Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53

Chiorean, E. Gabriela; Sanghani, Sonal P.; Schiel, Marissa A.; Yu, Menggang; Burns, Matthew J.; Tong, Yan; Hinkle, David T.; Coleman, Nicki; Robb, Bruce W.; Leblanc, Julia K.; Clark, Romnee; Bufill, José A.; Curie, Colleen; Loehrer, Patrick J.; Cárdenes, Higinia R.

doi:10.1007/s00280-012-1883-1

Cited by 16 publications

(15 citation statements)

References 23 publications

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“…Given the small numbers of patients, and the overall limited efficacy of the capecitabine regimen, it is difficult to determine association of TYMP , TYMS , and DPYD with response. Higher levels of TYMP have been associated with higher rates of pathological response to preoperative capecitabine or 5‐FU in colorectal cancer , and to prolonged time to progression from capecitabine in metastatic breast cancer , but in this study, there did not appear to be a trend with baseline TYMP and clinical, radiographic, or Miller–Payne response. However, as noted, it is difficult to draw conclusions with the small numbers of patients in each response group.…”

Section: Discussioncontrasting

confidence: 74%

A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

et al. 2014

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Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m2 daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller–Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer.

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Section: Discussioncontrasting

confidence: 74%

A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

et al. 2014

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“…In the present study, 55% of advanced tumors demonstrated high cytoplasmic expression of CES2. CES2 overexpression has been associated with increased irinotecan activity in vitro , even if its clinical relevance is less well determined [ 14 ]. Recently, Uchida et al .…”

Section: Resultsmentioning

confidence: 99%

“…In light of these findings, we suggest that Topo-I expression together with TS expression [ 14 ] could be associated with metastatic progression of CRC. TS expression correlates with clinical outcome of mCRC patients treated with a first-line FOLFIRI regimen.…”

Section: Discussionmentioning

confidence: 99%

CES2, ABCG2, TS and Topo-I Primary and Synchronous Metastasis Expression and Clinical Outcome in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Regimen

Silvestris

Simone

Partipilo

et al. 2014

IJMS

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Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox’ multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

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“…Irinotecan has also been employed in ovarian (76), non-small lung cell (77) and pancreatic and biliary tract cancers (78). Irinotecan is prescribed alone, or combined with: i) 5-fluorouracil and Leucovorin (FOLFIRI), ii) FOLFIRI plus oxaliplatin, iii) Cetuximab, a chimeric immunoglobulin G1 anti-epidermal growth factor receptor monoclonal antibody (37,79), or iv) capecitabine (80). The combined effects of the genetic variants in these drug-metabolizing enzymes need to be considered to reduce undesirable effects and to increase the effectiveness of the drugs.…”

Section: Examples Of Ugt1a Involvement In Pharmacogenomicsmentioning

confidence: 99%

Uridine 5'‑diphospho‑glucronosyltrasferase: Its role in pharmacogenomics and human disease (Review)

et al. 2018

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Biotransformation is an enzyme-catalyzed process in which the body converts endogenous compounds, xenobiotics and toxic substances into harmless or easily excreted metabolites. The biotransformation reactions are classified as phase I and II reactions. Uridine 5'-diphospho (UDP)-glucuronosyltransferases (UGTs) are a superfamily of phase II enzymes which have roles in the conjugation of xenobiotics or endogenous compounds, including drugs and bilirubin, with glucuronic acid to make them easier to excrete. The method the human body uses to achieve glucuronidation may be affected by a large interindividual variation due to changes in the sequences of the genes encoding these enzymes. In the last five years, the study of the genetic variants of the UGTs at a molecular level has become important due to its association with several diseases and the ability to predict adverse events due to drug metabolism. In the present review, the structure and the prominent genetic variants of the UGT1A subfamily and their metabolic and clinical implications are described.

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Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53

Abstract: This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR.

Cited by 16 publications

References 23 publications

A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

CES2, ABCG2, TS and Topo-I Primary and Synchronous Metastasis Expression and Clinical Outcome in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Regimen

Uridine 5'‑diphospho‑glucronosyltrasferase: Its role in pharmacogenomics and human disease (Review)

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