Wim Ceelen

Early- and Long-Term Outcome Data of Patients With Pseudomyxoma Peritonei From Appendiceal Origin Treated by a Strategy of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

PURPOSE Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. PATIENTS AND METHODS A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. RESULTS Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. CONCLUSION The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.

Prognostic Value of the Lymph Node Ratio in Stage III Colorectal Cancer: A Systematic Review

BackgroundAlthough nodal invasion represents one of the most powerful prognostic indicators in colorectal cancer, marked heterogeneity exists within stage III patients. Recently, the lymph node ratio (LNR), defined as the ratio of the number of positive nodes over the total number of examined nodes, was proposed to stratify outcome in stage III patients.MethodsA systematic search was performed for studies examining the prognostic significance of the LNR in colon or rectal cancer. Individual studies were assessed for methodological quality and summary data extracted. Hazard ratios from multivariate analyses were entered in a fixed-effects meta-analysis model.ResultsIn total, 16 studies were identified including 33,984 patients with stage III colon or rectal cancer. In all identified studies, the LNR was identified as an independent prognostic factor in patients with stage III cancer of the colon or rectum. The prognostic separation obtained by the LNR was superior to that of the number of positive nodes (N stage). The pooled hazard ratios for overall and disease-free survival were 2.36 (95% confidence interval, 2.14–2.61) and 3.71 (95% confidence interval, 2.56–5.38), respectively.ConclusionsThe LNR allows superior prognostic stratification in stage III colorectal cancer and should be validated in prospective studies.Although nodal invasion represents one of the most powerful prognostic indicators in colorectal cancer, marked heterogeneity exists within stage III patients. Recently, the lymph node ratio (LNR), defined as the ratio of the number of positive nodes over the total number of examined nodes, was proposed to stratify outcome in stage III patients. A systematic search was performed for studies examining the prognostic significance of the LNR in colon or rectal cancer. Individual studies were assessed for methodological quality and summary data extracted. Hazard ratios from multivariate analyses were entered in a fixed-effects meta-analysis model. In total, 16 studies were identified including 33,984 patients with stage III colon or rectal cancer. In all identified studies, the LNR was identified as an independent prognostic factor in patients with stage III cancer of the colon or rectum. The prognostic separation obtained by the LNR was superior to that of the number of positive nodes (N stage). The pooled hazard ratios for overall and disease-free survival were 2.36 (95% confidence interval, 2.14–2.61) and 3.71 (95% confidence interval, 2.56–5.38), respectively. The LNR allows superior prognostic stratification in stage III colorectal cancer and should be validated in prospective studies.

Mucinous subtype as prognostic factor in colorectal cancer: a systematic review and meta-analysis.

Background Mucinous adenocarcinoma (MAC) of the colorectum has been known and studied for many years. The prognostic significance of this histological subtype remains controversial. The authors reviewed the prognostic significance of mucinous differentiation in colorectal cancer. Materials and methods A systematic web-based search was performed using Web of Knowledge and Medline. Articles published in English, German or French which used the WHO definition of MAC and described cohort studies, case–control studies or cross-sectional studies comparing survival in patients with MAC and adenocarcinoma (AC) not otherwise specified were included. Data on first author, year of publication, country, number of patients included, prevalence of MAC, % stage IV disease, % disease located in the proximal colon, mean age at presentation, % male patients and 5-year overall survival were extracted from individual studies. A fixed-effects meta-analysis model was used for analysis. The primary outcome was survival, expressed as the HR. Differences between categorical outcome parameters were quantified using the RR and corresponding 95% CI. Results 44 studies and 222 256 patients were included. The RR for proximal disease versus distal disease was 1.55 (95% CI 1.53 to 1.58). Mucinous differentiation was less frequent in male subjects (RR 0.93 (95% CI 0.91 to 0.94)). Interestingly, the prevalence of stage IV disease was similar in MAC and AC (RR 0.99 (95% CI 0.96 to 1.02)). Thirty-five articles were included in the survival analysis. A worse survival in MAC versus AC was demonstrated (HR 1.05 (95% CI 1.02 to 1.08)). Conversely, three out of four studies reported a better survival in MAC with microsatellite instability (MSI). Due to heterogeneity a meta-analysis on the effect of MSI was not possible. Conclusion MAC more often originates from the right colon and is less frequent in male subjects. The authors did not identify a difference in the proportion of stage IV patients at presentation. Mucinous differentiation results in a 2–8% increased hazard of death, which persists after correction for stage. More research is needed to define the interaction between mucinous differentiation, MSI and outcome.

Intraperitoneal therapy for peritoneal tumors: biophysics and clinical evidence

In patients with tumors confined to the peritoneal cavity, there is established pharmacokinetic and tumor biology-related evidence that intraperitoneal drug administration is advantageous. Three large randomized trials in patients with stage III ovarian cancer who underwent optimal cytoreduction have demonstrated a significant survival benefit when intraperitoneal chemotherapy was added to systemic therapy. Although intraperitoneal therapy is associated with locoregional toxic effects, recent trials suggest that with some modification of the local delivery methods this approach is safe in 80% of patients in an ambulatory setting. Surgical cytoreduction immediately followed by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) ensures intraperitoneal delivery of the drug to all peritoneal surfaces and the advantages of combined hyperthermia to be exploited. An increasing number of centers are initiating this multimodality therapy in ovarian cancer and colorectal cancer. Clearly, intraperitoneal drug delivery is an important adjunct to surgery and systemic chemotherapy in selected patients. The optimal drug, dose and schedule for intraperitoneal delivery, the exact role of added HIPEC compared with cytoreduction alone, and the potential role of HIPEC in ovarian cancer and peritoneal mesothelioma are still undefined. Several randomized controlled trials addressing these uncertainties have been initiated.

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.

Total vs partial fundoplication in the treatment of gastroesophageal reflux disease: a meta-analysis.

OBJECTIVE To perform a meta-analysis of randomized trials comparing partial fundoplication (PF) with total (Nissen) fundoplication (TF) for gastroesophageal reflux disease in terms of morbidity, efficacy, and long-term symptomatology. DATA SOURCES A structured Medline search for published studies. STUDY SELECTION The available literature from 1975 until June 2007 was searched using the Medical Subject Headings of the National Library of Medicine term fundoplication and the free-text terms fundoplication, surgery, and reflux. Data were analyzed using Review Manager software (Cochrane Collaboration, Oxford, England). DATA EXTRACTION Eleven trials were identified comparing TF with PF in 991 patients. DATA SYNTHESIS Total fundoplication resulted in a significantly higher incidence of postoperative dysphagia (odds ratio [OR], 1.82-3.93; P < .001), bloating (OR, 1.07-2.56; P = .02), and flatulence (OR, 1.66-3.96; P < .001). No significant differences were noted in the incidence of esophagitis (OR, 0.72-2.7; P = .33), heartburn (OR, 0.48-1.52; P = .58), or persisting acid reflux (OR, 0.77-1.79; P = .45). The reoperation rate was significantly higher after TF compared with PF (OR, 1.13-3.95; P = .02). No significant differences were present in the proportion of patients experiencing a good or excellent long-term outcome (OR, 0.54-1.38; P = .53) or in the proportion of patients with a Visick I or II score (OR, 0.62-1.59; P = .99). CONCLUSIONS Partial fundoplication is a safe and effective alternative to TF, resulting in significantly fewer reoperations and a better functional outcome. The poor quality of the included trials warrants caution in the interpretation of the results of this meta-analysis.

Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases

Background:The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions.Methods:A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUVmax) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (Ktrans) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index.Results:Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P=0.002) and 40% (P=0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in Ktrans (P=0.019). In the group of radiological responders, the median baseline SUVmax was 3.77 (IQR: 2.88–5.60) compared with 7.20 (IQR: 4.67–8.73) in nonresponders (P=0.021). A higher follow-up SUVmax was correlated with worse PFS (P=0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P=0.016).Conclusion:High relative decrease in Ktrans, low follow-up SUVmax and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery.

Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: A systematic review and meta-analysis

Combining chemotherapy with preoperative radiotherapy (RT) has a sound radiobiological rationale. We performed a systematic review and meta‐analysis of trials comparing preoperative RT with preoperative chemoradiation (CRT) in rectal cancer patients. The Cochrane Central Register of Controlled Trials, Web of Science, Embase and Medline (Pubmed) were searched from 1975 until June 2007. Dichotomous parameters were summarized using the odds ratio while time to event data were analyzed using the pooled hazard ratio for death. From the primary search result of 324 trials, 4 relevant randomized trials were identified. The addition of chemotherapy significantly increased grade III and IV acute toxicity (p = 0.002) while no differences were observed in postoperative morbidity or mortality. Preoperative CRT significantly increased the rate of pathological complete response (p < 0.001) although this did not translate into a higher sphincter preservation rate (p = 0.29). The local recurrence rate was significantly lower in the CRT group (p < 0.001). No statistically significant differences were observed in disease free survival (p = 0.89) or overall survival (p = 0.79). Compared to preoperative RT alone, preoperative CRT improves local control in rectal cancer but is associated with a more pronounced treatment related toxicity. The addition of chemotherapy does not benefit sphincter preservation rate or long‐term survival. Future trials should address improvements in the rate of distant metastasis and overall survival by incorporating more active chemotherapy.

Safety and Efficacy of Hyperthermic Intraperitoneal Chemoperfusion with High-Dose Oxaliplatin in Patients with Peritoneal Carcinomatosis

BackgroundCytoreduction 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.MethodsFollowing complete cytoreduction, HIPEC was performed using 460 mg/m2 oxaliplatin in 5% dextrose for 30 min at a temperature of 41–42°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.ResultsFrom 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.ConclusionCytoreduction 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.

Recommendations for reporting outcome results in abdominal wall repair

BackgroundThe literature dealing with abdominal wall surgery is often flawed due to lack of adherence to accepted reporting standards and statistical methodology.Materials and methodsThe EuraHS Working Group (European Registry of Abdominal Wall Hernias) organised a consensus meeting of surgical experts and researchers with an interest in abdominal wall surgery, including a statistician, the editors of the journal Hernia and scientists experienced in meta-analysis. Detailed discussions took place to identify the basic ground rules necessary to improve the quality of research reports related to abdominal wall reconstruction.ResultsA list of recommendations was formulated including more general issues on the scientific methodology and statistical approach. Standards and statements are available, each depending on the type of study that is being reported: the CONSORT statement for the Randomised Controlled Trials, the TREND statement for non randomised interventional studies, the STROBE statement for observational studies, the STARLITE statement for literature searches, the MOOSE statement for metaanalyses of observational studies and the PRISMA statement for systematic reviews and meta-analyses. A number of recommendations were made, including the use of previously published standard definitions and classifications relating to hernia variables and treatment; the use of the validated Clavien-Dindo classification to report complications in hernia surgery; the use of “time-to-event analysis” to report data on “freedom-of-recurrence” rather than the use of recurrence rates, because it is more sensitive and accounts for the patients that are lost to follow-up compared with other reporting methods.ConclusionA set of recommendations for reporting outcome results of abdominal wall surgery was formulated as guidance for researchers. It is anticipated that the use of these recommendations will increase the quality and meaning of abdominal wall surgery research.