Efficacy of hyperthermic intraperitoneal chemotherapy in colorectal cancer: A phase I and III open label randomized controlled registry-based clinical trial protocol.

Standard treatment for patient with peritoneal metastases from colorectal cancer is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In recent years, the efficacy of oxaliplatin-based HIPEC has been challenged. An intensified HIPEC (oxaliplatin+irinotecan) in combination with early postoperative intraperitoneal chemotherapy (EPIC) has shown increased recurrence-free survival in retrospective studies. The aim of this trial is to develop a new HIPEC/EPIC regimen and evaluate its effect on morbidity, oncological outcome, and quality-of-life (QoL). This study is designed as a combined phase I/III multicenter randomized trial (RCT) of patients with peritoneal metastases from colorectal cancer eligible for CRS-HIPEC. An initial phase I dose escalation study, designed as a 3+3 stepwise escalation, will determine the maximum tolerable dose of 5-Fluorouracil (5-FU) as 1-day EPIC, enrolling a total of 15-30 patients in 5 dose levels. In the phase III efficacy study, patients are randomly assigned intraoperatively to either the standard treatment with oxaliplatin HIPEC (control arm) or oxaliplatin/irinotecan-HIPEC in combination with single dose of 1-day 5-FU EPIC (experimental arm). 5-FU is administered intraoperatively after CRS-HIPEC and closure of the abdomen. The primary endpoint is 12-month recurrence-free survival. Secondary endpoints include 5-year overall survival, 5-year recurrence-free survival (registry based), postoperative complications, and QoL up to 3 years after study treatment. This phase I/III trial aims to identify a more effective treatment of colorectal peritoneal metastases by combination of HIPEC and EPIC.

Role of matrix metalloproteinases in tumour invasion: immunohistochemistry of peritoneum from peritoneal carcinomatosis.

Colorectal cancer is one of the most common forms of cancer. Spread of tumour to the peritoneal cavity may lead to seeding of cancer cells that adhere to and invade the peritoneal membrane causing peritoneal carcinomatosis. Matrix metalloproteinases (MMPs) play an essential role in cancer cell invasion and dissemination. The aim of this study was to evaluate the morphology and presence of matrix metalloproteinases in peritoneal carcinomatosis. Biopsy samples of the parietal peritoneum were taken from patients undergoing cytoreductive surgery for peritoneal carcinomatosis. The samples were fixed in formalin, dehydrated and embedded in paraffin prior to cutting into 4-µm slices. Staining with haematoxylin/eosin was used for morphology studies, and MMP-1, MMP-2 and TIMP-1 levels were evaluated using immunohistochemistry and light microscopy. The microscopically tumour-free areas of the peritoneal membrane were thin compared to the peripheral invasion zone and the areas invaded by tumour. Peritoneum invaded by tumour was richly vascularised and contained inflammatory cells. MMP-1 was expressed in tumour-free peritoneum and in the invasion zone between tumour and peritoneal tissue, but not in tumour-invaded areas. MMP-2 and TIMP-1 were mostly expressed in the proximity of blood vessels and inflammatory cells in tumour-invaded areas, but was not seen in tumour-free areas. MMPs play an important role in the process of cancer cell invasion of the peritoneum in peritoneal carcinomatosis. The peripheral zone of the tumour appears to be of importance for tumour invasion.

Colorectal Cancer Cells Adhere to Traumatized Peritoneal Tissue in Clusters, An Experimental Study.

Purpose/Aim: Colorectal malignity is one of the most common forms of cancer. The finding of free intraperitoneal colorectal cancer cells during surgery has been shown to be associated with poor outcome. The aim of this study was to develop an experimental model designed to investigate adhesion of colorectal cancer cells to the peritoneal surface. MATERIALS AND METHODS: Two human experimental models were developed, the first using cultured mesothelial cells and the second consisting of an ex vivo model of peritoneal tissue. Both models were subjected to standardized trauma, following which labeled colorectal cancer cells (Colo205) were introduced. Adhesion of tumor cells was monitored using microscopy and detection of fluorochromes. RESULTS: The mesothelial cell layers and peritoneal membranes remained viable in culture medium for several weeks. In our experimental model, the tumor cells added were seen to adhere to the edges of the traumatized area in cluster formations. CONCLUSIONS: The use of human peritoneal tissue in an ex vivo model would appear to be a potentially useful tool for the study of interaction between human peritoneal membrane and free tumor cells. Experimental surgical trauma increases the ability of tumor cells to adhere to the peritoneal membrane. This ex vivo model should be useful in future studies on biological interactions between peritoneum and tumor cells in the search for novel forms of peritoneal cancer therapy.

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer.

BACKGROUND: Modufolin® ([6R]-5,10-methylene tetrahydrofolate; [6R]-MTHF) is an endogenous biomodulator that is being developed as an alternative to leucovorin, a folate prodrug used in the treatment of colorectal cancer. The objective of this phase 1 dose de-escalation trial was to estimate the minimum tolerated dose of [6R]-MTHF to be used in combination with pemetrexed 500 mg/m(2) in the neoadjuvant treatment of patients with rectal cancer. METHODS: Adult patients (≥18 years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10 mg/m(2) in combination with pemetrexed 500 mg/m(2). [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1 week prior to the first dose of pemetrexed and then once weekly for 9 weeks; pemetrexed was administered by i.v. infusion once every 21 days for three cycles. RESULTS: Twenty-four patients (mean [SD] age, 63.1 [12.9] years) were enrolled in the study. A total of 72 treatment-related adverse events (AEs) were reported, of which the most common were fatigue (n = 17; 23.6 %), nausea (n = 10; 13.9 %), and diarrhea (n = 5; 6.9 %). The incidence of treatment-related AEs by [6R]-MTHF dose level (500, 100, 50, 10 mg/m(2)) was 11.1 % (n = 8), 13.9 % (n = 10), 45.8 % (n = 33), and 29.2 % (n = 21), respectively. There were no dose-limiting toxicities, and only two (2.8 %) treatment-related AEs were grade 3 in severity. Of the 11 serious AEs reported, none were considered to be related to [6R]-MTHF treatment. CONCLUSIONS: The results of this phase 1 study indicate that the estimated minimum tolerated dose of [6R]-MTHF was 100 mg/m(2) once weekly in combination with pemetrexed 500 mg/m(2). The low toxicity profile of [6R]-MTHF supports its further evaluation as a component of systemic chemotherapy in the management of colon and rectal cancer.

Pro-inflammatory cytokine release in rectal surgery: comparison between laparoscopic and open surgical techniques.

The objective of the present study was to investigate whether laparoscopic rectal surgery causes a less pronounced release of pro-inflammatory cytokines as compared to open surgical technique. Twenty-four consecutive patients undergoing rectal surgery due to cancer disease were included in a prospective and randomized trial. The patients were randomized to laparoscopic (n = 12) or open surgery (n = 12). Blood was sampled at five occasions; after induction of anesthesia before start of surgery, at 180, 360 min and 24 h after start of surgery and the last sample was taken in the late post-operative period 3-5 days after surgery. The levels of interleukin (IL)-1α, IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein (CRP), white blood cells, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed using multiplex sandwich enzyme-linked immunosorbent assay. There was a release of both pro- and anti-inflammatory cytokines during colorectal surgery. The release of IL-6, IL-10 and CRP was significantly lower in the laparoscopic group. Rectal surgery causes release of both pro- and anti-inflammatory cytokines. The inflammatory response is lower in laparoscopic rectal surgery as compared to conventional open surgery. Less tissue trauma in laparoscopic rectal surgery and/or less peri-operative bleeding in the laparoscopic cases leads to a lower degree of inflammatory response.

Stage and size using magnetic resonance imaging and endosonography in neoadjuvantly-treated rectal cancer.

AIM: To assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS). METHODS: In this study, patients were recruited in a phase I/II trial of neoadjuvant chemotherapy for biopsy-proven rectal cancer planned for surgical resection with or without preoperative radiotherapy. The feasibility and accuracy of 1.5T MRI and 3D ERUS were compared with the histopathology of the fixed surgical specimen (pathology) to determine the stage and size of the rectal cancer before and after neoadjuvant chemotherapy. A Philips Intera 1.5T with a cardiac 5-channel synergy surface coil was used for the MRI, and a B-K Medical Falcon 2101 EXL 3D-Probe was used at 13 MHz for the ERUS. Our hypothesis was that the staging accuracy would be the same when using MRI, ERUS and a combination of MRI and ERUS. For the combination, MRI was chosen for the assessment of the lymph nodes, and ERUS was chosen for the assessment of perirectal tissue penetration. The stage was dichotomised into stage I and stage II or greater. The size was measured as the supero-inferior length and the maximal transaxial area of the tumour. RESULTS: The staging feasibility was 37 of 37 for the MRI and 29 of 36 for the ERUS, with stenosis as a limiting factor. Complete sets of investigations were available in 18 patients for size and 23 patients for stage. The stage accuracy by MRI, ERUS and the combination of MRI and ERUS was 0.65, 0.70 and 0.74, respectively, before chemotherapy and 0.65, 0.78 and 0.83, respectively, after chemotherapy. The improvement of the post-chemotherapy staging using the combination of MRI and ERUS compared with the staging using MRI alone was significant (P = 0.046). The post-chemotherapy understaging frequency by MRI, ERUS and the combination of MRI and ERUS was 0.18, 0.14 and 0.045, respectively, and these differences were non-significant. The measurements of the supero-inferior length by ERUS compared with MRI were within 1.96 standard deviations of the difference between the methods (18 mm) for tumours smaller than 50 mm. The agreement with pathology was within 1.96 standard deviations of the difference between imaging and pathology for all tumours with MRI (15 mm) and for tumours that did not exceed 50 mm with ERUS (22 mm). Tumours exceeding 50 mm in length could not be reliably measured by ERUS due to the limit in the length of each recording. CONCLUSION: MRI is preferable to use when assessing the size of large or stenotic rectal tumours. However, staging accuracy is improved by combining MRI with ERUS.

Long-term follow-up after preoperative chemotherapy using pemetrexed (Alimta) in rectal cancer.

AIM: To assess the long-term outcome in a cohort of patients treated with preoperative chemotherapy using pemetrexed (Alimta) for rectal cancer. PATIENTS AND METHODS: A prospective phase I/II study on preoperative chemotherapy using Alimta was conducted during 2006-2008. The long-term outcome was assessed here for both the study group (n=37) and the reference group (n=87). The focus was on cancer recurrence and survival with consideration of initial tumour stage and treatment response. RESULTS: There was one recurrence, each in stages I and II and three (23.1%) in stage III in the Alimta-treated group. One patient remains disease, free after surgery for metastasis. Patients with more symptoms remaining after treatment had a higher risk of recurrence. CONCLUSION: The initial Alimta study concluded that treatment was feasible in rectal cancer with significant reductions in tumour symptoms and size. The long-term outcome is acceptable and does not provide evidence against the concept of preoperative chemotherapy using Alimta.