H. W. Tilanus

Extended Lymph-Node Dissection for Gastric Cancer

BACKGROUNDnCurative 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.nnnMETHODSnBetween 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.nnnRESULTSnPatients 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).nnnCONCLUSIONSnOur 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.

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

PURPOSEnTo assess 3 years of quality of life in patients with esophageal cancer in a randomized trial comparing limited transhiatal resection with extended transthoracic resection.nnnPATIENTS AND METHODSnQuality-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.nnnRESULTSnA 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.nnnCONCLUSIONnNo 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.

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50u2009mgu2009m−2 and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4u2009Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3–4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.

Prognostic factors for survival in patients with advanced oesophageal cancer treated with cisplatin-based combination chemotherapy

The objective of this study was to identify prognostic factors for survival in patients with advanced oesophageal cancer, who are treated with cisplatin-based combination chemotherapy. We analysed the baseline characteristics of 350 patients who were treated in six consecutive prospective trials with one of the following regimens: cisplatin/etoposide, cisplatin/etoposide/5-fluorouracil, cisplatin/paclitaxel (weekly) and cisplatin/paclitaxel (biweekly). Predictive factors in univariate analyses were further evaluated using multivariate analysis (Cox regression). The median survival of all patients was 9 months. The 1, 2 and 5-year survival rates were 33, 12 and 4%, respectively. The main prognostic factors were found to be WHO performance status (0 or 1 vs 2), lactate dehydrogenase (normal vs elevated), extent of disease (limited disease defined as locoregional irresectable disease or lymph node metastases confined to either the supraclavicular or celiac region vs extensively disseminated disease) in addition to the type of treatment (weekly or biweekly cisplatin/paclitaxel regimen vs 4-weekly cisplatin/etoposide with or without 5-fluorouracil). Although weight loss, liver metastases and alkaline phosphatase were significant prognostic factors in univariate analyses, these factors lost their significance in multivariate analyses. The median survival for patients without any risk factors was 12 months, compared to only 4 months in patients with WHO 2 plus elevated LDH and extensive disease. The performance status, extent of disease, LDH and the addition of paclitaxel to cisplatin are independent prognostic factors in patients with advanced oesophageal cancer, who are treated with cisplatin-based combination chemotherapy.

Randomized clinical trial comparing feeding jejunostomy with nasoduodenal tube placement in patients undergoing oesophagectomy

Feeding jejunostomy is frequently performed in patients undergoing oesophageal surgery, but can lead to serious complications. This prospective randomized trial compared the efficacy and complications of feeding jejunostomy with those of nasoduodenal tube feeding in oesophageal surgery.

Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer

In a phase I study we demonstrated the feasibility of a bi-weekly combination of paclitaxel 180u2009mgu2009m−2 with cisplatin 60u2009mgu2009m−2. In this study we further assessed toxicity and efficacy of this schedule in the treatment of advanced cancer of the oesophagus or the gastro-oesophageal junction. Patients received paclitaxel 180u2009mgu2009m−2 administered over 3u2009h followed by a 3-h infusion of cisplatin 60u2009mgu2009m−2. Patients were retreated every 2 weeks unless granulocytes were <0.75 × 109 or platelets <75 × 109. Patients were evaluated after three and six cycles and responding patients received a maximum of eight cycles. Fifty-one patients were enrolled into the study. The median age was 56 years (range 32–78). WHO performance status were: 0 (19 patients); 1 (29 patients); 2 (three patients). All patients received at least three cycles of chemotherapy and all were evaluable for toxicity and response. Haematological toxicity consisted of uncomplicated neutropenia grade 3 in 39% and grade 4 in 31% of patients. Five patients (10%) were hospitalised, three patients because of treatment related complications and two patients because of infections without neutropenia. Sensory neurotoxicity was the predominant non-haematological toxicity; grade 1 and 2 neurotoxicity was observed in 43 and 20% of patients, respectively. Response evaluation in 51 patients with measurable disease: complete response 4%, partial response 39%, stable disease 43% and progressive disease in 14% of the patients. The median duration of response was 8 months. The median survival for all patients was 9 (range 2–29+) months and the one-year survival rate was 43%. Four patients who received additional local treatment (two patients surgery and two patients radiotherapy) are still disease free after a follow-up of 20–29 months. This bi-weekly treatment of paclitaxel and cisplatin is well tolerated by patients with advanced oesophageal cancer. The toxicity profile of this regimen compares favourable to that of previously used cisplatin- and paclitaxel-based regimens. Trials are underway evaluating this bi-weekly regimen in a neo-adjuvant setting.

Dysplasia and aneuploidy as markers of malignant degeneration in Barrett's oesophagus. The Rotterdam Oesophageal Tumour Study Group.

The role of dysplasia and aneuploidy as markers in columnar epithelium for malignant degeneration in Barretts oesophagus was compared in a case control study comprising 38 patients with benign Barretts oesophagus and 50 patients with Barretts oesophagus associated with adenocarcinoma. Tissue specimens of columnar epithelium were reviewed for the presence of specialised columnar epithelium and the grade of dysplasia. Ploidy was determined using the method for formalin fixed paraffin wax embedded tissue described by Hedley. There was no significant difference in the frequency of specialised columnar epithelium between both groups. Dysplasia was found more often in columnar epithelium associated with adenocarcinoma compared with benign Barretts oesophagus (p < 0.001). Multivariate analysis using logistic regression showed an increased risk of malignancy in Barretts oesophagus in case of dysplasia (odds ratio 9.4, p = 0.003 for mild dysplasia and 33.1, p < 0.001 for moderate or severe dysplasia). Ploidy was not statistically significantly correlated with dysplasia. Aneuploidy or increased G2/tetraploidy proved to be an independent risk factor for younger patients (age < 65 years: odds ratio 44.7, p = 0.003). In conclusion, dysplasia and aneuploidy or increased G2/tetraploidy in columnar epithelium are independent risk factors for malignant degeneration. Patients with these risk factors should be offered a more intensive screening programme.

Prognostic value of body mass index on short-term and long-term outcome after resection of esophageal cancer.

IntroductionCachexia and obesity have been suggested to be risk factors for postoperative complications. However, high body mass index (BMI) might result in a higher R0-resection rate because of the presence of more fatty tissue surrounding the tumor. The purpose of this study was to investigate whether BMI is of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer.MethodsIn 556 patients who underwent esophagectomy (1991–2007), clinical and pathological outcome were compared between different BMI classes (underweight, normal weight, overweight, obesity).ResultsOverall morbidity, mortality, and reoperation rate did not differ in underweight and obese patients. However, severe complications seemed to occur more often in obese patients (pxa0=xa00.06), and the risk for anastomotic leakage increased with higher BMI (12.5% in underweight patients compared with 27.6% in obese patients, pxa0=xa00.04). Histopathological assessment showed comparable pTNM stages, although an advanced pT stage was seen more often in patients with low/normal BMI (pxa0=xa00.02). A linear association between BMI and R0-resection rate was detected (pxa0=xa00.02): 60% in underweight patients compared with 81% in obese patients. However, unlike pT-stage (pxa0<xa00.001), BMI was not an independent predictor for R0 resection (pxa0=xa00.12). There was no significant difference in overall or disease-free 5-year survival between the BMI classes (pxa0=xa00.25 and pxa0=xa00.6, respectively).ConclusionsBMI is not of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer and is not an independent predictor for radical R0 resection. Patients oncologically eligible for esophagectomy should not be denied surgery on the basis of their BMI class.

Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.

Objectives:We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. Background:Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently “sterilize” regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Methods:Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. Results:One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12–27) and 14 (9–21), with 2 (1–6) and 0 (0–1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P = 0.007), but not in the multimodality arm (hazard ratio 1.00; P = 0.98). Conclusions:The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.