Comparing Survival Outcomes and Impact of EPIC in Patients Undergoing CRS/HIPEC for Mucinous Appendiceal Neoplasm.

BACKGROUND/AIM: This study sought to investigate the difference in survival outcomes in patients with complete cytoreduction (CC)-0 or CC-1 mucinous appendiceal cancer undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). It also investigated what effect early postoperative intraperitoneal chemotherapy (EPIC) may have on survival based on CC score and histology. PATIENTS AND METHODS: This was a retrospective single centre study of patients that underwent CRS/HIPEC +/- EPIC for mucinous appendiceal neoplasms from June 2003 to February 2022. RESULTS: A total of 545 patients were identified. Although there was a survival difference between CC-0 and CC-1 on univariate analyses, this was not statistically significant on multivariate analysis. Histology, peritoneal cancer index, and EPIC status were demonstrated to be independent factors that affected overall survival (OS) on multivariate analysis. Patients with CC-1 that received EPIC had significantly improved OS (mean OS 14 years) when compared to patients that did not receive EPIC (mean OS 6 years). In CC-1, OS was significantly improved in patients that received EPIC in both low-grade (p<0.001) and high-grade (p=0.012) disease. OS for patients that received EPIC at 1, 5, and 10 years was 95%, 80%, and 59%, respectively. OS for patients that did not receive EPIC at 1, 5, and 10 years was 84%, 49%, and 30%, respectively. CONCLUSION: There was no difference in OS between CC-0 and CC-1. The implementation of EPIC in patients with CC-1 significantly improved OS in both low-grade and high-grade disease and thus we recommend its addition in CC-1 disease to achieve optimal survival outcome.

Morbidity following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases with or without early postoperative intraperitoneal chemotherapy: A propensity score matched study.

BACKGROUND: Combining hyperthermic intraperitoneal chemotherapy (HIPEC) treatment with early postoperative intraperitoneal chemotherapy (EPIC) may increase postoperative morbidity. This study aims to investigate postoperative morbidity after HIPEC+EPIC compared with HIPEC alone in patients with peritoneal metastases (PM). MATERIALS AND METHODS: This is a retrospective propensity score matched cohort study. All patients undergoing PM treatment at Uppsala University Hospital between February 2004 and December 2014 were included. Propensity score matching with a 1:1 ratio was performed using sex, primary tumor site, preoperative chemotherapy, peritoneal cancer index, completeness of cytoreduction score, and HIPEC regimen. Length of hospital stay, morbidity, reoperation rate, and readmission rate within 6 months were selected as endpoints. RESULTS: A total of 390 consecutive patients were divided in two arms: HIPEC+EPIC (n = 115) and HIPEC alone (n = 275). The propensity score matching (n = 190) was successful with balanced covariates: 95 patients/arm. The length of stay (LOS) was longer in the HIPEC + EPIC group in the total cohort (30 vs 24 days, p < 0.001), with a trend towards significance in the propensity matched group (29 vs 25 days, p = 0.062). No other differences in endpoints were found. CONCLUSION: HIPEC+EPIC is associated with a prolonged hospital stay, but with no statistically significant relevant increase in postoperative morbidity, reoperation rate or incidence of readmission.

Hyperthermic intraperitoneal chemotherapy in prevention of gastric cancer metachronous peritoneal metastases: a systematic review.

Gastric cancer progression resulting in metachronous peritoneal metastasizing is almost always associated with an adverse prognosis. This review discusses various options of preventing metachronous peritoneal metastases in radically operated gastric cancer patients. Also examined are different hyperthermic intraperitoneal chemotherapy (HIPEC) regimens employed in gastric cancer treatment, postoperative morbidity and mortality rates and long-term treatment outcomes. The authors also review their own experience of using HIPEC based on the combination of cisplatin and doxorubicin in doses of 50 mg/m2 at 42 °C for 1 h to prevent gastric cancer peritoneal dissemination. As a result, progression-free survival rose from 19.6%±5.6% to 47.1%±6.3% (Plog-rank <0.001) and dissemination-free survival-from 22.7%±6.0% to 51.9%±6.3% (Plog-rank <0.001). It is noted that the combination of the described HIPEC regimen with systemic chemotherapy helped raise metastases-free 3-year survival rate to up to 91.0%±9.0% (Plog-rank =0.025) compared with 48.6%±6.4% for patients who underwent only a combined surgery/HIPEC treatment. HIPEC is a promising combined treatment strategy for radically operated gastric cancer patients that can improve patient survival and decrease peritoneal dissemination rate. However, the number of randomized studies on adjuvant HIPEC are still insufficient for a subgroup assessment of efficacy of the given chemotherapy regimens and generation of evidence-based recommendations on the individual use of chemotherapy agents and their combinations, and HIPEC procedural techniques. Further prospective randomized studies are needed to assess the practicability of complementing HIPEC with adjuvant systemic chemotherapies.

Review of management and treatment of peritoneal metastases from gastric cancer origin.

Gastric cancer (GC) is the third cause of cancer-related deaths in the world, with less than 25% survivors at 5 years. These results are largely related to the high incidence of peritoneal metastases (PM) in these patients. Nowadays, the standard treatment for GC with PM is palliative systemic chemotherapy (SCT) with a survival of 6 months. From the 2000s, the combination of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been gaining popularity for different neoplastic diseases that involve the peritoneal surface. The use of CRS and HIPEC has been studied for GC with PM, with promising results in selected patients, obtaining survival rates never seen before. Moreover, HIPEC and other intraperitoneal chemotherapy techniques have been used to prevent peritoneal recurrences in patients diagnosed on locally advanced GC without macroscopic PM (adjuvant or prophylactic HIPEC). Even, intraperitoneal chemotherapy [laparoscopic HIPEC and neoadjuvant intraperitoneal and systemic chemotherapy (NIPS)] has been used as neoadjuvant treatment to reduce peritoneal disease burden in order to improve the rate of patients in whom complete cytoreduction can be achieved. Finally, patients with high volume peritoneal disease can be treated by palliative intraperitoneal chemotherapy to control the symptoms resulting from malignant ascites, using laparoscopic HIPEC or pressurized intraperitoneal aerosol chemotherapy (PIPAC). This review aims to update the management of PM from GC origin in these different clinical scenarios, based on the literature and the experience of the authors.

Hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal and appendiceal peritoneal metastases: lessons learned from PRODIGE 7.

The treatment for peritoneal metastases from appendiceal, colon and rectal cancer (MO1) has relied on cytoreductive surgery (CRS) to remove all visible evidence of disease plus a perioperative chemotherapy for the entire abdomen to eliminate microscopic residual disease. Using the results obtained from the PRODIGE 7 randomized controlled trial, methodological issues were discussed and possible improvements to the hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin were sought. Possible methodological and pharmacologic flaws were identified. Several methodological flaws included the sample size, cross-over option, neoadjuvant chemotherapy use and timing of the peritoneal disease evaluation. The sample size issue raised the question of what the minimal clinically relevant benefit we want in future trials. Neoadjuvant FOLFOX may have induced acquired drug resistance to oxaliplatin. Several pharmacological issues were identified including limited 5-fluorouracil exposure as well as limited oxaliplatin peritoneal exposure time. Insufficient 5-fluorouracil accompanied the oxaliplatin as only a bolus dose was used and continuous 5-FU infusion has previously been an integral part of oxaliplatin treatment. Finally, only approximately one-half of the oxaliplatin entered body tissues or tumor. Three suggestions from the lessons learned from a critique of PRODIGE 7 were offered as adjustments to the HIPEC protocol. The Efficacy of HIPEC, a perioperative FOLFOX or a return to HIPEC with mitomycin C were described.

Intraperitoneal paclitaxel: pharmacology, clinical results and future prospects.

Paclitaxel administered into the peritoneal cavity is a chemotherapy agent that shows unusually prolonged retention within the peritoneal space. Using this pharmacokinetic fact as a starting point, the use of this drug to benefit patients with peritoneal metastases was investigated. The pharmacokinetics and drug characteristics of paclitaxel were identified from the oncologic literature. The experience to date with ovarian cancer, malignant peritoneal mesothelioma, gastric cancer and pancreas cancer was explored. Paclitaxel given by repeated instillation through an intraperitoneal port has demonstrable responses in ovarian cancer, peritoneal mesothelioma, gastric cancer and pancreas cancer when peritoneal metastases are present. Its role for prevention of peritoneal metastases in patients at high risk seems less well established. Randomized controlled studies have been positive in ovarian cancer but not in other diseases with peritoneal dissemination. A randomized controlled study in gastric cancer with peritoneal metastases produced suggestive but not conclusive results. Conversion surgery after repeated treatments with intraperitoneal paclitaxel has been reported with gastric cancer and pancreas cancer with peritoneal metastases. The pharmacology of intraperitoneal paclitaxel strongly suggest that intraperitoneal administration should be of benefit to prevent or treat peritoneal metastases. Protocols that the oncologist can follow to realize these potential benefits are not as yet available.

Preparation and Evaluation of Intraperitoneal Long-Acting Oxaliplatin-Loaded Multi-Vesicular Liposomal Depot for Colorectal Cancer Treatment.

Colorectal cancer with peritoneal metastasis has a poor prognosis because of inadequate responses to systemic chemotherapy. Cytoreductive surgery followed by intraperitoneal (IP) chemotherapy using oxaliplatin has attracted attention; however, the short half-life of oxaliplatin and its rapid clearance from the peritoneal cavity limit its clinical application. Here, a multivesicular liposomal (MVL) depot of oxaliplatin was prepared for IP administration, with an expected prolonged effect. After optimization, a combination of phospholipids, cholesterol, and triolein was used based on its ability to produce MVL depots of monomodal size distribution (1-20 µm; span 1.99) with high entrapment efficiency (EE) (92.16% ± 2.17%). An initial burst release followed by a long lag phase of drug release was observed for the MVL depots system in vitro. An in vivo pharmacokinetic study mimicking the early postoperative IP chemotherapy regimen in rats showed significantly improved bioavailability, and the mean residence time of oxaliplatin after IP administration revealed that slow and continuous erosion of the MVL particles yielded a sustained drug release. Thus, oxaliplatin-loaded MVL depots presented in this study have potential for use in the treatment of colorectal cancer.

Intraperitoneal delivery of chemotherapeutic agents for the treatment of peritoneal metastases: current challenges and how to overcome them.

Introduction: Peritoneal metastases of cancer remain a major cause of an adverse outcome and death following surgical treatment of malignancies that occur within the abdomen and pelvis. The administration of a chemotherapy solution directly into the peritoneal space has been used to improve the survival in this group of patients.Areas covered: Relevant manuscripts from my own publications and identified through Medline and PubMed were reviewed if they concerned neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), normothermic intraperitoneal chemotherapy (NIPEC). The pharmacologic information that will impact on the efficacy of intraperitoneal chemotherapy administration was also reviewed.Expert opinion: The four major technologies for obtaining peritoneal access of cancer chemotherapy to peritoneal metastases were studied. The differences in distribution of chemotherapy solution, in selection of chemotherapy agents to be delivered, and variations in delivery systems were presented and critically analyzed. The most obvious benefits of combined cytoreductive surgery and intraperitoneal chemotherapy have been demonstrated with appendiceal mucinous neoplasms and malignant peritoneal mesothelioma. Continued efforts with new intraperitoneal chemotherapy agents and methods of drug delivery continue for ovarian cancer, colorectal cancer, and gastric cancer.

Total pelvic exenterative surgery in patients with peritoneal metastases from appendiceal neoplasms. A case series of 2 patients.

BACKGROUND: Surgery which includes peritonectomy, visceral resections, and perioperative chemotherapy has been used extensively to treat peritoneal metastases from appendiceal mucinous adenocarcinoma. The results of treatment vary with the grade of the neoplasm, the extent of abdominal and pelvic disease and the completeness of tumor removal. METHODS: The clinical features, surgical procedures and outcome of two patients with mucinous appendiceal neoplasms were reviewed. The decision to move to total pelvic exenterative surgery after prior treatment failure was critically evaluated. RESULTS: Patient 1 had three extensive surgical procedures prior to total pelvic exenteration and one surgical procedure after. Patient 2 had one 16-h surgical procedure prior to total pelvic exenteration. Patient 1 had 8 years and 1 month survival from onset of disease until death. Patient 2 is free of disease at 27 years from onset of pseudomyxoma peritonei. After recovery of the patients from the extensive surgery, their quality of life was acceptable. CONCLUSION: Total pelvic exenteration surgery is seldom used in patients with peritoneal metastases from appendiceal neoplasms. These two patients were studied in an attempt to determine the indications for this procedure with this disease.

Revised management of advanced primary colon cancer: Case series of 2 patients.

BACKGROUND: The resection of a primary colon cancer has the opportunity to cure the patient of cancer by complete clearance and absolute containment of disease. Alternatively, if the cancer resection does not provide clearance and containment it will eventuate in local recurrence and peritoneal dissemination. METHODS: Culpability of recurrence of colorectal cancer is difficult to determine. Are the management strategies of the primary cancer evaluation and treatment at fault or is the underlying disease process is to be held responsible? The clinical and radiologic findings that could have been evaluated by a multidisciplinary team (MDT) were critically evaluated in 2 patients with right colon adenocarcinoma. Strategies to accomplish complete clearance and absolute containment of the primary malignancy as resectable for cure were suggested. RESULTS: Clinical evaluation of these 2 patients suggested that more knowledgeable preoperative evaluation by the multidisciplinary team (MDT) should have placed them in a high risk group for local recurrence and/or peritoneal dissemination. High carcinoembryonic antigen (CEA) tumor marker and by CT a large primary cancer infiltrating adjacent structures can be used to select advanced pre- and intraoperative treatment strategies. CONCLUSIONS: Two patients who had an approximately 50% possibility of long-term survival with optimal preoperative evaluation and expert surgical resection techniques may have been converted to a greatly reduced survival because of tumor dissemination and positive margins of resection at the time of primary cancer resection. Neither patient was evaluated by an MDT preoperatively. It is possible that these two patients entered the operating room with a contained malignancy but as result of suboptimal pre- and intraoperative management left the operating room with disseminated intraperitoneal disease.

Update on the management of malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma (MPM) is a rare disease whose natural history is confined to the peritoneal space. Systemic chemotherapy has little impact on survival of patients with MPM. A surgical procedure with a goal of resection of all visible evidence of disease, called cytoreductive surgery (CRS) has been utilized in MPM patients. Also, regional chemotherapy with hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic intraperitoneal chemotherapy long-term (NIPEC-LT) have been effectively utilized in MPM patients. In the absence of CRS and HIPEC the median survival of MPM patients is approximately 1 year. The aggressive surgical approach plus regional chemotherapy has increased the median survival to more than 5 years. With NIPEC-LT added on, 70% 5-year survival has been reported. Knowledgeable patient selection for treatment is mandatory. The use of CRS, HIPEC and NIPEC-LT has greatly benefited patients with MPM. Global application of these treatments is indicated.

Peritoneal Metastases from Malignant Mesothelioma.

Diffuse malignant peritoneal mesothelioma (MPM) is a rare cancer that is ultimately fatal in almost all afflicted individuals. Morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. Patients with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. MPM is considered a chemotherapy-resistant malignancy.

Early postoperative intraperitoneal chemotherapy is associated with survival benefit for appendiceal adenocarcinoma with peritoneal dissemination.

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.

Radical appendectomy as an alternative to right colon resection in patients with epithelial appendiceal neoplasms.

OBJECTIVE: Appendectomy is an extremely common surgical procedure usually performed for an inflammatory process within this organ. Upon occasion, the pathology within the appendix is a neoplastic process which requires definitive oncologic management. METHODS: The optimal management strategies for appendiceal neoplasms were reviewed and pertinent literature critically evaluated. The technology for appendectomy for an inflammatory process and an appendectomy for a neoplastic process were compared and contrasted. RESULTS: A new surgical procedure called "radical appendectomy" was described and its merits for optimizing the management of an appendiceal neoplasm enumerated. The technology of radical appendectomy was described. The possible shortcomings that may be encountered in performing a new surgical methodology for appendectomy was presented and the results of a technically perfect radical appendectomy enumerated. The integration of a radical appendectomy with perioperative hyperthermic chemotherapy was described. CONCLUSIONS: When a malignancy exists as the cause of appendiceal pathology, the radical appendectomy will provide the maximal amount of information required for optimal decisions regarding patient management.

Long-term regional chemotherapy for patients with epithelial malignant peritoneal mesothelioma results in improved survival.

PURPOSE: Malignant peritoneal mesothelioma (MPM) is a rare disease with about 300 new cases per year in the USA. Its natural history is described as local progression within the peritoneal space in the absence of liver metastases or systemic disease. METHODS: Cytoreductive surgery (CRS) is a series of peritonectomy procedures and visceral resections with a goal of complete removal of all visible disease from the abdomen and pelvis. Over 20 years, three protocols investigating increasing efficacy of additional chemotherapy treatments added to CRS have been initiated. Initially, hyperthermic perioperative chemotherapy (HIPEC) with doxorubicin and cisplatin was used in the operating room. Then, early postoperative intraperitoneal chemotherapy (EPIC) with paclitaxel was added for the first 5 days after CRS. The third protocol employed HIPEC, then EPIC, and then long-term intraperitoneal (IP) paclitaxel or IP pemetrexed plus intravenous (IV) cisplatin as a adjuvant normothermic intraperitoneal chemotherapy (NIPEC). RESULT: The 5-year survival of 42 patients treated with CRS and HIPEC was 44%, for 58 patients treated with EPIC and HIPEC was 52% and 29 patients who received HIPEC, EPIC, and NIPEC was 75% (p = 0.0374). Prognostic variables of age, gender, treatment administered, peritoneal cancer index (PCI) and completeness of cytoreduction were significant by univariate analysis and treatments administered and completeness of cytoreduction significant by multivariate analysis. CONCLUSIONS: Long-term regional chemotherapy was associated with improved survival in patients with MPM. In this rare disease, additional phase 2 investigations are suggested.

Overview of the optimal perioperative intraperitoneal chemotherapy regimens used in current clinical practice.

Peritoneal surface malignancy (PSM) is a common manifestation of digestive and gynecologic malignancies alike. At present, patients with isolated PSM are treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The combination of CRS and intraperitoneal (IP) chemotherapy should now be considered standard of care for PSM from appendiceal epithelial cancers, colorectal cancer and peritoneal mesothelioma. Although there is a near universal standardization regarding the CRS, we are still lacking a much-needed standardization among the various IP chemotherapy treatment modalities used today in clinical practice. Pharmacologic evidence should be generated to answer important questions raised by the myriad of variables associated with IP chemotherapy.

Cytoreductive surgery and intraperitoneal chemotherapy: an evidence-based review-past, present and future.

Peritoneal carcinomatosis (PC) has historically been considered a terminal condition with merely palliative treatment achieving a survival rate measured in months. Cytoreductive surgery (CyRS) and intraperitoneal chemotherapy (IPC) have emerged as potentially effective regional treatments with the potential for long-term survival in well-selected patients. The fundamentals of CyRS and IPC are patient selection and complete cytoreduction. Since there is now sufficient evidence for the superiority of CyRS and IPC to systemic chemotherapy alone in a highly select group of patients, surgeons and oncologists should be aware of this modality as a potential benefit for patients with PC. The aim of this report is to highlight cancer-specific evidence in the context of ongoing studies regarding the outcome of this treatment.

Cytoreductive surgery and heated intraperitoneal chemotherapy for peritoneal carcinomatosis secondary to mucinous adenocarcinoma of the appendix.

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a radical but effective treatment option for select peritoneal malignancies. We sought to determine our early experience with this method for peritoneal carcinomatosis secondary to mucinous adenocarcinomas of appendiceal origin. As such, we performed a retrospective clinical study of 30 consecutive patients undergoing CRS with planned HIPEC at the Princess Alexandra Hospital, between June 2009 to December 2012, with mucinous adenocarcinomas of the appendix. CRS was performed in 30 patients, 13 received HIPEC intraoperatively and 17 received early postoperative intra-peritoneal chemotherapy (EPIC) in addition. Mean age was 52.3 years and median hospital stay was 26 days (range 12-190 days). Peritoneal cancer index scores were 0-10 in 6.7% of patients, 11-20 in 20% of patients and >20 in 73.3% of patients. Complete cytoreduction was achieved overall in 21 patients. In total, 106 complications were observed in 28 patients. Ten were grade 3-A, five were grade 3-B and one grade-5 secondary to a fatal PE on day 97. In patients who received HIPEC, there was no difference in disease-free survival (P = 0.098) or overall survival (P = 0.645) between those who received EPIC versus those who did not. This study demonstrates that satisfactory outcomes with regards to morbidity and survival can be achieved with CRS and HIPEC, at a single-centre institution with growing expertise in the technique. Our results are comparable with outcomes previously described in the international literature.

Peritoneal debulking/intraperitoneal chemotherapy-non-sarcoma.

The combination of cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is widely practiced for appendiceal, colorectal, gastric, and ovarian cancers with isolated peritoneal metastasis as well as for primary peritoneal cancer. The aim of this report is to explain the rationale and available techniques for CRS and IPC, and to highlight disease-specific considerations that should be taken into account when evaluating potential candidates for CRS and IPC.