Colorectal Peritoneal Carcinomatosis Research Articles

Curative cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis and synchronous resectable liver metastases arising from colorectal cancer

ObjectivesThis study describes the outcomes of patients with colorectal peritoneal carcinomatosis (PC) with or without liver metastases (LMs) after curative surgery combined with hyperthermic intraperitoneal chemotherapy, in order to assess prognostic factors. BackgroundCytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) increases overall survival (OS) in patients with PC. The optimal treatment both for PC and for LMs within one surgical operation remains controversial. MethodsPatients with PC who underwent CRS followed by HIPEC were evaluated from a prospective database. Overall survival and disease free survival (DFS) rates in patients with PC and with or without LMs were compared. Univariate and multivariate analyses were performed to evaluate predictive variables for survival. ResultsFrom 1999 to 2011, 22 patients with PC and synchronous LMs (PCLM group), were compared to 36 patients with PC alone (PC group). No significant difference was found between the two groups. The median OS were 36 months [range, 20–113] for the PCLM group and 25 months [14–82] for the PC group (p > 0.05) with 5-year OS rates of 38% and 40% respectively (p > 0.05). The median DFS were 9 months [9–20] and 11.8 months [6.5–23] respectively (p = 0.04). The grade III–IV morbidity and cytoreduction score (CCS) >0 (p < 0.05) were identified as independent factors for poor OS. Resections of LMs and CCS >0 impair significantly DFS. ConclusionsSynchronous complete CRS of PC and LMs from a colorectal origin plus HIPEC is a feasible therapeutic option. The improvement in OS is similar to that provided for patients with PC alone.

Surgical Treatment of Colorectal Cancer with Peritoneal and Liver Metastases Using Combined Liver and Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Report from a Single-Centre Experience.

Chemotherapeutic advances have enabled successful cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) expansion in treating metastatic colorectal cancer. The aims of this study were to evaluate the safety of combining liver surgery (LS) with HIPEC and CRS (which remains controversial) and its impact on overall survival (OS) rates. From 2007 to 2015, a total of 77 patients underwent CRS/HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. Twenty-five of these patients underwent concomitant LS for suspicion of liver metastases (LM; group 2), and were compared with patients who underwent CRS/HIPEC only (group 1). Demographic and clinical data were reviewed retrospectively. Among the group 2 patients, two underwent major hepatectomies, six underwent multiple wedge resections, 16 underwent single wedge resections (one with radiofrequency ablation), and one underwent radiofrequency ablation alone. For groups 1 and 2, median peritoneal cancer index was 6 and 10 (range 0-26; p=0.08), complication rates were 15.4 and 32.0% (Dindo-Clavien ≥3; p=0.15), and median follow-up was 34.2 and 25.5months (range 0-75 and 3-97), respectively. One group 2 patient died of septic shock after 66days. Pathology confirmed LM in 21 patients in group 2 (four with benign hepatic lesions were excluded from long-term outcome analysis). Two-year OS rates were 89.5 and 70.2% (p=0.04), and 2-year recurrence-free survival rates were 38.3 and 13.4% (p=0.01) in groups 1 and 2, respectively. Simultaneous surgery for colorectal LM and PC is both feasible and safe, with low postoperative morbidity. Further longer-term studies would help determine its impact on patient survival.

A new technique to improve surgery for peritoneal colorectal metastases?

A new technique to improve surgery for peritoneal colorectal metastases?

Efficacy of Surgical Treatment of Peritoneal Carcinomatosis in Patients with Colorectal Cancer

Colorectal cancer is one of the most common types of cancer in Ukraine. Prognosis for patients with peritoneal carcinomatosis is unfavorable, and life expectancy is typically less than 6 months. Cytoreductive surgery was introduced as a new method of treating these patients to prolong their survival time.The objective of the research was to evaluate and compare the efficacy of cytoreductive surgery, chemotherapy and symptomatic treatment of patients with colorectal cancer and peritoneal carcinomatosis.Materials and methods. The research included 93 patients with colorectal cancer and peritoneal carcinomatosis. All patients were divided into 3 groups depending on the method of treatment being used after the detection of peritoneal carcinomatosis: Group I - cytoreductive surgery, Group II - palliative chemotherapy, Group III - symptomatic treatment. Cumulative overall survival in three groups was analyzed using the Kaplan-Meier method.Results. Statistically significant difference in overall survival was observed between patients treated with different methods. The median overall survival of patients of Group I (n=44) was 15.5 months; the median overall survival of patients of Group II (n=27) was 5.9 months; in patients of Group III (n=22) it was 3.1 months (p &lt;0.0001). The analysis of patients’ survival in Group I depending on the application of palliative chemotherapy after cytoreductive surgery showed no significant difference in overall survival: 16.5 months with chemotherapy versus 14.2 months without chemotherapy (p = 0.12).Conclusions. Overall survival of patients with colorectal cancer and peritoneal carcinomatosis was higher when treated with cytoreductive surgery compared to palliative chemotherapy and symptomatic treatment. Palliative chemotherapy had no effect on survival after cytoreductive surgery for peritoneal carcinomatosis.

306. Survival prognostic factors in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and intraoperative hyperthermic intreperitoneal chemotherapy – A single institution experience

306. Survival prognostic factors in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and intraoperative hyperthermic intreperitoneal chemotherapy – A single institution experience

49. Timing of systemic chemotherapy in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and HIPEC

49. Timing of systemic chemotherapy in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and HIPEC

98. Perioperative outcomes of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal carcinomatosis: PRODIGE 7 randomized trial

98. Perioperative outcomes of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal carcinomatosis: PRODIGE 7 randomized trial

Intraperitoneal-Free Cancer Cells Represent a Major Prognostic Factor in Colorectal Peritoneal Carcinomatosis.

Intraperitoneal-free cancer cells are considered as an important prognostic tool in gastric and ovarian cancer. However, their significance in colorectal cancer remains more controversial. This study aimed to determine the role of intraperitoneal-free cancer cells as a prognostic tool in the outcome in colorectal peritoneal carcinomatosis treated with curative intent by complete cytoreductive surgery. This study is an analysis of a prospectively maintained database. Between 1991 and 2012, all patients treated in a single institution for colorectal peritoneal carcinomatosis by complete cytoreductive surgery with peritoneal cytology available were evaluated. Peritoneal cytology was stained in the conventional way (May Grumwald Giemsa). Among a population of 162 patients treated for colorectal peritoneal carcinomatosis by complete cytoreductive surgery, 38 presented positive intraperitoneal-free cancer cells (23.5%). Systemic chemotherapy was administered to 135 patients (85%) during the preoperative course. Median follow-up was 34.5 months. Median overall survival was 19 and 44 months for positive and negative intraperitoneal-free cancer cells (p = 0.018). In multivariate analysis, Peritoneal Carcinomatosis Index and positive intraperitoneal-free cancer cells were significant prognostic factors of overall survival (HR, 2.3 (1.18-4.52), p = 0.014; HR, 1.9 (1.08-3.38), p = 0.027). Retrospective analysis and the long period were limitations of study. Along with the Peritoneal Carcinomatosis Index, intraperitoneal-free cancer cells are a strong prognostic factor for patients treated with curative intent for colorectal peritoneal carcinomatosis by complete cytoreductive surgery. The presence of intraperitoneal-free cancer cells should lead to the consideration of different treatment strategies such as extensive intraperitoneal lavage, targeted intraperitoneal therapies, or repeated intraperitoneal chemotherapy.

Secretory TRAIL-Armed Natural Killer Cell-Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft.

Since its discovery in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest among oncologists due to its remarkable ability to induce apoptosis in malignant human cells, but not in most normal cells. However, one major drawback is its fast clearance rate in vivo Thus, the development of an alternative means of delivery may increase the effectiveness of TRAIL-based therapy. In this study, we developed a secretory TRAIL-armed natural killer (NK) cell-based therapy and assessed its cytotoxic effects on colorectal cancer cells and its tumoricidal efficacy on colorectal peritoneal carcinomatosis xenograft. We generated genetically modified NK cells by transduction with a lentiviral vector consisting of a secretion signal domain, a trimerization domain, and an extracellular domain of the TRAIL gene. These NK cells secreted a glycosylated form of TRAIL fusion protein that induced apoptotic death. Intraperitoneally, but not intravenously, injected NK cells effectively accumulated at tumor sites, infiltrated tumor tissue, induced apoptosis, and delayed tumor growth. These results shed light on the therapeutic potential of genetically engineered NK cells to treat peritoneal carcinomatosis. Mol Cancer Ther; 15(7); 1591-601. ©2016 AACR.

Impacts of peritoneal cancer index on the survival outcomes of patients with colorectal peritoneal carcinomatosis

IntroductionPeritoneal cancer index (PCI) has been suggested to be the most important prognostic factors for the outcomes in colorectal peritoneal carcinomatosis (CRPC). MethodsThis 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. ResultsHospital 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). ConclusionCombined 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.

Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity.

One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.

Is preoperative chemotherapy related to the survival of patient operated for peritoneal colorectal carcinomatosis and can it induce complete pathological response?

e15159Background: Preoperative Systemic chemotherapy (pCT) often complements cytoreductive surgery and intraperitoneal chemotherapy in the peritoneal colorectal carcinomatosis (PCC) treatment. But ...

Thermosensitive hydrogel system assembled by PTX-loaded copolymer nanoparticles for sustained intraperitoneal chemotherapy of peritoneal carcinomatosis

Intraperitoneal (IP) chemotherapy is a preferable treatment option for peritoneal carcinomatosis of malignancies by delivering chemotherapeutic drugs into the abdominal cavity. A persistent major challenge in IP chemotherapy is the need to provide effective drug concentration in the peritoneal cavity for an extended period of time. In the present work, the thermosensitive hydrogel system (PTX/PECTgel) assembled by PTX (paclitaxel)-loaded amphiphilic copolymer (PECT, poly (ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly (ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)) nanoparticles was developed for sustained IP chemotherapy of peritoneal carcinomatosis model. Cytotoxicity assay indicated that PECT hydrogel was biocompatible with very low cytotoxicity and PTX/PECTgel had enhanced cytotoxicity than free PTX. In vivo toxicity study demonstrated the biocompatibility and biosafety of PECT hydrogel as an IP chemotherapy carrier. The fluorescence imaging method was employed to monitor the intraperitoneal degradation of PECT hydrogel by labeling PECT with rhodamine B. PECT hydrogel with the dose of 200μL showed about 8days’ retention time and most of the injected hydrogel was located in the intestine. The anti-tumor efficacy study was carried out in mice bearing CT26 intraperitoneal ascites fluid as colorectal peritoneal carcinomatosis model. The result showed that intraperitoneal administration of PTX/PECTgel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, compared with Taxol® group. The pharmacokinetic studies demonstrated that PTX/PECTgel could improve the bioavailability of PTX by being formulated in PECT hydrogel. Overall, sustained drug concentration at peritoneal levels in combination with drug in the form of nanoparticle contributes to the enhanced anti-tumor efficacy. Thus, our results suggested that PTX/PECTgel may have great potential applications in IP chemotherapy.

What made hyperthermic intraperitoneal chemotherapy an effective curative treatment for peritoneal surface malignancy: A 25-year experience with 1,125 procedures.

To review our 25-year experience with hyperthermic intra-peritoneal chemotherapy (HIPEC). Combining cytoreductive surgery (CRS) and HIPEC as local treatments for peritoneal carcinomatosis (PC) was proposed 25 years ago. A prospective database of all patients undergoing HIPEC for PC since 1989 was searched for clinicopathological data, 90-day morbidity and mortality, and survival. Among 1,125 HIPEC procedures, PC origin was colorectal (342; 30%), ovarian (271; 24%), pseudomyxoma peritonei (189; 17%), gastric (127; 11%), malignant mesothelioma (84; 8%), or other (112; 10%). Between 2004-2009 (n = 321) and 2010-2015 (n = 560), the median peritoneal cancer index decreased (11 vs. 8; P < 0.001), fewer patients underwent incomplete cytoreduction (CC2-3: 4% vs. 0.5%; P < 0.001), and more were included in randomized trials (5% vs. 16%; P < 0.001). Postoperative morbidity (52% vs. 50%, P = 0.672) was not different, but mortality significantly decreased (5% vs. 2%; P = 0.030). Median overall-survival was 42 months, and improved significantly for each 5-year period except for 2006-2010 vs. 2011-2015 (P = 0.097). The 10-year survival without recurrence was 53%, 14%, 4%, 10%, and 9% for pseudomyxoma, mesothelioma, ovarian, colorectal, and gastric PC, respectively. This study demonstrated that CRS and HIPEC provide long-term survival irrespective of PC origin, and survival improves with experience. J. Surg. Oncol. 2016;113:796-803. © 2016 Wiley Periodicals, Inc.

Evaluation of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Origin in the Era of Value-Based Medicine.

Peritoneal spread from colorectal cancer is second only to the liver as a site for metastasis. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a well-established treatment option for patients with peritoneal carcinomatosis (PC) of colorectal origin. However, due to concerns regarding both its clinical benefit and high cost, its universal adoption as the standard of care for patients with limited peritoneal dissemination has been slow. The purpose of this review was to clarify the clinical utility and cost effectiveness of CRS-HIPEC in the treatment of colorectal PC using the framework of value-based medicine, which attempts to combine both benefit and cost into a single quantifiable metric. Our comprehensive review of the clinical outcomes and cost effectiveness of CRS-HIPEC demonstrate that it is a highly valuable oncologic therapy and a good use of healthcare resources.

Value of KRAS, BRAF, and PIK3CA Mutations and Survival Benefit from Systemic Chemotherapy in Colorectal Peritoneal Carcinomatosis.

It is well known that peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is associated with a poor prognosis. However, data on the prognostic significance of modern chemotherapy containing bevacizumab, cetuximab or panitumumab are not available. This retrospective review concerned 526 patients with metastatic CRC who were classified into two groups according to the presence or absence of PC, and were treated with systemic chemotherapy, with or without bevacizumab or anti-EGFR antibodies. The genetic background, in particular KRAS, BRAF, and PIK3CA gene mutations, and overall survival (OS) were compared between the two groups. The median OS values were 23.3 and 29.1 months for PC and non-PC patients, respectively (hazard ratio [HR]=1.20; p=0.17). Among all patients, tumor location, number of metastatic sites and BRAF mutation status were significant prognostic factors, whereas the presence of PC was not. In the PC group, chemotherapy with bevacizumab resulted in a significantly longer OS than forchemotherapy without bevacizumab (HR=0.38, p<0.01), but this was not the case in the non-PC group (HR=0.80, p=0.10). Furthermore, the incidence of the BRAF V600E mutation was significantly higher in PC than in non-PC patients (27.7% versus 7.3%, p<0.01). BRAF mutations displayed a strong correlation with shorter OS in non-PC (HR=2.26), but not PC patients (HR=1.04). Systemic chemotherapy, especially when combined with bevacizumab, improved survival in patients with PC from CRC as well as non-PC patients. While BRAF mutation demonstrated a high frequency in PC patients, but it was not associated with prognosis.

Animal models of colorectal peritoneal metastasis.

Colorectal cancer remains an important cause of mortality worldwide. The presence of peritoneal carcinomatosis (PC) causes significant symptoms and is notoriously difficult to treat. Therefore, informative preclinical research into the mechanisms and possible novel treatment options of colorectal PC is essential in order to improve the prognostic outlook in these patients. Several syngeneic and xenograft animal models of colorectal PC were established, studying a wide range of experimental procedures and substances. Regrettably, more sophisticated models such as those giving rise to spontaneous PC or involving genetically engineered mice are lacking. Here, we provide an overview of all reported colorectal PC animal models and briefly discuss their use, strengths, and limitations.

Mesenchymal Stem Cells Engineered to Secrete Pigment Epithelium-Derived Factor Inhibit Tumor Metastasis and the Formation of Malignant Ascites in a Murine Colorectal Peritoneal Carcinomatosis Model.

The therapeutic effects of conventional treatments for advanced colorectal cancer with colorectal peritoneal carcinomatosis (CRPC) and malignant ascites are not very encouraging. Vascular endothelial growth factor-A/vascular permeability factors (VEGF-A/VPF) play key roles in the formation of malignant ascites. In previous work, we demonstrated that pigment epithelium-derived factor (PEDF) antagonized VEGF-A and could repress tumor growth and suppress metastasis in several cancer types. Thus, PEDF may be a therapeutic candidate for treating malignant ascites. Mesenchymal stem cells (MSCs) are promising tools for delivering therapeutic agents in cancer treatment. In the study, MSCs derived from bone marrow were efficiently engineered to secrete human PEDF by adenoviral transduction. Then, intraperitoneal Ad-PEDF-transduced MSCs were analyzed with respect to CRPC and malignant ascites in a CT26 CRPC model. MSCs engineered to secrete PEDF through adenoviral transduction significantly inhibited tumor metastasis and malignant ascites formation in CT26 CRPC mice. Antitumor mechanisms of MSCs-PEDF (MSCs transduced with Ad-PEDF: MOI 500) were associated with inhibiting tumor angiogenesis, inducing apoptosis, and restoring the VEGF-A/sFLT-1 ratio in ascites. Moreover, MSC-mediated Ad-PEDF delivery reduced production of adenovirus-neutralizing antibodies, prolonged PEDF expression, and induced MSCs-PEDF migration toward tumor cells. As a conclusion, MSCs engineered to secrete PEDF by adenoviral transduction may be a therapeutic approach for suppressing tumor metastasis and inhibiting malignant ascites production in CRPC.

Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum.

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Besides the lymphatic and haematogenous routes of dissemination, CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity, which ultimately leads to peritoneal carcinomatosis (PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However, this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements, involving several well-defined steps, together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor, gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum, subsequently invade the subperitoneal space, where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript, we review current data regarding the molecular mechanisms underlying the development of colorectal PC, with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread.

Systemic treatment of patients with metachronous peritoneal carcinomatosis of colorectal origin.

Combining chemotherapy and targeted therapies has resulted in an enhanced survival in metastatic colorectal cancer (mCRC) patients. However, the result of this palliative treatment in patients with metachronous peritoneal carcinomatosis (PC) remains unknown. The current population-based study aims to investigate the use and effect of palliative systemic treatment in patients with metachronous PC of colorectal origin. Data on metachronous PC were collected between 2010 and 2011 for all patients who were diagnosed with M0 colorectal cancer between 2003 and 2008 in the Dutch Eindhoven Cancer Registry. Patient demographics and detailed data on chemotherapeutic treatment were collected and compared. Ninety-two patients with metachronous PC received chemotherapy in a palliative setting compared to 94 patients without treatment. In 36 patients, Bevacizumab was added to the treatment (39%). Overall survival was 3.4, 13, and 20.3 months in the no treatment, systemic treatment and systemic treatment + Bevacizumab respectively (P < 0.001). Male gender was a positive predictor and right sided primary tumor location a negative predictor of receiving bevacizumab. Approximately 40% of patients with metachronous PC received bevacizumab in addition to chemotherapy. Treatment with systemic chemotherapy in combination with bevacizumab may increase survival in a patients with metachronous colorectal PC.