Instrumental clinical restaging, pathological evaluation, and tumor regression grading: how to assess the response to neoadjuvant chemoradiotherapy for rectal cancer.

INTRODUCTION: The object of neoadjuvant chemoradiotherapy regimens is a downstaging or downsizing of advanced rectal tumor to increase the rate of curative resection and reduce loco-regional failure. A reliable method of assessing response to adjuvant therapies is required to help standardize the assessments of new multimodality therapies. The purpose of this study was to evaluate the role played by tumor regression grading on the evaluation of pathological response to chemoradiotherapy, compared with both the predicting value of the clinical response to neoadjuvant therapy and pathologic response evaluation. METHODS: From 1994 to 2003, 58 patients with a primary diagnosis of rectal cancer were studied at our department and enrolled in a single center, not randomized study based on 5-week sessions of radiotherapy associated with a 30-day 5-fluorouracil (FU) infusion, followed by surgical resection. Instrumental restaging and routine histological examination, including tumor regression grading, were performed to asses the response to neoadjuvant therapy. RESULTS: The cCR rate corresponds to pCR rate, while a 3.5% of cPR and a 3.4% of cSD corresponded to a pPD. cPR and cSD show a PPV of 92.8% and 90.9% respectively, while cPD NPV is 20%. No case was found with no regression (grade 0). Tumor regression was defined grade 1 in 24.5% of cases, grade 2 was found in 58.5% of cases, 7.5% were grade 3, and 9.5% showed complete regression (grade 4). Pathologic response resulted to be associated with regression grade (p=0.006). Tumor regression grading is an independent variable for pT (p=0.0002), pN status (p=0.00004), pathologic staging (p=0.000001) and local recurrence (p=0.003). CONCLUSION: Our results lead us to consider only pathologic evaluation to determine the response to neoadjuvant treatment: the application of tumor regression grading on the specimens obtained after combined neoadjuvant chemoradiotherapy and surgery is useful to plan a better therapeutic strategy on the ground of a quantitative evaluation of the response to neoadjuvant treatment; it shows it is an important comparable pathological feature, useful in comparing different protocols' results and differences between patient's response as well as prognostic factors.

Multigene methylation analysis of gastrointestinal tumors: TPEF emerges as a frequent tumor-specific aberrantly methylated marker that can be detected in peripheral blood.

BACKGROUND: Gene promoter methylation is a mechanism for tumor suppressor gene silencing and inactivation. The development of highly sensitive methods for revealing aberrant cancer-associated DNA methylation allows the identification of tumor markers not only in tumor samples, but also in body fluid, an approach that can be useful in the early detection of neoplasms. METHODS: We analyzed the methylation status at 16 loci in tumor samples of the gastrointestinal tract and in early or pre-neoplastic lesions of the colon. RESULTS: Tumor samples revealed that methylation at the transmembrane protein containing epidermal growth factor and follistatin domains (TPEF) locus had the best ratio of discrimination between tumor samples versus normal tissues (83 versus 0%). Its combination with hypermethylated in cancer 1 (HIC1), death-associated protein kinase (DAPK) and O-6-methylguanine DNA methyltransferase (MGMT), allowed the detection of aberrant methylation in 98% of colorectal carcinomas and 100% of gastric carcinomas. The same alterations were also detected in colon adenomas and tissues surrounding the adenomas, indicating that hypermethylation at these loci occurred early in tumor progression. Analysis of DNA from peripheral blood revealed that TPEF methylation was detectable in colorectal tumor patients and patients with early or pre-neoplastic lesions, but not in healthy volunteers. CONCLUSIONS: Our results identify TPEF as a tumor marker that could be useful in the follow-up of gastrointestinal cancer patients or the screening of individuals at risk of developing gastrointestinal neoplasms.