Východisko. Neoadjuvantná konkomitantná chemorádioterapia je štandardnou liečbou lokálne pokročilých nádorov konečníka. Jej cieľom je zredukovať objem nádoru, viesť k sfinkter-šetriacemu radikálnemu chirurgickému zákroku. Charakteristická je menšia toxicita a menej lokoregionálnych recidív. Je založená na fluoropyrimidínoch (5-fluorouracil, kapecitabín) s konkomitantnou rádioterapiou. Cieľom našej štúdie bolo charakterizovať na molekulárnej úrovni pacientov, ktorí sú rezistentní k neoadjuvantnej chemorádioterapii. Metódy a výsledky. Do pilotnej štúdie bolo zaradených 17 pacientov s histologicky verifikovaným adenokarcinómom rekta v klinickom štádiu II a III podľa IUCC. Odpoveď na liečbu bola hodnotená klinicky pomocou transrektálnej ultrasonografie a CT/MRI pred a po liečbe a histopatologicky pomocou TRG (Tumor Regression Grade) podľa Mandarda. Pacienti s TRG 1–2 boli zaradení do skupiny respondérov a pacienti charakterizovaní TRG 4–5 tvorili skupinu nonrespondérov. Použili sme nízkohustotné oligonukleotidové čipy nesúce sondy pre detekciu 440 génov. K identifikácii génov rozdielne exprimovaných medzi dvoma skupinami pacientov sme použili t-test a metódu SAM (Significance Analysis of Microarrays) s výsledným počtom 8 génov signifikantne up-regulovaných u nonrespondérov (RB1, RBBP4, HYOU1, JUNB, MDM4, CANX, MMP2, TCF7L2). Závery. Po rozšírení súboru, validácii výsledkov na úrovni mRNA metódou qRT-PCR a imunohistochemicky na proteínovej úrovni, by tieto sady génov mohli slúžiť k individualizácii terapie pacientov s lokálne pokročilým karcinómom rekta.
Background. Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It can reduce tumor volume, thus increases a feasibility of sphincter-sparing surgery, shows less acute toxicity, improves local control rate. It is based on fluoropyrimidines (5-fluorouracil, capecitabine) with concurrent radiotherapy. The aim of the study was to evaluate the capability of gene expression method to identify nonresponders (NR) pretherapeutically. Methods and Results. 17 patients with LARA, clinical stage II, III according to IUCC were enrolled into our pilot study. Response to therapy was determined clinically by transrectal ultrasonography and CT/MRI before and after therapy and histopathologically by TRG (tumor regression grade) according to Mandard. Patients with TRG 1–2 were included to responders group (R) and patients with TRG 4–5 composed NR group. Gene expression levels of 440 genes were obtained by low-density oligonucleotide microarrays. Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t-test methods identified 8 genes (RB1, RBBP4, HYOU1, JUNB, MDM4, CANX, MMP2, TCF7L2) significantly upregulated in NR.
Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It leads to shrinkage of the tumor mass and subsequently to an increase in complete resections (R0 resections), increasing a feasibility of sphincter-sparing intervention avoiding colostomy. It is based on concurrent application of fluoropyrimidines (5-fluorouracil, capecitabine) and radiotherapy (45 - 50,4 Gy). It shows less acute toxicity and improves local control rate in comparison to adjuvant treatment. Unfortunately, neoadjuvant chemoradiotherapy is not beneficial for all patients. The treatment response ranges from a complete pathological remission (pCR, ypT0ypN0) to a resistance. It is reported that cca 15 percent of patients with advanced rectal cancer show pCR which is indicative of improved long-term prognosis. DESIGN: The following is a review of the significance of neoadjuvant concomitant chemoradiotherapy in the treatment algorithm of patients with LARA and summary of potentional clinical-pathological and molecular markers of response prediction to neoadjuvant therapy. The most important clinical studies concern serum tumor markers levels, clinical lymph node classification. The components of the carcinogenic pathways are explored, including oncogenes, tumor supressor genes, microsatellite instability (MSI) and potentional markers involved in apoptosis, angiogionesis, proliferation as well as metastasis and invasion, are reviewed. Finally, the role of specific enzymes associated with the metabolism of fluoropyrimidines are examined. CONCLUSIONS: No one marker has been consistently identified as clinically applicable. Studies designed to determine the potentional markers are hampered by various techniques as well as tumor heterogenity and recent scientific approach--studying individual molecular markers. Gene expression profiling analysis of multiple genes from the same tumor is becoming reality. We suppose that this assessment will lead in future in finding combination of markers for predicting prognosis and response to therapy in rectal cancer.
- MeSH
- adenokarcinom farmakoterapie chirurgie radioterapie MeSH
- adjuvantní chemoterapie MeSH
- adjuvantní radioterapie MeSH
- deoxycytidin analogy a deriváty terapeutické užití MeSH
- fluoruracil analogy a deriváty terapeutické užití MeSH
- lidé MeSH
- nádorové biomarkery analýza MeSH
- nádory rekta farmakoterapie chirurgie radioterapie MeSH
- neoadjuvantní terapie MeSH
- prognóza MeSH
- protinádorové antimetabolity terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
