The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.

OBJECTIVE: To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery. SUMMARY BACKGROUND DATA: Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years. METHODS: One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 x 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. RESULTS: Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins. CONCLUSIONS: With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.

Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases.

Recently, we showed that Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) forms a distinct clinicopathologic entity with a better prognosis due to lower incidence of lymph node metastases (LN+). Here we investigated whether in EBV-positive GC more pronounced activation of cellular immune responses is associated with absence of (micro)metastases. Twenty EBV-positive primary tumors (PT) (9 LN+) were matched with 28 EBV-negative GC (11 LN+) for T- and N-stage, gender, and age. The PT (n = 28) and its LNs were analyzed by EBER RNA in situ hybridization and by immunohistochemistry for MHC class I and II expression, for CD3, CD8, CD4, CD20, CD56, CD83, and Granzyme B (GzB) expression. In LN metastases of EBV-positive GC, the EBV genome is maintained, excluding tumor escape by virus deletion. All GC express MHC class I independently of EBV status. In comparison with EBV-negative GC, EBV-positive GC have higher expression of MHC class II on the tumor cells (P = 0.029) and a more extensive infiltrate (P < 0.0001) of activated GzB+ CD8+ T cells (P = 0.028), which is most abundant in those EBV-positive tumors that do not metastasize (P < 0.0001). In addition, in EBV-positive GC without metastases, the infiltrate contains higher numbers of mature dendritic cells (DC) (P = 0.018). At present, the antigenic target has to be determined. These data support the notion that local triggering of cellular immune responses in EBV-positive GC prevents lymph node metastasis formation.

Clinical relevance of occult tumor cells in lymph nodes from gastric cancer patients.

The current method for staging in gastric cancer is not sufficient as even after a complete primary tumor resection, patients with node-negative gastric cancer suffer from disease recurrence. In this study, the relation between disease recurrence and the presence of occult tumor cells (OTC) in lymph nodes from gastric cancer patients was evaluated. In a case-control design, lymph nodes from 40 cases (disease recurrence) and 41 controls (no disease recurrence and followed for at least five years) with gastric cancer were examined for the presence of OTC, that comprised micrometastases (MM; >0.2 mm and < or =2.0 mm) and isolated tumor cells (ITC; < or =0.2 mm). The original hematoxylin and eosin-stained sections of all lymph nodes from cases and controls were previously considered as tumor-negative by the local pathologist. Fresh hematoxylin and eosin-stained sections were screened by conventional microscopy. Histologic sections stained by immunohistochemistry with anticytokeratin antibodies CAM5.2 were screened by conventional and automated microscopy. Tumor cells were detected in lymph nodes from 40 of 81 (49%) patients. There was no significant difference in the presence of OTC, MM, or ITC between the case and control groups (P = 0.658, P = 0.691, P = 0.887, respectively). However, significantly more cases presented with 20% or more OTC-positive lymph nodes (P = 0.015). A multivariate logistic regression analysis showed that examination of less than five lymph nodes (odds ratio, 13.8; 95% confidence interval, 1.6-120.6, P = 0.018) was the only significant independent risk factor for disease recurrence, especially for locoregional disease recurrence (odds ratio, 20.4; 95% confidence interval, 2.2-190.8, P = 0.008). A similar analysis for distant disease recurrence showed a percentage of 20% or more OTC-positive lymph nodes to be the only significant independent risk factor (odds ratio, 15.6, 95% confidence interval, 1.6-151.4, P = 0.018). The sensitivity of immunohistochemistry evaluated by microscopy to identify cases with 20% or more OTC-positive lymph nodes increased from 8% for conventional microscopy to 22% for automated microscopy (McNemar's test, P = 0.063). The mere presence of OTC-positive lymph nodes in gastric cancer patients did not predict disease recurrence. However, the number of examined lymph nodes and the percentage of OTC-positive lymph nodes were independent risk factors for locoregional disease recurrence and distant disease recurrence, respectively. Automated microscopy was essential in identifying patients with 20% or more OTC-positive lymph nodes. Therefore, a maximum number of lymph nodes should be removed and meticulously examined for OTC to identify high-risk patients. These patients should be considered for additional treatment.

Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.

BACKGROUND: Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 x 5 Gy). PATIENTS AND METHODS: The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n = 990). RESULTS: Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P = .006). PRT had a negative effect on sexual functioning in males (P = .004) and females (P < .001). Irradiated males had more ejaculation disorders (P = .002), and erectile functioning deteriorated over time (P < .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P = .004) and psychologic dimension (P = .007) than LAR patients, but worse on voiding (P = .0007). CONCLUSION: Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL.

Validation of a nomogram for predicting disease-specific survival after an R0 resection for gastric carcinoma.

BACKGROUND: A statistical model for predicting disease-specific survival in patients with gastric carcinoma, based on a single U.S. institution experience, was tested for validity in a sample of patients treated at different institutions. METHODS: The authors analysed 459 patients from the Dutch Gastric Cancer trial that compared limited (D1) with extended (D2) lymph node dissection. The discrimination ability of the nomogram with respect to 5 and 9-year disease-specific survival probabilities was superior to that of the American Joint Committee on Cancer (AJCC) staging system. RESULTS: There was considerable heterogeneity of risk within many of the AJCC stages. Calibration plots suggested that predicted probabilities from the nomogram corresponded closely to actual disease-specific survival. The gastric carcinoma nomogram performed well when applied to patients treated in a large number of institutions. CONCLUSIONS: The nomogram provided predictions that discriminated better than the AJCC staging system, regardless of the extent of lymph node dissection. Patient counseling and adjuvant therapy decision-making should benefit from use of the nomogram.

A rapid and reliable enzyme immunoassay PCR-based screening method to identify EBV-carrying gastric carcinomas.

Epstein-Barr virus (EBV) is associated with a substantial number of gastric adenocarcinomas worldwide, as confirmed by EBER1/2-RNA in situ hybridization (RISH). In the present study, we developed a rapid and sensitive PCR-based prescreening method for the detection of EBV in gastric carcinomas to reduce the amount of laborious EBER1/2-RISH assays to be performed. The method was evaluated by testing gastric adenocarcinomas (n = 242) using both BamHI W PCR-enzyme immunoassay (EIA) and EBER1/2-RISH, in combination with appropriate DNA and RNA quality controls. Seventy-four percent of the paraffin-embedded gastric adenocarcinomas had good DNA quality as shown by beta-globin polymerase chain reaction (PCR) after proteinase K and boiling pretreatment, whereas after DNA purification this was increased to 90%. Thirty-two percent of all cases were EBV-DNA positive after PCR-EIA, whereas 10% of these gastric cancers contained EBV transcripts in the neoplastic cells as confirmed by EBER1/2-RISH. Interestingly, only samples with high optical density (OD) 405/630 values in PCR-EIA, equivalent to the maximum reading of the assay as determined by the positive control, contained EBV-positive tumor cells in the EBER1/2-RISH. In contrast, the weak positive samples, as determined by low OD readings in the PCR-EIA were EBER1/2-RISH negative. In conclusion, high OD values in EBV PCR-EIA are very valuable to prescreen EBV-carrying gastric carcinomas as confirmed by EBER1/2-RISH. Only these samples and those with poor DNA quality will require testing in the EBER1/2-RISH, thereby reducing the amount of laborious RISH assays with 85%.

Short-term preoperative radiotherapy interferes with the determination of pathological parameters in rectal cancer.

Short-term preoperative radiotherapy in combination with surgery has been shown to decrease the rate of local recurrence in rectal cancer patients. The effects of this type of radiotherapy on the histopathology of rectal carcinoma has been hitherto unknown. Since various histopathological factors are associated with prognosis, the study of alterations induced by irradiation is an important issue. This paper examines the histopathology of resection specimens from 1306 patients who were treated in a randomized trial that evaluated the benefits of preoperative radiotherapy. In this trial, patients were treated with short-term radiotherapy (5 x 5 Gy) and operated on within 5 days after radiation. Histopathological parameters were determined by the Pathology Review Committee of the trial and we compared tumours of patients with and without preoperative radiotherapy. Tumours of patients who were treated with preoperative radiotherapy were smaller, more often mucinous carcinomas (13% versus 7%, p < 0.001) and more often poorly differentiated (35% versus 24%, p<0.001). After radiotherapy, there was less inflammatory reaction around the tumour (extensive in 7% versus 18%, p<0.001), which was mainly caused by a decrease in T lymphocytes and neutrophil granulocytes. The fibroblastic reaction was more pronounced in the radiotherapy group (extensive in 22% versus 10%, p <0.001). Remarkable histological alterations occurred within a week after 5 days of irradiation of rectal carcinomas. The prognostic value of these factors therefore needs to be re-evaluated for irradiated patients.

Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit.

Despite improved surgical treatment strategies for rectal cancer, 5-15% of all patients will develop local recurrences. After conservative surgery, circumferential resection margin (CRM) involvement is a strong predictor of local recurrence. The consequences of a positive CRM after total mesorectal excision (TME) have not been evaluated in a large patient population. In a nationwide randomized multicenter trial comparing preoperative radiotherapy and TME versus TME alone for rectal cancer, CRM involvement was determined according to trial protocol. In this study we analyze the criteria by which the CRM needs to be assessed to predict local recurrence for nonirradiated patients (n = 656, median follow-up 35 months). CRM involvement is a strong predictor for local recurrence after TME. A margin of < or = 2 mm is associated with a local recurrence risk of 16% compared with 5.8% in patients with more mesorectal tissue surrounding the tumor (p <0.0001). In addition, patients with margins < or = 1 mm have an increased risk for distant metastases (37.6% vs 12.7%, p <0.0001) as well as shorter survival. The prognostic value of CRM involvement is independent of TNM classification. Accurate determination of CRM in rectal cancer is important for determination of local recurrence risk, which might subsequently be prevented by additional therapy. In contrast to earlier studies, we show that an increased risk is present when margins are < or = 2 mm.