The impact of surgical resection of the primary tumor on the development of synchronous colorectal liver metastasis: a systematic review.

BACKGROUND: In recent years different therapeutic strategies for synchronously liver metastasized colorectal cancer were described. Apart from the classical staged surgical approach, simultaneous and liver-first strategies are now commonly used. One theoretical drawback of the classical approach is, however, the stimulatory effect on liver metastases growth that may result from resection of the primary tumour. This systematic review, therefore, aims to investigate the current insights on the stimulatory effects of colorectal surgery on the growth of synchronous colorectal liver metastases in humans. METHODS: The systematic review was conducted according to the PRISMA statement. A literature search was performed using PubMed and Embase. Articles investigating the effects of colorectal surgery on synchronous colorectal liver metastases were included. Primary endpoints were metastatic tumor volume, metabolic and proliferative activity and tumour vascularization. RESULTS: Four articles meeting the selection criteria were found involving 200 patients. These studies investigate the effects of resection of the primary tumour on synchronous liver metastases using histological and radiological techniques. These papers support a possible stimulatory effect of resection of the primary tumor. CONCLUSIONS: Some limited evidence supports the hypothesis that colorectal surgery might stimulate the growth and development of synchronous colorectal liver metastases.

Recent insights into the pathophysiology of omental metastases.

Although, useful in inflammatory conditions, the greater omentum represents an important site of metastasis in peritoneal carcinomatosis and is therefore frequently removed as a staging or therapeutic tool. Apart from the milky spots, omental adipose stem cells, and adipocytes have recently been identified to play a role in the preferential homing of tumor cells to the omentum. The extent of omentectomy and whether a routine omentectomy should be done are still known unknowns.

Clinical research in surgery: threats and opportunities.

Surgery is a discipline which profoundly affects human integrity. Therefore, there is an ethical and scientific imperative that surgical practice depends on the best possible trial-based evidence. Traditionally, the quality and quantity of clinical research have been lagging behind other disciplines in clinical medicine. However, recent collaborative initiatives, such as the IDEAL framework which tests surgical innovation, international registries, and quality assurance platforms, the development of modified randomized controlled trials and alternative trial designs as well as the impending reforms of the regulatory framework surrounding nonpharmaceutical interventions and devices offer significant and timely opportunities to enhance the relevance of clinical research in surgery. Here, we provide an overview of the current state of clinical research in surgery, identify possible obstacles, and discuss realistic and emerging solutions that have the potential to change the way surgical research is organized, funded, and translated to the patient's benefit.

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.

Cytoreduction and hyperthermic intraperitoneal chemoperfusion in women with heavily pretreated recurrent ovarian cancer.

BACKGROUND: Limited data are available on the use of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC) in patients with recurrent stage III ovarian cancer. METHODS: Patients with recurrent, heavily pretreated ovarian cancer were enrolled onto a phase II multimodal protocol consisting of extensive cytoreduction followed by HIPEC. RESULTS: Forty-two women were treated from October 2002 until January 2009. Chemoperfusion was performed with cisplatin in 59% and oxaliplatin in 41% of patients. A macroscopically complete resection was achieved in 50% of patients. No mortality occurred, and the major morbidity rate was 21%. After a mean follow-up of 21 months, median overall survival (OS) was 37 months (95% confidence interval 12.2-61.8) and median progression-free survival was 13 months (95% confidence interval 6.9-19.1). In univariate analysis, OS was influenced by completeness of cytoreduction, type of chemoperfusion drug, nodal status, and tumor grade. In a Cox regression model, only completeness of cytoreduction (hazard ratio 0.06-0.8, P=.022) and tumor grade (hazard ratio 1.23-12.6, P=.021) were independent predictors of OS. CONCLUSIONS: In selected patients with heavily pretreated recurrent ovarian cancer, cytoreduction combined with HIPEC may provide a meaningful OS with acceptable morbidity. Optimal results are achieved in patients with a macroscopically complete resection and biologically favorable disease.

First order correction for T2*-relaxation in determining contrast agent concentration from spoiled gradient echo pulse sequence signal intensity.

PURPOSE: To investigate the accuracy of a method neglecting T(2)*-relaxation, for the conversion of spoiled gradient echo pulse sequence signal intensity to contrast agent (CA) concentration, in dynamic contrast enhanced MRI studies. In addition a new closed form conversion expression is proposed that accounts for a first order approximation of T(2)*-relaxation. MATERIALS AND METHODS: The accuracy of both conversion methods is compared theoretically by means of simulations for four pulse sequences from literature. Both methods are tested in vivo against the numerical conversion method for measuring the arterial input function in mice. RESULTS: Simulations show that the T(2)*-neglecting method underestimates typical tissue CA concentrations (0 mM to 2 mM) up to 6%, while the errors for arterial concentrations (0 mM to 10 mM) range up to 43%. The results from our first order method are numerically indistinguishable from the simulation input values in tumor tissue, while for arterial concentrations the error is reduced up to a factor 10. In vivo, peak Gd-DOTA concentration is underestimated up to 14% with the T(2)*-neglecting method and up to 0.9% with our first order method. CONCLUSION: Our conversion method reduces the underestimation of CA concentration severely in a broad physiological concentration range and is easy to perform in any clinical setting.

Antitumour efficacy of two paclitaxel formulations for hyperthermic intraperitoneal chemotherapy (HIPEC) in an in vivo rat model.

PURPOSE: To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy with paclitaxel/randomly-methylated-ß-cyclodextrin (Pac/RAME-ß-CD) versus Taxol® at normo- and hyperthermic conditions in rats. METHODS: Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations at a Pac concentration of 0.24 mg/ml. Tumour evaluation was performed via positron emission tomography (PET) and magnetic resonance imaging (MRI) imaging, measuring tumour activity and tumour volume, respectively. Scans were taken at 2 and 7 days post treatment. RESULTS: PET and MRI data showed a significant reduction in tumour activity and tumour volume for rats treated with Pac/RAME-ß-CD (at normo- and hyperthermic conditions), compared to the control group. Treatment with Taxol® did not result in a significant reduction of tumour activity and tumour volume. No significant differences between the normo- and hyperthermic conditions were observed for both formulations, indicating that hyperthermia and paclitaxel were not synergistic despite the direct cytotoxic effect of hyperthermia. CONCLUSION: Monitoring tumour growth via PET and MRI indicated that Pac/RAME-ß-CD inclusion complexes had a significantly higher efficacy compared to Taxol® in a rat model for peritoneal carcinomatosis.

Assessment of tumor vascularization in pancreatic adenocarcinoma using 128-slice perfusion computed tomography imaging.

OBJECTIVE: Computed tomography (CT) perfusion studies can provide valuable information regarding tumor vascularization. We report on a study assessing CT perfusion characteristics in the normal pancreas and in patients with pancreatic adenocarcinoma. METHODS: Twenty healthy subjects and 20 patients with histologically confirmed pancreatic adenocarcinoma were included in the study after written informed consent and approval by our institutional review board. All subjects underwent perfusion CT imaging of the pancreas using 128-slice dual-source CT. The scanning sequence included 18 scans. Parametric maps of blood volume (BV), blood flow (BF), and permeability surface area product (PS) were generated and compared with density measurements. RESULTS: In normal pancreas, no significant difference in perfusion values was observed between head, body, and tail of the pancreas. Mean organ values were 76.76 (SD, 15.6) mL/100 g/min, 15.80 (SD, 2.40) mL/100 g, and 27.74 (SD, 16.8) mL/100 g/min for BF, BV, and PS, respectively. Compared with the normal pancreas, a 60% reduction in BF and BV was observed in the tumor tissue. Perfusion values gradually increased toward the tumor rim. Necrotic tumor areas were identified in 25% of patients. No significant differences were observed when comparing normal pancreas and healthy pancreatic tissue in adenocarcinoma patients. CONCLUSIONS: The feasibility of whole-tumor perfusion imaging using 128-slice CT was demonstrated in patients with pancreatic adenocarcinoma. Perfusion CT provides additional information compared with image assessment based on density measurements (Hounsfield units) and allows noninvasive assessment of vascularization in the tumor tissue.

Precision analysis of kinetic modelling estimates in dynamic contrast enhanced MRI.

OBJECT: Dynamic contrast enhanced MRI and pharmacokinetic modelling provide a powerful tool for tumour diagnosis and treatment evaluation. However, several studies show low reproducibility of the technique and poor precision of the transendothelial transfer constant K (trans). This work proposes a theoretical framework describing how finite signal-noise-ratio (SNR) in the MR images is propagated throughout the measurement protocol to uncertainty on the kinetic parameter estimates. MATERIALS AND METHODS: After deriving a distribution for the contrast agent concentration, a maximum likelihood estimator (MLM) is proposed that exhibits Cramer-Rao lower bounds (CRLB). An analytical expression is derived for the CRLB that can be used to determine confidence intervals for kinetic parameters and to investigate the influence of protocol parameters as scan time and temporal resolution on K (trans)-precision. RESULTS: K (trans)-uncertainty can be reduced up to 30% by using MLM in comparison with least square estimator. K (trans)-precision is proportional to the SNR and depends strongly on the kinetic parameter values themselves. Minimal scan time and temporal resolution were found to be 15 min and 15 s, respectively, for Gd-DTPA. Temporal resolution should be enhanced by decreasing the NEX parameter (NEX ≤ 1). CONCLUSION: CRLB provide a golden standard to construct 95% confidence intervals, which can be used to perform protocol optimization and to test the statistical significance of K (trans)-changes in treatment evaluation.

Assessment of neovascular permeability in a pancreatic tumor model using dynamic contrast-enhanced (DCE) MRI with contrast agents of different molecular weights.

OBJECT: We evaluated the relationship of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters and contrast agents with different molecular weights (MW) in a pancreatic tumor mouse model. MATERIALS AND METHODS: Panc02 tumors were induced in mice at the hind leg. DCE-MRI was performed using Gadolinium (Gd)-based contrast agents with different MW: Gd-DOTA (0.5 kDa), P846 (3.5 kDa), and P792 (6.47 kDa). Quantitative vascular parameters (AUC, K(trans), V(e), and V(p)) were calculated according to a modified Tofts two-compartment model. Values for all contrast groups were compared for tumor and control (muscle) tissues. RESULTS: Values for K(trans) and V(e) were significantly higher in tumor tissue than in muscle tissue. When comparing contrast agents, lowest absolute K(trans) values were observed using P792. The relative increase in K(trans) in tumor tissue compared with normal tissue was highest after the use of P792. In both tumor and normal tissues, K(trans) decreased with increasing molecular weight of the contrast agent used. CONCLUSION: It was demonstrated that values for the different DCE-MRI vascular (permeability) parameters are highly dependent on the contrast agent used. Due to their potential to better differentiate tumor from muscle tissue, higher molecular weight contrast agents show promise when evaluating tumors using DCE-MRI.

The Feasibility of Pressurised Intraperitoneal Aerosolised Virotherapy (PIPAV) to Administer Oncolytic Adenoviruses.

BACKGROUND: The prognosis of patients with peritoneal metastases is poor. Treatment options are limited because systemically delivered chemotherapy is not usually effective in this type of disease. Pressurised intraperitoneal aerosolised chemotherapy (PIPAC) is a recently developed alternative technology for delivering intraperitoneal chemotherapy, potentially enhancing treatment efficacy. Here, we assess the feasibility of pressurised intraperitoneal aerosolised virotherapy (PIPAV) to deliver a different class of anticancer agents, oncolytic adenoviruses, in vitro and in vivo. METHODS: Adenoviral vectors expressing reporter genes green fluorescence protein (Ad5.GFP) or firefly luciferase (Ad5.Luc) were subject to pressurised aerosolisation. The ability of the virus to survive PIPAV was assessed in vitro and in vivo by monitoring reporter gene activity. Wistar rats subjected to PIPAV were assessed for any adverse procedure related events. RESULTS: In vitro transduction assays demonstrated that Ad5 retained viability following pressurised aerosolisation and could transduce permissive cells equally effectively as non-aerosolised control vector. PIPAV was well tolerated in rats, although minimal transduction was observed following intraperitoneal administration. CONCLUSIONS: PIPAV appears viable and well tolerated, though in vivo efficacy requires further optimisation.

Peritoneal minimal residual disease in colorectal cancer: mechanisms, prevention, and treatment.

Roughly one in five patients with colorectal cancer develops peritoneal minimal residual disease after surgical resection, and about one in seven patients develops peritoneal carcinomatosis. By contrast with the vast body of research addressing haematogenous metastasis, little is known about the biology of peritoneal spread of colorectal cancer. The development of peritoneal carcinomatosis involves well-defined steps including cell shedding and transport, adhesion to the mesothelial layer, invasion of and proliferation into the submesothelial stroma, and potential access to the systemic circulation. In this Review, we summarise the molecular mechanisms and potential preventive measures associated with each step of the peritoneal metastatic cascade.

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 STRATEGY: We searched the Cochrane Central Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until june 2007. 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 2007. 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: Four trials were identified and included in the meta-analysis. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) while no differences were observed in postoperative morbidity or mortality. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.52-5.27, P < 0.001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.31, P = 0.29). 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.

Safety and efficacy of hyperthermic intraperitoneal chemoperfusion with high-dose oxaliplatin in patients with peritoneal carcinomatosis.

BACKGROUND: Cytoreduction with hyperthermic intraperitoneal chemoperfusion (HIPEC) has an established role in selected patients with peritoneal carcinomatosis (PC). We analyzed the safety and efficacy of HIPEC using high-dose oxaliplatin, a cytotoxic agent commonly used in metastatic colorectal cancer and showing promising activity in ovarian cancer and mesothelioma. METHODS: Following complete cytoreduction, HIPEC was performed using 460 mg/m(2 )oxaliplatin in 5% dextrose for 30 min at a temperature of 41-42 degrees C. Open perfusion (coliseum technique) was performed in all patients. Metabolic, electrolyte, and hemodynamic changes were recorded during chemoperfusion as well as postoperative morbidity, mortality, late toxicity, and survival. RESULTS: From July 2005 to January 2007, 52 patients were treated. Chemoperfusion with 5% dextrose resulted in temporary significant hyperglycemia, hyponatremia, and metabolic acidosis. Major morbidity developed in 24% of patients, while 30-day mortality did not occur. One patient developed unexplained repeated episodes of hemoperitoneum. Chemoperfusion with oxaliplatin resulted in mild hepatic toxicity evidenced by persistent elevation of glutamyl transferase and alkaline phosphatase 1 month after surgery. After a mean follow-up time of 14.5 months, nine patients died from disease progression. In colorectal cancer patients, actuarial overall survival was 80% at 1 year. CONCLUSION: Cytoreduction with HIPEC using high-dose oxaliplatin leads to manageable metabolic and electrolyte disturbances and frequent mild hepatic toxicity without discernible impact on postoperative morbidity. Longer follow-up in a larger patient cohort will be required to assess the real risk of unexplained hemoperitoneum observed in one patient, and to establish the long-term effect on local relapse and survival.

Pharmacokinetics and Tissue Transport of Intraperitoneal Chemotherapy.

The presence of a peritoneal barrier results in a pharmacokinetic advantage associated with intraperitoneal (IP) delivery of anticancer drugs. The anticancer efficacy of IP chemotherapy depends, however, on its ability to penetrate the tumor stroma. Tumor tissue transport is governed by diffusion and convection and is affected by numerous physical, biological, and pharmaceutical variables. From preclinical and clinical studies, it appears that tissue penetration after IP chemotherapy delivery is very limited. Several approaches are studied in order to improve tissue penetration of small molecular and macromolecular anticancer drugs after IP instillation.

Preclinical activity of melflufen (J1) in ovarian cancer.

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

Use of hyperthermic intraperitoneal chemotherapy (HIPEC) in management of peritoneal carcinomatosis from colorectal origin.

Approximately 1 in 30 patients suffering from colorectal cancer (CRC) will develop peritoneal carcinomatosis (PC) in the absence of systemic spread. The mechanisms giving rise to PC in CRC are incompletely understood, but involve a complex stepwise interaction between the malignant cell and mesothelial layer. Systemic palliative chemotherapy is usually offered, but of limited activity in PC. Cytoreductive surgery followed by intraperitoneal hyperthermic chemoperfusion (HIPEC) has been described recently in management of isolated PC originating from CRC, based on a sound biological rationale of synergism and a pharmacokinetical advantage. Several retrospective series, one prospective randomized trial, and a meta analysis have clearly shown a survival benefit for patients treated with cytoreduction + HIPEC provided a complete (R0) resection is performed. Toxicity of the procedure is considerable, and mainly depends on the extent of surgery. Future trials are needed to provide more solid evidence in favor of surgery in PC originating from CRC in the era of modern chemotherapy and to better define the role of HIPEC as an adjunct to surgery.

Retroperitoneal liposarcoma: current insights in diagnosis and treatment.

Retroperitoneal liposarcoma (RLS) is a rare, biologically heterogeneous tumor that present considerable challenges due to its 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.

Gastric banding for clinically severe obesity: results with the Swedish band.

Parallel with the rise of the obesity pandemic, bariatric surgery is quickly becoming one of the most frequently performed GI procedures. In selected, well-informed patients, restrictive surgery offers a good alternative to more complex malabsorption-inducing procedures. Laparoscopic gastric banding is a reversible, technically straightforward procedure. Both early and late complications seen with the original models are less common with the Swedish adjustable gastric band SAGB (Ethicon Endosurgery, Johnson & Johnson, Dilbeek, Belgium) engineered as a low-pressure device. This chapter is a review of our experience with the SAGB and provides an overview of current controversies regarding its place in management of severe obesity.