Extent of surgery in cancer of the colon : is more better?

Since the introduction of total mesorectal excision as the standard approach in mid and low rectal cancer, the incidence of local recurrence has sharply declined. Similar attention to surgical technique in colon cancer (CC) has resulted in the concept of complete mesocolic excision (CME), which consists of complete removal of the intact mesentery and high ligation of the vascular supply at its origin. Although renewed attention to meticulous surgical technique certainly has its merits, routine implementation of CME is currently unfounded. Firstly, in contrast to rectal cancer, local recurrence originating from an incompletely removed mesentery is rare in CC and usually a manifestation of systemic disease. Secondly, although CME may increase nodal counts and therefore staging accuracy, this is unlikely to affect survival since the observed relationship between nodal counts and outcome in CC is most probably not causal but confounded by a range of clinical variables. Thirdly, several lines of evidence suggest that metastasis to locoregional nodes occurs early and is a stochastic rather than a stepwise phenomenon in CC, in essence reflecting the tumor-host-metastasis relationship. Unsurprisingly, therefore, comparative studies in CC as well as in other digestive cancers have failed to demonstrate any survival benefit associated with extensive, additional or extra-mesenteric lymphadenectomy. Finally, routine implementation of CME may cause patient harm by longer operating times, major vascular damage and autonomic nerve injury. Therefore, data from randomized trials reporting relevant endpoints are required before CME can be recommended as a standard approach in CC surgery

Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer

Background : Preoperative radiotherapy (RT) decreases local recurrence rate and improves survival in stage II and III rectal cancer patients. The combination of chemotherapy with RT has a sound radiobiological rationale, and phase II trials of combined chemoradiation (CRT) have shown promising activity in rectal cancer. Objectives : To compare preoperative RT with preoperative CRT in patients with resectable stage II and III rectal cancer. Search methods : We searched the Cochrane Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until June 2012. A manual search was performed of Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys and the proceedings of ASTRO, ECCO and ASCO from 1990 until June 2012. Selection criteria : Relevant studies randomized resectable stage II or III rectal cancer patients to at least one arm of preoperative RT alone or at least one arm of preoperative CRT. Data collection and analysis : Primary outcome parameters included overall survival (OS) at 5 years and local recurrence (LR) rate at 5 years. Secondary outcome parameters included disease free survival (DFS) at 5 years, metastasis rate, pathological complete response rate, clinical response rate, sphincter preservation rate, acute toxicity, postoperative mortality and morbidity, and anastomotic leak rate. Outcome parameters were summarized using the Odds Ratio (OR) and associated 95% confidence interval (CI) using the fixed effects model. Main results : Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years. Authors' conclusions : Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials

BEV-IP : perioperative chemotherapy with bevacizumab in patients undergoing cytoreduction and intraperitoneal chemoperfusion for colorectal carcinomatosis

Background: Selected patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) benefit from cytoreductive surgery (CRS) combined with intraperitoneal chemoperfusion (IPC). However, even after optimal cytoreduction, systemic and locoregional recurrence are common. Perioperative chemotherapy with bevacizumab (BEV) may improve the outcome of these patients. Methods/Design: The BEV-IP study is a phase II, single-arm, open-label study aimed at patients with colorectal or appendiceal adenocarcinoma with synchronous or metachronous PC. This study evaluates whether perioperative chemotherapy including BEV in combination with CRS and oxaliplatin-based IPC results in acceptable morbidity and mortality (primary composite endpoint). Secondary endpoints are treatment completion rate, chemotherapy-related toxicity, pathological response, progression free survival, and overall survival. Discussion: The BEV-IP trial is the first prospective assessment of the safety and efficacy of perioperative chemotherapy combined with anti-angiogenic treatment in patients undergoing CRS and IPC for colorectal peritoneal metastases

Exploring the HYDRAtion method for loading siRNA on liposomes : the interplay between stability and biological activity in human undiluted ascites fluid

Delivery of small interfering RNA (siRNA) is recently gaining tremendous attention for the treatment of ovarian cancer. The present study investigated the potential of different liposomal formulations composed of (2,3-dioleoyloxy-propyl)trimethylammonium (DOTAP) and 1,2-dioleoyl-sn-glycero-3phosphoethanolamine (DOPE) encapsulating siRNA (hydration method) for their ability to knockdown luciferase (Luc) activity in human ovarian cancer SKOV-3 cells. Fluorescence single particle tracking (fSPT) and fluorescence correlation spectroscopy (FCS) in human-undiluted ascites fluid obtained from a peritoneal carcinomatosis patient revealed that cationic hydra-lipoplexes (HYDRA-LPXs) and HYDRA-LPXs decorated with stable DSPE-PEG (DSPE HYDRA-LPXs) showed high stability during at least 24 h. HYDRA-LPXs decorated with sheddable C8 and C16 PEG-Ceramides (Cer HYDRA-LPXs) resulted in rapid and premature release of siRNA already in the first hours. Despite their role in preventing aggregation in vivo, liposomes decorated with stable PEG residues resulted in a poor transfection compared to the ones decorated with sheddable PEG residues in reduced serum conditions. Yet, the transfection efficiency of both Cer HYDRA-LPXs significantly decreased following 1 h of incubation in ascites fluid due to a drastic drop in the cellular uptake, while DSPE HYDRA-LPXs are still taken up by cells, but too stable to induce efficient gene silencing

Intraperitoneal chemotherapy for peritoneal metastases : an expert opinion

Introduction: The rationale for intraperitoneal (IP) drug delivery for patients with peritoneal metastases (PM) is based on the pharmacokinetic advantage resulting from the peritoneal-plasma barrier, and on the potential to adequately treat small, poorly vascularized PM. Despite a history of more than three decades, many aspects of IP drug delivery remain poorly studied. Areas covered: We outline the anatomy and physiology of the peritoneal cavity, including the pharmacokinetics of IP drug delivery. We discuss transport mechanisms governing tissue penetration of IP chemotherapy, and how these are affected by the biomechanical properties of the tumor stroma. We provide an overview of the current clinical evidence on IP chemotherapy in ovarian, colorectal, and gastric cancer. We discuss the current limitations of IP drug delivery and propose several potential areas of progress. Expert opinion: The potential of IP drug delivery is hampered by off-label use of drugs developed for systemic therapy. The efficacy of IP chemotherapy for PM depends on cancer type, disease extent, and mode of drug delivery. Results from ongoing randomized trials will allow to better delineate the potential of IP chemotherapy. Promising approaches include IP aerosol therapy, prolonged delivery platforms such as gels or biomaterials, and the use of nanomedicine

Retroperitoneal liposarcoma : current insights in diagnosis and treatment

Retroperitoneal liposarcoma (RLS) are rare, biologically heterogeneous tumors that present considerable challenges due to their size and deep location. As a consequence, the majority of patients with high grade RLS will develop locally recurrent disease following surgery, and this constitutes the cause of death in most patients. Here, we review current insights and controversies regarding histology, molecular biology, extent of surgery, (neo)adjuvant treatment, and systemic treatment including novel targeted agents in RLS

Estimators for kinetic modeling of dynamic contrast-enhanced magnetic rensonance data from spoiled gradient echo pulse sequences

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