Neoadjuvant Сhemoradiotherapy of Locally Advanced Rectal Cancer with Local 5-Fluoracil Radiomodification

Chemoradiotherapy, along with following surgical treatment, including total mesorectal excision, is a current standard for treatment of locally advanced rectal cancer. Neoadjuvant chemoradiotherapy allows to downsize the tumor, up to complete clinical response in one third of all cases, which, in turn, allows increase in sphincter preserving operations, disease-free period and overall survivability. Derivatives of 5-fluoracil are used as basic chemotherapeutic agents. These drugs have a substantial amount of side effects, which lead to either plan corrections, or may even prevent its completion. Thus, search for new ways to increase chemotherapy agent in the tumor cells with reduction of systemic toxicity to improve neoadjuvant chemoradiotherapy results is an acute task for modern medicine. In this article authors suggest intrarectal application of sterile hydrogel material based on sodium alginate with incorporated 5-fluoracil as a method of neoadjuvant chemoradiotherapy.

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Computertomography-Based Prediction of Complete Response Following Neoadjuvant Chemoradiotherapy of Locally Advanced Rectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.623144 ◽

2021 ◽

Vol 11 ◽

Author(s):

Marina Maslova ◽

Heinz Herden ◽

Karin Schork ◽

Michael Turewicz ◽

Martin Eisenacher ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Treatment Strategies ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Individual Treatment ◽

Watch And Wait ◽

Current Standard

Therapeutic strategies for patients with locally advanced rectal cancer (LARC) who are achieving a pathological complete response (pCR) after neoadjuvant radio-chemotherapy (neoCRT) are being increasingly investigated. Recent trials challenge the current standard therapy of total mesorectal excision (TME). For some patients, the treatment strategy of “watch-and-wait” seems a preferable procedure. The key factor in determining individual treatment strategies following neoCRT is the precise evaluation of the tumor response. Contrast-enhanced computer tomography (ceCT) has proven its ability to discriminate benign and malign lesions in multiple cancers. In this study, we retrospectively analyzed the ceCT based density of LARC in 30 patients, undergoing neoCRT followed by TME. We compared the tumors´ pre- and post-neoCRT density and correlated the results to the amount of residual vital tumor cells in the resected tissue. Overall, the density decreased after neoCRT, with the highest decrease in patients achieving pCR. Densitometry demonstrated a specificity of 88% and sensitivity of 68% in predicting pCR. Thus, we claim that ceCT based densitometry is a useful tool in identifying patients with LARC who may benefit from a “watch-and-wait” strategy and suggest further prospective studies.

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MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients

Cancers ◽

10.3390/cancers12061655 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1655 ◽

Cited By ~ 2

Author(s):

Ion Cristóbal ◽

Jaime Rubio ◽

Andrea Santos ◽

Blanca Torrejón ◽

Cristina Caramés ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Preoperative Treatment ◽

Dependent Manner ◽

Current Standard ◽

Poor Outcome

Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.

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Use of MRI-defined tumor distance from the anal verge to predict tumor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.573 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 573-573

Author(s):

Stanley Ka Tung Yu ◽

Gina Brown ◽

Diana M. Tait

Keyword(s):

Rectal Cancer ◽

Surgical Resection ◽

Anal Verge ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Low Rectal Cancer ◽

Resected Specimen ◽

Current Standard

573 Background: Neoadjuvant Chemoradiotherapy (CRT) and surgical resection is the current standard management for patients with locally advanced rectal cancer (i.e. T3 or 4 N0/1 M0) (LARC). Tumour predictive factors for response to CRT in rectal cancer remain controversial. Staging investigations are not standardised and MRI has not been used consistently to approach this. The aim of this study is to investigate whether tumour distance from anal verge, as measured on MRI, is a predictive factor for response to CRT in LARC. Methods: This is a retrospective study. Patients with LARC or low T2 N0/1 M0 rectal cancer (i.e. ≤ 5cm from anal verge measured by MRI) treated with preoperative CRT in 2003- 2009 were included. Pelvic MRIs acquired before CRT and no less than 4 weeks post CRT were reviewed. Patients with ypT0-2 in the resected specimen were classified as responders because ypT0-2 has been shown with significant OS and DFS benefit (Valentini V et al. Int J Radiat Oncol Biol Phys. 2002; 53(3): 664-74). Downstage of mrT2 low rectal cancer was defined as ypT0-1 post CRT. Univariate binary logistic regression (UBLR) was used to analyse the predictor associated between responders and non-responders to CRT treated in the same period of time. Results: 281 patients with LARC who underwent CRT were included in the study. 96% patients in this study had T3/T4 LARC and 4% had T2 low rectal cancer. 114 (41%) were responders as defined above, 167 (59%) were non-responders to CRT. The mean MRI defined tumour distance from anal verge was significantly less in responders (6.4cm [Confidence Intervals (CI) = 5.7 -7.1]) when compared with non-responders (7.9cm [CI =7.3 – 8.6]) (P<0.05). Conclusions: The UBLR analysis from our study indicated that an MRI measured tumour distance of ≤ 5cm from the anal verge independently predicted higher tumour downstaging rate (p < 0.001) to CRT in LARC. Further investigation is recommended regarding tumour downstaging and sphincter preserving surgical resection rate in low rectal cancer post neoadjuvant CRT. [Table: see text]

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Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer

Cells ◽

10.3390/cells10061539 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1539

Author(s):

Virgílio Souza e Silva ◽

Emne Ali Abdallah ◽

Bianca de Cássia Troncarelli Flores ◽

Alexcia Camila Braun ◽

Daniela de Jesus Ferreira Costa ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Transforming Growth Factor ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-β receptor I (TGF-βRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS− was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-βRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

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