5]. This is achieved with cell-cycle specific cytotoxic agents such as 5-fluorouracil or paclitaxel delivered into the peritoneum 23 hours a day for 5 days [1,6]. ...
... In their study of macroscopic tumours in appendiceal adenocarcinoma, patients with hard tumours had a significant decrease in survival. This was explained by the higher presence of signet cells in hard tumours which alters mucin production and structure leading to increased tumour resistance to chemotherapy [6]. This is similar to the findings of our study, where there were worse survival outcomes in signet cell cancers despite response to EPIC. ...
... This is similar to the findings of our study, where there were worse survival outcomes in signet cell cancers despite response to EPIC. In Huang et al.'s study, soft lesions such as mucinous tumours appeared to be more susceptible to 5-FU and EPIC due to their gelatinous nature allowing penetration of chemotherapy [4,6,12]. Mucinous tumours were the second most likely to respond in this study, and this is reflective of previous reports on EPIC efficacy [12]. ...
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Background: Early Post-operative Intra-Peritoneal Chemotherapy (EPIC) following Cytoreductive Surgery (CRS) and Hyperthermic Intra-Peritoneal Chemotherapy (HIPEC) in high-grade appendiceal peritoneal cancer remains controversial with unclear survival benefit. The following study evaluates the survival outcomes in highgrade appendiceal cancer patients receiving varying days of EPIC in addition to CRS and HIPEC, and if survival varied between different appendiceal cancer subtypes. Patients and Methods: A monocentric retrospective analysis of patients with high-grade appendiceal cancers managed from 1994 to 2018 was undertaken. An analysis was performed comparing survival between patients who received HIPEC, HIPEC+EPIC, HIPEC+EPIC <3 days and HIPEC+EPIC ≥3days. All patients received CRS. Results: 212 patients were included in the study. The 5years overall survival was 60% and 55% in the HIPEC+EPIC and HIPEC groups respectively. Patients who received ≥3days of EPIC had an 8% reduction in risk of death compared to those who had <3 days (HR 0.92, CI 0.89-0.94), with a 5-year survival of 62% in the ≥3days group compared to 55% in the <3day group. Patients with signet cell carcinoma had the greatest 5year survival advantage when both HIPEC and EPIC were given (HR 01.23, CI 01.21-01.26). Conclusion: EPIC in combination with HIPEC and CRS offers survival benefit at 5years in high-grade appendiceal peritoneal cancer and is most advantageous in signet cell carcinoma. Completing a ≥3day course of EPIC increases chance of survival at 5years compared to a <3 days course.
... To our knowledge, this is the only study describing the specific characteristics (beyond localization and presence of ascites) of peritoneal carcinomatosis in patients with ovarian cancer prospectively. Most description of PC have been reported in gastric and appendiceal tumors (18,19). However, even here the focus has remained on describing localization and presence of ascites (19)(20)(21)(22). ...
... Most description of PC have been reported in gastric and appendiceal tumors (18,19). However, even here the focus has remained on describing localization and presence of ascites (19)(20)(21)(22). ...
... There have been very few reports on descriptive morphological features of peritoneal carcinomatosis in patients with EOC. In one retrospective observational study, the authors aim to describe texture and consistency features of appendiceal tumors with peritoneal metastases (19). Features such as hard consistency significantly correlated with lower survival outcome as compared to tumors that were described as soft in consistency (19,20). ...
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Background Peritoneal carcinomatosis in ovarian cancer is frequent and generally associated with higher stage and poorer outcome. The clinical features of peritoneal carcinomatosis are diverse and their relevance for surgical and long-term outcome remains unclear. We conducted this prospective study to describe intraoperatively the different features of peritoneal carcinomatosis(PC) and correlate them with clinicopathological features, progression-free(PFS) and overall survival (OS),. Methods We performed a systematic analysis of all patients with documented intraoperative PC and a primary diagnosis of epithelial ovarian, tubal, or peritoneal cancer from January 2001 to September 2018. All data were evaluated by using the systematic tumor bank tool. Specific PC features included texture(soft-hard), consistency(coarse-fine or both), wet vs dry(PC with ascites vs. PC without ascites), and localization(diffuse-local). PC characteristics were then evaluated for correlation with age, FIGO-stage, histology, lymph-node involvement, grade, and presence of residual tumor at primary surgery. Moreover, the influence of PC characteristics on OS and PFS was analyzed. Results A total of 1686 patients with PC and primary epithelial ovarian cancer were included. Majority of the patients were characterized by diffuse PC(73.9%). The majority of peritoneal nodules were fine in texture (55.3%) and hard in consistency (87.4%). Moreover, 27.6% of patients had dry PC. Diffuse PC localization was significantly associated with higher FIGO-stage (p<0.001), high-grade (p=0.003) and serous tumors (p=0.006) as well as residual tumor as compared to local PC (p<0.001). Wet PC also significantly correlated with diffuse localization (p <0.001) and residual tumor as compared to dry PC (p<0.001). Coarse PC was significantly associated with residual tumor as compared to fine PC (p=0.044). All other PC features didn´t correlate with clinicopathological features. As for survival outcomes, diffuse peritoneal localization (p<0.001), wet PC (p<0.001), and additional lymph node involvement (p<0.001) were associated with lower OS and PFS rates. Other PC features did not significantly impact survival. Conclusion Diffuse localization of peritoneal carcinomatosis was significant predictor of recurrence. Lower OS and PFS were associated with diffuse peritoneal localization, wet PC, and additional lymph node involvement. Further prospective trials are warranted with the inclusion of translational research aspects to better understand the different peritoneal carcinomatosis patterns.
... This article aims to review the whole body of literature surrounding the use of EPIC for lower gastrointestinal neoplasms with PC. Most recent publications from our group and others, suggest that EPIC may have a survival advantage when added to HIPEC, without increasing postoperative complications [18][19][20][21][22][23] The search yielded 79 studies and 3 more were identified by screening previous systematic reviews on the use of intraperitoneal chemotherapy for lower gastrointestinal tumors with peritoneal metastases. The PRIMA Flow diagram is presented in Figure 1. ...
... We later published interesting findings on the correlation between subjective tumor consistency of PMCAs and long-term survival [23]. In this retrospective study of 192 patients, subjects with softer tumors tended to have received EPIC more commonly on top of HIPEC but when adjusting for EPIC in the multivariate analysis, subjective tumor consistency was found as an independent survival prognostic factor. ...
... p=0.005) and intermediate (p=0.06) tumors [23]. ...
Article
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Background Early postoperative intraperitoneal chemotherapy (EPIC) can be used in combination with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat patients with peritoneal carcinomatosis (PC) of multiple origins. The present study is a systematic review to evaluate the role of EPIC after CRS + HIPEC for appendiceal and colorectal cancers with PC. Content We conducted a systematic search in PubMed according to the PRISMA guidelines and included all studies published before June 27 of 2019 comparing EPIC to HIPEC or the combination of both. Our search found 79 articles. After excluding non-relevant articles, a total of 13 retrospective clinical studies reporting on the efficacy and safety of EPIC compared to HIPEC or as a combination therapy for lower gastrointestinal neoplasms were analyzed. Initial EPIC reports led to its declined usage because of concerns with increased postoperative morbidity and uncertain added benefit on survival. Recent retrospective studies have been promising, showing significant improvements in OS and fewer issues with complications when adding EPIC to CRS + HIPEC. Conclusions Current evidence is entirely retrospective and is conflicting. It is hoped that ongoing clinical trials and additional studies will clarify EPIC’s role in the treatment of patients with PC.
... These observations could be put into perspective by the mucin consistency angle of analysis of PMP behaviour. Morris et al. defined three types of mucin with respect to hardness index (soft, semi-hard and hard), which correlated with survival [45,46]. It is possible that variations in mucin consistency are also responsible for the heterogeneity of of the impact of scalloping on the assessed outcomes. ...
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Pseudomyxoma peritonei (PMP) is ideally treated by cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), leading to significant morbidity. Beyond the histologic grade, the prognosis lies in the completeness of cytoreduction (CC-score of 0/1 vs. 2/3) and the severe complication rate. The mucinous nature of the peritoneal implants sometimes induces liver and/or spleen scalloping on imaging. The predictive value of scalloping was assessed regarding resectability, grade, survival and severe morbidity. This monocentric, retrospective analysis compared CC-0/1 with CC-2/3 groups regarding liver and spleen scalloping parameters, assessed on pre-operative computed tomography (CT) scan, reviewed for the study. In addition, prognostic factors of severe complications and recurrence-free and overall survivals were explored in the CC-0/1 population. Overall, 129 patients were included (109 CC-0/1, 20 CC-2/3), with 58 (45%) exhibiting scalloping. All patients with splenic scalloping also had a liver one. Scalloping was more frequent (75% vs. 39%), with greater median maximal depth (21 vs. 11 mm) and higher PCI (32 vs. 14) in the CC-2/3 population, but was not predictive of either grade or survival. In CC-0/1 patients, survivals and postoperative complications were not affected by scalloping parameters. Scalloping appeared as a marker of advanced PMP, but was not predictive of grade, severe complications, or long-term outcomes.
... Intra-operative macroscopic tumour consistency is assessed as either hard, semi-hard or soft, with tumours classified as hard being associated with significantly shorter OS (HR 4.43, 95% CI 2.19-9.00) 74 . ...
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Peritoneal surface malignancies (PSMs) are usually associated with a poor prognosis. Nonetheless, in line with advances in the management of most abdominopelvic metastatic diseases, considerable progress has been made over the past decade. An improved understanding of disease biology has led to the more accurate prediction of neoplasia aggressiveness and the treatment response and has been reflected in the proposal of new classification systems. Achieving complete cytoreductive surgery remains the cornerstone of curative-intent treatment of PSMs. Alongside centralization in expert centres, enabling the delivery of multimodal and multidisciplinary strategies, preoperative management is a crucial step in order to select patients who are most likely to benefit from surgery. Depending on the specific PSM, the role of intraperitoneal chemotherapy and of perioperative systemic chemotherapy, in particular, in the neoadjuvant setting, is established in certain scenarios but questioned in several others, although more prospective data are required. In this Review, we describe advances in all aspects of the management of PSMs including disease biology, assessment and improvement of disease resectability, perioperative management, systemic therapy and pre-emptive management, and we speculate on future research directions.
... Limitations of BromAc direct tumour injection or peritoneal application include the difficulty of differentiation between the various grades of hardness in mucin by radiological imaging. It is clear from our in vitro and in vivo studies that the drug combination is much more effective in the soft textured mucinous tumours, which are present in up to 70% of cases [7,8,25,26]. Softer tumours are considerably easier to dissolve than hard tumours, which may be related to known biochemical differences, the increased cellularity seen in harder tumours or ability for drug to disseminate easier. ...
Article
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.
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Introduction. Tumour neoplasms of the appendix represent a rare pathology with a frequency of up to 0.1 % and 0.5 % of all performed appendectomies and all forms of malignant tumours of the colon, respectively. Due to the lack of specific diagnosis and asymptomatic development of the disease, such neoplasms are diagnosed accidentally during an emergency operation for acute appendicitis or according to the results of a morphological study of postoperative material.Materials and methods. A retrospective analysis of appendix neoplasm cases was performed in patients hospitalised in the surgical departments of City Clinical Hospital No. 8 in 2006-2016. A total of 3298 surgical interventions for acute appendicitis were carried out for this period in the patients aged from 18 to 86 years.Results. Upon admission, all patients had a clinical status of appendicitis. In 3 cases, preoperative ultrasound revealed an expansion of the intestinal loops, pneumatosis and local fluid accumulation. In the setting of mucocele, the sonogram revealed a 70x48 mm ovoid thin-walled liquid formation with smooth contours and peripheral blood flow. In the remaining patients, no pathological changes were detected by ultrasound.Discussion. According to the results of histological examination, 6 carcinoid tumours were diagnosed in 5 men and 1 woman aged 38-62 years (0.18 %). The appendix adenocarcinoma was diagnosed in 2 women and 1 man aged 7681 years (0.09 %). One case of an appendix mucinous tumour in a 67-year-old woman was established intraoperatively (0.03 %). The appendix neoplasm frequency comprised 0.3 % of all appendectomies performed.Conclusions. The conducted analysis showed that, even with the possibility of the comprehensive examination of patients, the diagnosis of tumour diseases of the appendix in emergency surgical care remains to problematic.
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Introduction: Early recurrence (ER) is defined as development of loco-regional peritoneal disease within 12-month of the initial CRS/PIC. Our aims were to identify overall survival (OS), recurrence-free survival (RFS) and independent prognostic factors associated with ER in PM of appendiceal neoplasm. Materials and methods: A prospectively-maintained database for patients with appendiceal neoplasm undergoing cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) from year 1996-2018 was retrospectively analysed. Results: 208 female and 185 male patients were identified. With a median follow-up of 40-month, 40.2% of the patients developed ER. The median OS for ER was 24 months compared to late (LR) at 64 months. Median OS was not reached in non-recurrence (NR). 5-year survival for ER was less favourable compared to LR and NR (19.3%vs54.6%vs94%). No patients in ER group survived beyond 10-year. Independent negative predictors associated with ER on multivariate analysis were male patient (p = 0.013), blood transfusion of >8 units (p = 0.013), elevated preoperative CEA levels (>5 ng/ml; p = 0.002) and hard intraoperative tumour consistency (p < 0.001). Protective factor was a combination of CC1, hard tumour consistency and use of EPIC (p = 0.039). Independent prognostic factors that predicted recurrence of appendiceal PM were PCI >20 (p = 0.049), non-use of EPIC (p = 0.012), hard tumour consistency (p = 0.004) and use of previous chemotherapy (p = 0.023). Conclusion: ER following CRS and PIC of appendiceal PM is associated with reduced survival outcomes. Our data alludes to the importance of optimising the risk factors in order to delay loco-regional recurrence and improve long-term survival of these patients.
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Compared to current treatment for pseudomyxoma peritonei (PMP), the extraction of solubilised mucin through peritoneal catheter can be minimally invasive. However, mucin has variable appearance that may influence mucolysis. Hence, we investigated the mucolysis of 36 mucin samples with a novel agent. Using visual inspection and hardness index, PMP mucin was classified into three grades. The mucin pathological category was identified from patient record. Subsequently, the dissolution of the samples was tested. For in vitro, 1 g of mucin was treated to the mucolytic agent in 10 ml TRIS buffer at 37 deg. Celsius for 3 hours, with weighing of residual mucin. Control treatment was similar but received TRIS buffer. For in vivo, 2 g of implanted intra-peritoneal mucin in nude rats was treated to mucolytic (2 X 500 ul/24 hr, over 48 hours, plus another treatment before sacrifice at 56 hours, with weighing of residual mucin. Controls were treated but only with TRIS buffer. Six animals were used for each mucin grade (3 mucolytic treated & and 3 controls). Grades of mucin were soft mucin (62%), semi hard (20%) and hard mucin (18%). Diffuse peritoneal adenomucinosis had 50% of soft mucin and peritoneal mucinous carcinoma had 11% (P = 0.0382). In vitro and in vivo absolute disintegration was 100% for soft, 57.38% and 48.67% for semi hard, 50% and 28.67% for hard mucin. Majority of mucin were soft with complete disintegration, the rest showed variable disintegration, suggesting that the mucolytic has potential for treating PMP.
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Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.Modern Pathology advance online publication, 14 March 2014; doi:10.1038/modpathol.2014.37.
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Background. The peritoneal surface is an acknowledged locoregional failure site of abdominal malignancies. Previous treatment attempts with medical therapy alone did not result in long-term survival. During the last two decades, new treatment protocols combining cytoreductive surgery with perioperative intraperitoneal and intravenous cancer chemotherapy have demonstrated very encouraging clinical results. This paper aims to clarify the pharmacologic base underlying these treatment regimens. Materials and Methods. A review of the current pharmacologic data regarding these perioperative chemotherapy protocols was undertaken. Conclusions. There is a clear pharmacokinetic and pharmacodynamic rationale for perioperative intraperitoneal and intravenous cancer chemotherapy in peritoneal surface malignancy patients.
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Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.
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Gastrointestinal malignancy may spread to peritoneal surfaces in the absence of lymphatic or hematogenous metastases. To treat peritoneal carcinomatosis, a uniformly lethal disease process, extensive cytoreductive surgery and i.p. chemotherapy were combined. Early postoperative i.p. chemotherapy was instilled in the first few days after the surgical procedure in an attempt to treat anatomic sites that would be sealed off by postoperative adhesions. Mitomycin C was given on the first postoperative day at two doses, 10 and 12 mg/m2. 5-Fluorouracil was given on postoperative days 2-5 at 15 and 20 mg/kg, respectively. Median area under the curve ratio i.p./i.v. was 117 for 5-fluorouracil and 21.6 for mitomycin C. Elevated intraportal levels of drug were observed for i.p. 5-fluorouracil but not for mitomycin C. The marked pharmacokinetic advantage of postoperative i.p. suggests that this treatment strategy should be considered in a clinical trial in patients at risk for progression of peritoneal carcinomatosis.
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Peritoneal carcinomatosis from gastrointestinal cancer has new treatment options for surgical management. The approach uses cytoreductive surgery which combines peritonectomy and visceral resection in an effort to remove all visible cancer within the abdomen and pelvis. Then the peritoneal cavity is flooded with chemotherapy solution in an attempt to eradicate residual disease. In order to select patients for this approach the quantitative prognostic indicators for carcinomatosis were reviewed, compared and contrasted. Prognostic indicators to be used to select patients for this aggressive approach at the initiation of surgery and after completion of cytoreduction were studied. Four quantitative assessments to be used at the time of abdominal exploration were the Gilly staging, Japanese gastric cancer P score, peritoneal cancer index (PCI), and the simplified peritoneal cancer index (SPCI). All have value with the PCI being the most validated and most precise. Preoperative assessments include the tumor histopathology and the prior surgical score. The completeness of cytoreduction score is an assessment of residual disease after a maximal surgical effort. An opportunity for long-term survival following treatment for carcinomatosis requires a complete cytoreduction in all reports for gastrointestinal cancer. Quantitative prognostic indicators need to be knowledgeably employed when patients with carcinomatosis are being treated. Improved patient selection with greater benefit and reduced morbidity and mortality should result.
Article
Introduction: The combined approach of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has achieved encouraging outcomes for patients with PMCA with peritoneal dissemination. However, there is little evidence for the use of EPIC in addition to HIPEC in this group of patients. Patients and methods: This was a retrospective study of prospectively collected data of consecutive patients with PMCA who underwent CRS and perioperative intraperitoneal chemotherapy by one surgical team at St George Hospital in Sydney, Australia between Jan 1996 and Aug 2016. Results: A total of 185 patients formed the cohort of this study. However, there was no significant difference in terms of hospital mortality (p = 0.632), major morbidity rate (i.e. Grade III/IV) (p = 0.444), intensive unit care stay (p = 0.638) and total hospital stay (p = 0.0.078). However, patients who received HIPEC and EPIC had a significant longer stay in high dependency unit (p < 0.001). Multivariate analysis showed combined HIPEC with EPIC is an independent prognostic factor for better overall survival (Hazard ratio (HR) = 0.42, 95% confidence interval (CI) = 0.19-0.92, P = 0.030) and disease free survival (HR = 0.66, 95%CI = 0.44-0.99, p = 0.045), adjusted for age, sex, peritoneal cancer index, completeness of cytoreduction score, CEA ≥ 6.5 mg/L, CA19-9 ≥ 24.0 U/mL and CA125 ≥ 32.0 U/mL. Conclusions: In summary, the combination of HIPEC and EPIC could potentially provide additional survival benefit for patients with PMCA with peritoneal spread as compared to HIPEC alone without increasing postoperative morbidity and mortality. More studies are warranted to further confirm the potential benefits of EPIC in PMCA and address the question of optimal drug and/or duration of EPIC.
Article
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.
Article
Background There is little evidence for the use of early postoperative intraperitoneal chemotherapy (EPIC) in patients with low-grade appendiceal mucinous neoplasms (LAMNs) with pseudomyxoma peritonei (PMP). This study aims to assess the outcomes regarding the use of EPIC in a large cohort of patients with LAMNs with PMP uniformly treated by cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC), all of whom received hyperthermic intraperitoneal chemotherapy (HIPEC), and most of whom also received EPIC. Methods This was a retrospective study of prospectively collected data of consecutive patients with peritoneal carcinomatosis of appendiceal origin who underwent CRS and PIC by one surgical team at St George Hospital in Sydney, Australia, between January 1996 and November 2015. Subgroup analyses were performed for patients with a high Peritoneal Cancer Index (PCI) >20 and also based on histopathological subtypes of LAMNs. ResultsA total of 250 patients formed the cohort of this study. No significant differences were observed in terms of hospital mortality (p = 0.153), major morbidity rate (i.e., grade III/IV; p = 0.593), intensive care unit stay (p = 0.764), and total hospital stay (p = 0.927); however, patients who received HIPEC + EPIC had a significantly longer stay in the high dependency unit. Multivariate analysis showed combined HIPEC with EPIC is an independent prognostic factor for better survival outcomes (hazard ratio 0.30, 95 % confidence interval 0.12–0.74; p = 0.009), adjusted for age, PCI, and histopathological subtypes. Conclusions The combination of HIPEC + EPIC can provide additional survival benefits for patients with LAMNs with PMP compared with HIPEC alone, without increasing postoperative morbidity and mortality. EPIC should be considered following CRS and HIPEC for patients with LAMNs with PMP.
Article
Introduction: Peritoneal cancer index (PCI) has been suggested to be the most important prognostic factors for the outcomes in colorectal peritoneal carcinomatosis (CRPC). Methods: This was a retrospective study of prospectively collected data of 168 consecutive patients with CRPC following cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC). Patients were divided into five groups according to their PCI. Results: Hospital mortality was 0%. Patients in low PCI groups had a significantly lower major morbidity rate, shorter intensive care unit and high dependency unit stay and higher overall survival (p=0.017, 0.001, 0.046, p<0.001 respectively). Conclusion: Combined CRS with PIC can be safely performed to provide encouraging survival benefits for patients with CRPC. Our findings suggest that this approach is particularly beneficial for patients with low volume of disease. Early referral to specialist centre for evaluation is warranted for better survival outcomes.
Article
Background: Tumors that show a signet ring or adenocarcinoid histomorphology have been associated with a poor prognosis. This study aimed to analyze the clinicopathologic and prognostic features in patients with peritoneal metastasis from mucinous adenocarcinoma (PMCA), adenocarcinoma with signet ring cell (PMCA-S), or adenocarcinoid (PMCA-A) of the appendix treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy. Methods: Retrospective analysis of a prospectively maintained database for all patients treated for appendiceal adenocarcinoma from 1989 to 2012 was performed. Results: The study cohort consisted of 494 patients including 361 patients with PMCA (73.1 %), 80 patients with PMCA-S (16.2 %), and 53 patients with PMCA-A (10.7 %). The patients comprised 273 men (55.3 %) and 221 women (44.7 %) with a mean age at presentation of 50.7 years for the PMCA-S patients, 47.3 years for the PMCA patients, and 47.5 years for the PMCA-A patients (p < 0.03). The 3- and 5-year survival rates were respectively 51 and 38 % for PMCA compared with 30 and 22 % for PMCA-S and 26 and 15 % for PMCA-A. The median survival time was 45.4 months for PMCA compared with 18.9 months for PMCA-S and 26.8 months for PMCA-A (p < 0.000). The groups did not differ significantly in the completeness of cytoreduction achieved, with 53.5 % of the PMCA patients having a CC0/1 compared with 46.2 % of the PMCA-S patients and 41.6 % of the PMCA-A patients (p < 0.20). In the multivariate analysis, the independent predictors of a reduced survival were incompleteness of cytoreduction, histomorphology of PMCA-S or PMCA-A, and distant metastasis. Conclusion: The findings showed that PMCA-S or PMCA-A histomorphology contributes to the poor prognosis associated with peritoneal metastasis from appendiceal adenocarcinoma. The independent predictors for a poor overall survival included incompleteness of cytoreduction, PMCA-S and PMCA-A histomorphology, and distant metastasis.
Article
Background: The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods: Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). Results: The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. Conclusions: A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.
Article
Purpose: The prognosis of peritoneal carcinomatosis (PC) from colorectal cancer has been improved with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, benefits of postoperative chemotherapy (CT) are unclear. Methods: This retrospective, multicenter study included 231 patients treated by CRS and HIPEC for isolated PC of colon cancer in four expert's centers. Overall survival (OS), progression-free survival (PFS), and peritoneal recurrence-free survival (PRFS) were compared between patients with adjuvant CT (started within 3 months after surgery) and patients with surveillance only. Results: After exclusion of 10 patients for early postoperative death (4 %), 221 patients were included (CT group: n = 151; surveillance group: n = 70). Main postoperative CT regimens (median of 6 cycles) were Folfox (28 %), Folfiri bevacizumab (24.5 %), Folfiri (16 %), and Folfiri cetuximab (12.5 %). The median OS after surgery was 43.3 months with no difference between CT and surveillance groups. In multivariate analysis, a low peritoneal cancer index (p < 0.0001) and a long delay between diagnosis of CP and HIPEC (p = 0.001) were associated with increased OS. The median PFS and PRFS were 12.4 and 17 months, respectively. At 1 year, more patients were without progression (p = 0.001) or PC recurrence (0.0004) in the CT group, but with prolonged follow-up this difference was no longer significant. Conclusions: Early postoperative CT does not improve OS after CRS and HIPEC for colon carcinomatosis. However, a transient effect on PFS and PRFS was observed. A subgroup of patients who may benefit more from CT remain to be defined.
Article
Introduction: The combination of cytoreductive surgery (CRS) and perioperative chemotherapy (PIC) have been proposed as an innovative technique for peritoneal carcinomatosis and is currently considered as a standard treatment for colorectal peritoneal carcinomatosis (CRPC) in selected patients. Peritoneal cancer index (PCI) has been suggested to be the most important prognostic factors for the outcomes of patients with CRPC. In this paper, we have studied patients with CRPC and a very low PCI of 5 or less and their survival outcomes. Methods: This is a retrospective study of prospectively collected data of 60 consecutive patients with CRPC and PCI ≤5, who underwent CRS and PIC by the same surgical team at St George hospital in Sydney, Australia between January 1996 and April 2015. Clinical outcomes of these patients were analysed. Results: Hospital mortality was 0%. 14 patients (23.4%) had grade III/IV morbidity. The median follow-up was 22.2 months (range=0.1-104.2). The median survival was 80.6 months (95% confidence interval (CI)=35.1-126.1), with an overall 1-year, 3-year, and 5-year survival rate of 96.1%, 72.6% and 54.7% respectively. Among 60 patients, 31 patients experienced the recurrence of the disease (51.7%). The median disease-free survival was 10.8 months (95%CI=7.2-14.4). Conclusion: This innovative approach combining CRS and PIC has shown encouraging outcomes and offers hope for patients with CRPC. Our results suggest that CRS and PIC can be performed safely to provide significant survival benefits for patients with low volume of disease. Early referral to specialist centre for evaluation is warranted for better survival outcomes.
Article
Malignant neoplasms of the appendix have different behavior based on their histologic subtypes in anecdotal series. Current staging systems do not capture the diversity of histologic subtypes in predicting outcomes. We queried all patients with appendiceal malignancies captured in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2007. Tumors were classified as colonic type adenocarcinoma, mucinous adenocarcinoma, signet ring cell type, goblet cell carcinoid, and malignant carcinoid. We compared incidence, overall survival, and disease-specific survival for these tumors on the basis of patient, tumor, and therapy characteristics. Estimates from Cox proportional hazard modeling were used to predict hazard ratios for differing histologic subtypes with similar tumor, node, metastasis system (TNM) stages. Of the 5672 patients identified, we included 5655 (99%) in our analysis. The 5-year disease-specific survival rates were 93% for malignant carcinoid, 81% for goblet cell carcinoid, 55% for colonic type adenocarcinoma, 58% for mucinous adenocarcinoma, and 27% for signet ring cell type. Predicted estimates of adjusted hazard ratios revealed an 8-fold difference between histologic subtypes for similar TNM stages. Histologic subtype is an important predictor of disease-specific survival and overall survival in patients with appendiceal neoplasms. Addition of the histologic subtype to the TNM staging is simple and may improve prognostication.
Article
To analyze a large series of patients with pseudomyxoma peritonei (PMP) treated with cytoreductive surgery associated with perioperative intraperitoneal chemotherapy (PIC) in 18 French-speaking centers. From March 1993 to December 2007, 301 patients with diffuse PMP were treated by cytoreductive surgery with PIC. Complete cytoreductive surgery was achieved in 219 patients (73%), and hyperthermic intraperitoneal chemotherapy (HIPEC) was performed in 255 (85%), mainly during the latter period of the study. Postoperative mortality and morbidity were 4.4% and 40%, respectively. The mean follow-up was 88 months. The 5-year overall and disease-free survival rates were 73% and 56%, respectively. The multivariate analysis identified 5 prognostic factors: the extent of peritoneal seeding (p=0.004), the center (p=0.0004), the pathologic grade (p=0.03), gender (p=0.02), and the use of HIPEC (p=0.04). When only the 206 patients with complete cytoreductive surgery were considered, the extent of peritoneal seeding was the only significant prognostic factor (p=0.004). This large multicentric retrospective study confirms that cytoreductive surgery combined with PIC (with the use of hyperthermia) should be considered as the gold standard treatment of PMP and should be performed in specialized centers. It underlines the prognostic impact of the extent of peritoneal seeding, especially in patients treated by complete cytoreductive surgery. This prognostic impact appears to be greater than that of the pathologic grade.
Article
The treatment of gastrointestinal cancer and the prognosis of patients with this disease have changed very little over the past several decades. No screening tools have been developed which allow this disease to be surgically treated for cure at an early stage. None of the forms of adjuvant chemotherapy instituted in the months and years after surgical resection of cancer have been successful. We show that resection site recurrence and spread of disease on the peritoneal surfaces are the most common sites for surgical treatment failure. By changing the route of administration and the timing of chemotherapy, the efficacy of drugs now routinely employed in gastrointestinal cancer can be markedly improved. Our early studies suggest that there is a definite change in the natural history of these malignancies when intraperitoneal chemotherapy is administered immediately after surgery. The pharmacology and physiology of drug delivery in the immediate postoperative period are explored. Toxicity studies have been performed in a series of treatment protocols already in use. These protocols need to be subjected to randomized controlled trials in the near future.
Article
The aim of this investigation was to determine the prognostic variables and optimal surgical procedure for patients with adenocarcinoma of the appendix. Primary adenocarcinoma of the appendix is a rare malignancy that constitutes less than 0.5% of all gastrointestinal neoplasms. However, the prognostic factors and the preferred surgical procedure and outcome are poorly understood. The authors reviewed their institutional experience from 1976 to 1992 in treating 94 consecutive patients with primary adenocarcinoma of the appendix. Patients with carcinoid tumors or those in whom the diagnosis of primary cecal cancer could not be ruled out were excluded from the study. Fifty-two (55%) patients had the mucinous variety, of which 22 had pseudomyxoma peritonei; the other 45% had the colonic and adenocarcinoid types of tumor. The most common presentation was that of acute appendicitis. Interestingly, in no patients was the correct diagnosis made before surgery, and it was entertained intraoperatively in only 30 patients (32%). The cure 5-year survival rate was 55%, but it varied with stage (A, 100%; B, 67%; C, 50%; and D, 6%; p < 0.01) and with grade (I, 68%, and III, 7%; p < 0.01). Patients with the mucinous type had a better prognosis than those with the colonic type (p < 0.01). The survival rate was superior after right hemicolectomy versus appendectomy alone (68% vs. 20%, p < 0.001). Right hemicolectomy performed as a secondary procedure resulted in the upstaging of 38% of the patients' tumors. A second primary malignancy occurred in 33 patients (35%), of which 17 were located in the gastrointestinal tract. Primary adenocarcinoma of the appendix should be treated by right hemicolectomy, even if it is a secondary procedure. Surveillance for synchronous or metachronous tumors, especially in the gastrointestinal tract, is warranted.
Article
Surgical cytoreduction combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been recently advocated as the standard of care for pseudomyxoma peritonei (PMP). We reviewed our 10-year monoinstitutional case series to identify selection factors predicting postoperative outcome. One hundred and four patients with PMP were operated on with the aim of performing adequate cytoreduction (residual tumor nodules < or =2.5 mm) and closed-abdomen HIPEC with mytomicin-C and cisplatin. Previously, 26 patients had systemic chemotherapy. PMP was histologically classified into disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and intermediate/discordant group (ID). Immunohistochemical stains were performed for cytokeratin (CK)-7, CK-20, CDX-2, MUC-2, MUC-5AC, CD-44s. The significance of 22 potential clinical, pathological, and biological prognostic variables was assessed by multivariate analysis. Adequate cytoreduction was performed in 89 patients, suboptimal cytoreduction in six, palliative surgery in nine. Operative mortality was 1%. Seventy-eight patients were diagnosed with DPAM, 26 with PMCA, and none with ID. Median follow-up was 37 months (range, 1-110) for the overall series. Five-year overall survival (OS) and progression-free survival (PFS) were 78.3% and 31.1%, respectively. At multivariate analysis, adequate cytoreduction, no previous systemic chemotherapy, and DPAM correlated to better OS and PFS, elevated serum CA19.9 correlated only to better PFS. In most cases, CK20, CDX-2, and MUC-2 were diffusely positive, while CK-7, MUC-5AC, and CD44s were variably expressed. CK20 expression correlated to prognosis at univariate analysis. Favorable outcome after comprehensive treatment can be expected in patients with DPAM, not treated with preoperative systemic chemotherapy and amenable to adequate cytoreduction. MUC-2, CK-20, and CD44s expression may be related to PMP unique biologic behavior.
Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis.
  • Jacquet P.
  • Sugarbaker P.H.
Hyperthermic intraperitoneal chemotherapy+ early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis.
  • Lam J.Y.
  • McConnell Y.J.
  • Rivard J.D.
A Language and Environment for Statistical Computing.
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Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality.
  • Chua T.C.
  • Yan T.D.
  • Saxena A.
  • Morris D.L.