J.J.B. van Lanschot

Extended Lymph-Node Dissection for Gastric Cancer

BACKGROUND Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery. METHODS Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results. RESULTS Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P= 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent). CONCLUSIONS Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.

Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients

For patients with gastric cancer deemed curable the only treatment option is surgery, but there is disagreement about whether accompanying lymph-node dissection should be limited to the perigastric nodes (D1) or should extend to regional lymph nodes outside the perigastric area (D2). We carried out a multicentre randomised comparison of D1 and D2 dissection. 1078 patients were randomised (539 to each group). 26 allocated D1 and 56 allocated D2 were found not to satisfy eligibility criteria (histologically confirmed adenocarcinoma of the stomach without clinical evidence of distant metastasis). Each of the remainder was attended by one of eleven supervising surgeons who decided whether curative resection was possible and, if so, assisted with the allocated procedure. Among the 711 patients (380 D1, 331 D2) judged to have curable lesions, D2 patients had a higher operative mortality rate than D1 patients (10 vs 4%, p = 0.004) and experienced more complications (43 vs 25%, p < 0.001). They also needed longer postoperative hospital stays (median 25 [range 7-277] vs 18 [7-143] days, p < 0.001). Morbidity and mortality differences persisted in almost all subgroup analyses. While we await survival results, D2 dissection should not be used as standard treatment for western patients.

Is a single-item visual analogue scale as valid, reliable and responsive as multi-item scales in measuring quality of life?

Purpose: To compare the validity, reliability and responsiveness of a single, global quality of life question to multi-item scales. Method: Data were obtained from 83 consecutive patients with oesophageal adenocarcinoma undergoing either transhiatal or transthoracic oesophagectomy. Quality of life was measured at baseline, 5 weeks, 3 and 12 months post-operatively with a single-item Visual Analogue Scale (VAS) ranging from 0 to 100, the multi-item Medical Outcomes Study Short Form-20 (MOS SF-20) and Rotterdam Symptom Check-List (RSCL). Convergent and discriminant validity, test–retest reliability and both distribution-based and anchor-based responsiveness were evaluated. Major findings: At baseline and at 5 weeks, the VAS showed high correlations with the MOS SF-20 health perceptions scale (r = 0.70 and 0.72) and moderate to high correlations with all other subscales of the MOS SF-20 and RSCL (r = 0.29–0.70). The test–retest reliability intra-class correlation for the VAS was 0.87. At 5 weeks post-operatively, the distribution-based responsiveness was moderate for the VAS (standardised response mean: −0.47; effect size: −0.56), high for the physical subscales of the MOS SF-20 and RSCL (−1.08 to −1.51) and low for the psychological subscales (0.11 to −0.25). Five weeks post-operatively, anchor-based responsiveness was highest for the VAS (r = 0.54). Conclusion: The VAS is an instrument with good validity, excellent reliability, moderate distribution-based responsiveness and good anchor-based responsiveness compared to multi-item questionnaires. Its use is recommended in clinical trials to assess global quality of life.

Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma

Background—The efficacy of endoscopic biopsy surveillance of Barrett’s oesophagus in reducing mortality from oesophageal cancer has not been confirmed. Aims—To investigate the impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett’s carcinoma. Methods—A clinicopathological comparison was made between patients who initially presented with oesophageal adenocarcinoma (n=54), and those in whom the cancer had been detected during surveillance of Barrett’s oesophagus (n=16). Results—The surveyed patients were known to have Barrett’s oesophagus for a median period of 42 months (range 6–144 months). Prior to the detection of adenocarcinoma or high grade dysplasia, 13 of 16 patients (81%) were previously found to have low grade dysplasia. Surgical pathology showed that surveyed patients had significantly earlier stages than non-surveyed patients (p=0.0001). Only one surveyed patient (6%) versus 34 non-surveyed patients (63%) had nodal involvement (p=0.0001). Two year survival was 85.9% for surveyed patients and 43.3% for non-surveyed patients (p=0.0029). Conclusions—The temporal course of histological progression in our surveyed patients supports the theory that adenocarcinoma in Barrett’s oesophagus develops through stages of increasing severity of dysplasia. Endoscopic biopsy surveillance of Barrett’s oesophagus permits detection of malignancy at an early and curable stage, thereby potentially reducing mortality from oesophageal adenocarcinoma.

Systematic Review of the Staging Performance of 18F-Fluorodeoxyglucose Positron Emission Tomography in Esophageal Cancer

PURPOSE Despite the increasing number of publications concerning (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) for staging of esophageal cancer and the increasing availability of this novel diagnostic modality, its exact role in preoperative staging of these tumors is still unknown. The aim of this study was to systematically review the literature regarding the diagnostic performance of FDG-PET in preoperative staging of patients with esophageal cancer, and to calculate summary estimates of its sensitivity and specificity. METHODS The databases of PubMed, Embase, and Cochrane were searched for relevant studies. Two reviewers independently assessed the methodological quality of each study. A meta-analysis of the reported sensitivity and specificity of each study was performed. RESULTS Twelve studies met the inclusion criteria. The studies had several design deficiencies. Pooled sensitivity and specificity for the detection of locoregional metastases were 0.51 (95% CI, 0.34 to 0.69) and 0.84 (95% CI, 0.76 to 0.91), respectively. For distant metastases, pooled sensitivity and specificity were 0.67 (95% CI, 0.58 to 0.76) and 0.97 (95% CI, 0.90 to 1.0), respectively. CONCLUSION FDG-PET showed moderate sensitivity and specificity for the detection of locoregional metastases, and reasonable sensitivity and specificity in detection of distant lymphatic and hematogenous metastases.

Quality of Life After Transhiatal Compared With Extended Transthoracic Resection for Adenocarcinoma of the Esophagus

PURPOSE To assess 3 years of quality of life in patients with esophageal cancer in a randomized trial comparing limited transhiatal resection with extended transthoracic resection. PATIENTS AND METHODS Quality-of-life questionnaires were sent at baseline and at 5 weeks; 3, 6, 9, and 12 months; and 1.5, 2, 2.5, and 3 years after surgery. Physical and psychological symptoms, activity level, and global quality of life were assessed with the disease-specific Rotterdam Symptom Checklist. Generic quality of life was measured with the Medical Outcomes Study Short Form-20. RESULTS A total of 199 patients participated. Physical symptoms and activity level declined after the operation and gradually returned toward baseline within the first year (P < .01). Psychological well-being consistently improved after baseline (P < .01), whereas global quality of life showed a small initial decline followed by continuous gradual improvement (P < .01). Quality of life stabilized in the second and third year. Three months after the operation, patients in the transhiatal esophagectomy group (n = 96) reported fewer physical symptoms (P = .01) and better activity levels (P < .01) than patients in the transthoracic group (n = 103), but no differences were found at any other measurement point. For psychological symptoms and global quality of life, no differences were found at any follow-up measurement. A similar pattern was found for generic quality of life. CONCLUSION No lasting differences in quality of life of patients who underwent either transhiatal or transthoracic resection were found. Compared with baseline, quality of life declined after the operation but was restored within a year in both groups.

Clinical decision making in Barrett's oesophagus can be supported by computerized immunoquantitation and morphometry of features associated with proliferation and differentiation.

Grading of dysplasia in Barretts oesophagus has a therapeutic impact, but subjective grading is associated with substantial observer variation. Quantitative pathological methods could help to achieve a more accurate and reproducible diagnosis. In the present study, the immunoquantitation of p53 and Ki67 and the morphometric analysis of features associated with proliferation and differentiation were evaluated for this purpose. In slides of 35 oesophagectomy specimens, 73 areas that displayed either no dysplasia (ND), low‐grade dysplasia (LGD), high‐grade dysplasia (HGD), or intramucosal carcinoma (ImCa) were initially considered. Agreement on double blind examination by two experienced pathologists was reached in 58 areas, which were used as the ‘learning set’. The 15 areas of disagreement were used as a second set. In the univariate analysis, the most significant differences in the learning set were found for Ki67, p53, stratification index (SI), mean nuclear area, and volume. Further multivariate analysis showed that for discrimination between ND and LGD, the combination of Ki67 and SI resulted in 94 per cent correctly classified areas. Likewise, for the discrimination between LGD and HGD, Ki67 and SI were the most powerful combination (again, 94 per cent of areas classified correctly). The discrimination between HGD and ImCa with any combination of the quantitative parameters never exceeded 80 per cent correct classification. The addition of p53 was of no value in improving the discrimination of ND vs. LGD, or of LGD vs. HGD. In the 15 original disagreement areas of the initial set of 73, three of the five ND/LGD areas could be uniquely classified as either ND or LGD by Ki67 and SI. Moreover, three of the four LGD/HGD disagreement areas could be uniquely classified with the combination of Ki67 and SI as either LGD or HGD. We conclude that the quantitative assessment of cytometric and morphometric features associated with proliferation and differentiation (especially Ki67 and SI) can be a valuable adjunct tool for clinical decision making in Barretts oesophagus.

Prognostic value of Laurén classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction.

Background: The prognostic value of the Laurén classification and of c-erbB-2 oncogene overexpression has been described for gastric cancer. The aim of this study was to investigate the clinical significance of these factors in adenocarcinoma of the esophagus and/or gastroesophageal junction (GEJ).Methods: Forty-one adenocarcinomas of the esophagus and/or GEJ were reviewed for tumor stage, lymph node status, Laurén classification, and c-erbB-2 overexpression, as assessed by immunohistochemical analysis.Results: According to the Laurén classification, tumors were classified as intestinal-, mixed-, or diffuse-type (54%, 32%, and 15%, respectively). Diffuse-type tumors were associated with a significantly worse prognosis than were intestinal-type tumors (P = .018; log-rank test). The prognostic value of the Laurén classification was independent of stage (P = .048; Cox regression model). Overexpression of c-erbB-2 was detected in 24% of the tumors and was present exclusively in intestinal-type tumors and in intestinal-type areas of mixed-type tumors. Ten of the 30 stage III/IV tumors (33%) were c-erbB-2-positive, whereas none of the 11 stage I/II tumors (0%) overexpressed the oncogene product (P = .04; Fisher exact test). The prognostic value of c-erbB-2 overexpression was not independent of stage (P = .7; Cox regression model).Conclusions: (1) The Laurén classification is an independent prognostic factor in adenocarcinoma of the esophagus and GEJ. (2) c-erbB-2 overexpression is limited to (areas of) intestinal-type tumors, indicating that intestinal- and diffuse-type tumors differ oncogenetically. (3) c-erbB-2 overexpression is associated with the stage of disease, indicating that it is a late event during tumor progression.

Morbidity of Temporary Loop Ileostomies

Background/Aims: A temporary loop ileostomy is constructed to protect a distal colonic anastomosis. Closure is usually performed not earlier than 8–12 weeks after the primary operation. During this period, stoma-related complications can occur and enhance the adverse effect on quality of life. The aim of this study was to evaluate the length of time between ileostomy construction and closure, to quantify stoma-related morbidity and to examine the potential advantages of early ileostomy closure. Methods: Sixty-nine patients with a temporary, protective loop ileostomy (constructed between January 1996 and December 2000) were retrospectively analysed. The analysis was done by reviewing the medical records and the notes of the stoma care nurse. Results: Sixty ileostomies (87%) were closed after a median period of 24 weeks (range 2–124 weeks). Stoma-related complications occurred in 29 of the 69 patients (42%), and 11 patients (18%) had complications after ileostomy closure. Conclusion: The length of time between ileostomy construction and closure was substantially longer than initially planned. Earlier ileostomy closure (preferably even during the initial admission) could reduce the frequently occurring stoma-related morbidity in these patients and thus improve quality of life.

The value of p53 and Ki67 as markers for tumour progression in the Barrett's dysplasia-carcinoma sequence

In the Barretts oesophagus (BE) progression from metaplasia, via dysplasia, into invasive cancer, an aberrant cell proliferation governed by genetic change plays a central role. Alterations of the p53 tumour-suppressor gene appear especially critical and, like the proliferation marker Ki67, can be detected by immunohistochemistry. The purpose of this study therefore was to investigate the clinical value of p53 and Ki67 as markers for tumour progression in BE, and at the same time test the validity of the concept of a metaplasia-dysplasia-carcinoma sequence in BE by correlating the expression of these markers with various grades of dysplasia. Thirty-two lesions (seven negative for dysplasia, five indefinite for dysplasia, 11 low-grade dysplasia and nine high-grade dysplasia) from 25 archival resection specimens were selected for study. Increasing grades of dysplasia showed increasingly p53 accumulation; p53 accumulation was never observed in mucosa without dysplasia. The increasing p53 expression was accompanied by an increased Ki67-labelling index and an upward shift of the proliferative compartment. The results lend support to the multistep progression model of a metaplasia-dysplasia-carcinoma sequence in BE. Expression of p53 and Ki67, markers which can be easily applied on archival material, can be valuable adjuncts for the histopathological diagnosis of dysplasia and may have predictive value for cancer risk.