Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized CROSS trial.

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods: Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results: After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen's d -0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen's d -0.56 and 0.51, respectively, both P < 0.001). Conclusions: Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number: Netherlands Trial Register NTR487.

Overall survival before and after centralization of gastric cancer surgery in the Netherlands.

BACKGROUND: Centralization of surgery has been shown to improve outcomes for oesophageal and pancreatic cancer, and has been implemented for gastric cancer since 2012 in the Netherlands. This study evaluated the impact of centralizing gastric cancer surgery on outcomes for all patients with gastric cancer. METHODS: Patients diagnosed with non-cardia gastric adenocarcinoma in the intervals 2009-2011 and 2013-2015 were selected from the Netherlands Cancer Registry. Clinicopathological data, treatment characteristics and mortality were assessed for the periods before (2009-2011) and after (2013-2015) centralization. Cox regression analyses were used to assess differences in overall survival between these intervals. RESULTS: A total of 7204 patients were included. Resection rates increased slightly from 37·6 per cent before to 39·6 per cent after centralization (P = 0·023). Before centralization, 50·1 per cent of surgically treated patients underwent gastrectomy in hospitals that performed fewer than ten procedures annually, compared with 9·2 per cent after centralization. Patients who had gastrectomy in the second interval were younger and more often underwent total gastrectomy (29·3 per cent before versus 41·2 per cent after centralization). Thirty-day postoperative mortality rates dropped from 6·5 to 4·1 per cent (P = 0·004), and 90-day mortality rates decreased from 10·6 to 7·2 per cent (P = 0·002). Two-year overall survival rates increased from 55·4 to 58·5 per cent among patients who had gastrectomy (P = 0·031) and from 27·1 to 29·6 per cent for all patients (P = 0·003). Improvements remained after adjustment for case mix; however, adjustment for hospital volume attenuated this association for surgically treated patients. CONCLUSION: Centralization of gastric cancer surgery was associated with reduced postoperative mortality and improved survival.

Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study).

BACKGROUND: Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer. METHODS: This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3-4b, N0-3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study. DISCUSSION: In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of €916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems. TRIAL REGISTRATION: NCT03208621 . This trial was registered prospectively on June 30, 2017.

Home visits as part of a new care pathway (iAID) to improve quality of care and quality of life in ostomy patients: a cluster-randomized stepped-wedge trial.

AIM: Morbidity in patients with an ostomy is high. A new care pathway, including perioperative home visits by enterostomal therapists, was studied to assess whether more elaborate education and closer guidance could reduce stoma-related complications and improve quality of life (QoL), at acceptable cost. METHOD: Patients requiring an ileostomy or colostomy, for any inflammatory or malignant bowel disease, were included in a 15-centre cluster-randomized 'stepped-wedge' study. Primary outcomes were stoma-related complications and QoL, measured using the Stoma-QOL, 3 months after surgery. Secondary outcomes included costs of care. RESULTS: The standard pathway (SP) was followed by 113 patients and the new pathway (NP) by 105 patients. Although the overall number of stoma-related complications was similar in both groups (SP 156, NP 150), the proportion of patients experiencing one or more stoma-related complications was significantly higher in the NP (72% vs 84%, risk difference 12%; 95% CI: 0.3-23.3%). Although in the NP more patients had stoma-related complications, QoL scores were significantly better (P < 0.001). In the SP more patients required extra care at home for their ostomy than in the NP (60.6% vs 33.7%, respectively; risk difference 26.9%, 95% CI: 13.5-40.4%). Stoma revision was done more often in the SP (n = 11) than in the NP (n = 2). Total costs in the SP did not differ significantly from the NP. CONCLUSION: The NP did not reduce the number of stoma-related complications but did lead to improved quality of care and life, against similar costs. Based on these results the NP, including perioperative home visits by an enterostomal therapist, can be recommended.

A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer.

BACKGROUND: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. METHODS/STUDY DESIGN: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. DISCUSSION: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. TRIAL REGISTRATION: NCT02371304 , registration date: February 2015.

Preoperative chemoradiotherapy for esophageal or junctional cancer.

BACKGROUND: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Low radiographic muscle density is associated with lower overall and disease-free survival in early-stage colorectal cancer patients.

BACKGROUND: In cancer patients with a poor prognosis, low skeletal muscle radiographic density is associated with higher mortality. Whether this association also holds for early-stage cancer is not very clear. We aimed to study the association between skeletal muscle density and overall mortality among early-stage (stage I-III) colorectal cancer (CRC) patients. Furthermore, we investigated the association between skeletal muscle density and both CRC-specific mortality and disease-free survival in a subset of the study population. METHODS: Skeletal muscle density was assessed in 1681 early-stage CRC patients, diagnosed between 2006 and 2015, using pre-operative computed tomography images. Adjusted Cox proportional hazard models were used to evaluate the association between muscle density and overall mortality, CRC-specific mortality and disease-free survival. RESULTS: The median follow-up time was 48 months (range 0-119 months). Low muscle density was detected in 39% of CRC patients. Low muscle density was significantly associated with higher mortality (low vs. normal: adjusted HR 1.91, 95% CI 1.53-2.38). After stratification for comorbidities, the association was highest in patients with ≥ 2 comorbidities (HR 2.11, 95% CI 1.55-2.87). Furthermore, low skeletal muscle density was significantly associated with poorer disease-free survival (HR 1.68, 95% CI 1.14-2.47), but not with CRC-specific mortality (HR 1.68, 95% CI 0.89-3.17) in a subset of the study population. CONCLUSION: In early-stage CRC patients, low muscle density was significantly associated with higher overall mortality, and worse disease-free survival.

Impact of Centralizing Gastric Cancer Surgery on Treatment, Morbidity, and Mortality.

INTRODUCTION: Centralization of gastric cancer surgery is thought to improve outcome and has been imposed in the Netherlands since 2012. This study analyzes the effect of centralization in terms of treatment outcome and survival in the Eastern part of the Netherlands. METHODS: All gastric cancer patients without distant metastases who underwent a gastrectomy in six hospitals in the Eastern part of the Netherlands between 2008 and 2011 (pre-centralization) and 2013-2016 (post-centralization) were selected from the Netherlands Cancer Registry. Patient and tumor characteristics and treatment outcomes (duration of surgery, blood loss, resection margin, lymphadenectomy, chemotherapy, postoperative complications and hospital stay, and overall and disease-free survival) were analyzed and compared between pre- and post-centralization. RESULTS: One hundred forty-four patients were included pre-centralization and 106 patients post-centralization. Patient and tumor characteristics were almost similar in the two periods. After centralization, more patients were treated with perioperative chemotherapy (25 vs. 42% p < 0.01). The proportion of patients treated with an adequate lymphadenectomy (21 vs. 93% p < 0.01) and laparoscopic surgery (6 vs. 40% p < 0.01) increased significantly (p < 0.01). The amount of cardiac complications (16 vs. 7.5% p < 0.05) decreased; however, complications needing a re-intervention were comparable (42 vs. 40% p = 0.79). Median hospital stay decreased from 10 to 8 days (p < 0.01). A 30-day mortality did not differ significantly (4.2 vs. 1.9%). A 1-year overall (78 vs. 80% p = 0.17) and disease-free survival (73 vs. 74% p = 0.66) remained stable. DISCUSSION: Centralizing gastric cancer treatment in the Eastern part of the Netherlands resulted in improved lymph node harvesting and a successful introduction of laparoscopic gastrectomies. Centralization has not translated into improved mortality, and other variables may also have led to these improved outcomes. Further research using a nationwide population-based study will be needed to confirm these data.

Moderate effect of preoperative blood transfusions on pancreas allograft survival in rats and dogs.

Treatment of type I diabetes by early pancreas transplantation requires the availability of a safe and effective transplantation technique. With the currently available immunosuppressive drugs it is difficult to obtain long-term pancreatic allograft survival. In this respect pancreas grafts compare unfavorably with heart or kidney grafts. Using a relatively simple and safe subcutaneous transplantation technique we investigated the effect of blood transfusions combined with low-dose immunosuppressive drugs in rats and dogs in order to attain an immunosuppressive schedule of low toxicity. Subcutaneous pancreas transplantation appeared to be a feasible technique, with long-term graft survival in syngeneically transplanted rats and autotransplanted dogs. Only a moderate prolongation of pancreatic allograft survival by blood transfusions was demonstrated in both models. In rats one or three preoperative donor-specific blood transfusions significantly prolonged pancreas graft survival to 23 +/- 15 and 29 +/- 15 days, respectively, compared with 12 +/- 2 days in untreated controls. Low-dose cyclosporine (15 mg/kg on the day of operation) led to improved graft survival in nontransfused recipients (17 +/- 4 days), however, this treatment could not further prolong graft survival in transfused animals (34 +/- 20 days). In dogs, treated postoperatively with azathioprine and prednisolone, three preoperative third-party blood transfusions led to 29 +/- 19 days of pancreas graft survival, which was not significantly different from nontransfused controls (17 +/- 5 days). These results indicate that, in rats as well in dogs, pancreatic allografts are less sensitive to the immunomodulating effect of blood transfusions than heart and kidney grafts.

Small but significant survival benefit in patients who undergo routine follow-up after colorectal cancer surgery.

BACKGROUND: The benefit of follow-up for patients after resection of primary colorectal cancer is unproven. The aim of this study was to evaluate the value of a standardised follow-up program considering detection of recurrent disease, eligibility for surgical treatment and survival. METHODS: Five hundred and sixty-four patients' records were evaluated. Detection of recurrent disease was distinguished in routine follow up (RF), interval visit (IV) or accidental finding (AF). RESULTS: One hundred and forty-nine patients (26%) had recurrent disease of which 68 were detected by routine follow-up. In 42 patients a resection was performed with curative intent (RF 18, IV 14, AF 10). In 26 patients radical resection (R(0)) was possible (RF 13, IV 5, AF 8), seven of them were long-term survivors. Routine follow-up itself had no significant influence on overall survival (P=0.08), although increased survival was observed if recurrent disease was detected by routine follow-up and resection was performed with curative intent (P=0.006). Median survival after resection was 4.2 years if recurrent disease was detected during routine follow-up and 0.5 years if detected during interval visits. CONCLUSIONS: Patients undergoing resection with curative intent for recurrent disease survive significantly longer if the disease is detected by routine follow-up. Routine follow-up itself did not improve overall survival.

Parastomal hernia: complications of extra-peritoneal onlay mesh placement.

OBJECTIVE: To determine the complication and infection risks following extra-peritoneal onlay mesh placement in parastomal hernia repair. DESIGN: A retrospective analysis of medical records was performed. BACKGROUND: Parastomal hernia is a frequent complication of enterostomata. Fascial repair using a prosthetic mesh has been generally accepted as the best method of parastomal hernia repair. New studies suggest the use of a prophylactic mesh placement at the initial operation, but fear of wound infection and mesh removal is still high. PATIENTS AND METHODS: A retrospective review of patient records was performed of all patients with extra-peritoneal parastomal hernia repair using a prosthetic mesh between 1997 and 2006. The patient demographic data, enterostomy indication, therapy, and outcome were recorded. RESULTS: In the 10-year study period, 16 parastomal hernia repairs using an extra-peritoneal prosthetic mesh in the onlay position were performed. In one patient, a mesh infection occurred, resulting in mesh removal (6.2%). The recurrence rate was 19% after a mean follow-up of 33 months. CONCLUSION: Parastomal hernia repair using a prosthetic mesh is a safe and effective method, with the lowest recurrence rates and acceptably low infection rates. Prosthetic materials should not be used in cases of fecal contamination.

Colonic explosion during endoscopic polypectomy: avoidable complication or bad luck?

We were confronted recently by an intraluminal colonic explosion during a colonic polypectomy procedure using snare loop electrocautery, probably caused by the presence of hydrogen and/or methane in combustible concentrations. Our patient needed immediate surgery, when several lacerations were found in the colon: a right hemicolectomy and a partial sigmoid resection with primary anastomoses were performed. Colonic bacteria, rests of fecal fluids, certain cleansing solutions, and oxygen insufflation are the main factors involved in cases of colonic explosion. We describe this dramatic event in our patient and discuss whether this complication might be avoidable in the future.

Does seeding of intraluminal tumour cells cause anastomotic recurrence after oesophageal resection?

BACKGROUND: Recurrence at the cervical anastomosis of a tumour of the oesophagogastric junction after resection of the oesophagus with gastric tube reconstruction is a peculiar phenomenon in view of the distance of the primary tumour from the proximal anastomosis. It is hypothesised that contamination with tumour cells from the nasogastric tube or the gastric reconstruction tube could be responsible for this phenomenon. METHOD: Fifteen patients with a tumour of the oesophagus or gastric cardia were included. During the operation the nasogastric tube was left in the resected specimen. Debris from the tube was washed out for cytological examination. Also the gastric reconstruction tube was washed out and the debris examined for malignant cells. RESULTS: In all of the patients with a tumour extending intraluminally malignant cells were found in the nasogastric tube or the gastric reconstruction tube or both. In 92% of these patients malignant cells were found in the nasogastric tube, while 60% of the gastric reconstruction tubes were contaminated with tumour cells. CONCLUSION: The presence of intraluminal malignant cells during oesophageal resection and gastric tube reconstruction is very high, possibly leading to anastomotic recurrence. Measures should be taken to minimise local contamination with tumour cells.

Laparoscopy and laparoscopic ultrasonography in staging of oesophageal and cardial carcinoma.

BACKGROUND: The ideal method for staging tumours of the oesophagus and gastric cardia is not known. This paper was designed to assess the value of laparoscopy and laparoscopic ultrasonography in the staging of oesophageal and cardial carcinoma. METHODS: From October 1993 to January 1996, 60 patients in whom no metastases were seen on gastroscopy, ultrasonography of the abdomen and supraclavicular region, helical computed tomography of the chest and abdomen or endosonography were scheduled for laparoscopy and laparoscopic ultrasonography. RESULTS: Some 40 patients had carcinoma of the oesophagus, in one of whom liver metastases were found at laparoscopy and proven histologically. On laparoscopic ultrasonography metastases were found in four patients but were impossible to biopsy. These lymph node metastases were confirmed at exploratory laparotomy. Twenty patients had carcinoma of the gastric cardia; distant metastases were found in four at laparoscopy. On laparoscopic ultrasonography metastases were present in four further patients, all proven by biopsy. CONCLUSION: In this study laparoscopy was not an effective staging technique for oesophageal carcinoma. The inclusion of laparoscopic ultrasonography was of little benefit. A problem that was encountered was biopsy under laparoscopic guidance. In carcinoma of the gastric cardia, laparoscopy was more effective; adding laparoscopic ultrasonography doubled the number of patients seen to have metastatic disease.