A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: Nucleotide excision repair (NER) as potential chemoresistance marker

ArticleinCancer Chemotherapy and Pharmacology 71(3) · January 2013with15 Reads
DOI: 10.1007/s00280-013-2073-5 · Source: PubMed
Purpose: The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. Methods: Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m(2) b.i.d.) on days 1-14 and docetaxel (60 mg/m(2)) plus cisplatin (60 mg/m(2)) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. Results: A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4%, and disease control ratio was 100%. Grade 4 neutropenia developed in 53.5% of patients and febrile neutropenia in 16.3%. Non-hematological grade 3/4 adverse events were anorexia (23.3%), nausea (14.0%), and diarrhea (23.3%), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7%, and a pathological response was found in 65.9% of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5%. Conclusions: Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy.
    • "One key element in the NER system is excision repair cross-complementing 1 protein (ERCC1), or XPF. Changes in the expression levels of this endonuclease have been associated with clinical resistance to platinum-based chemotherapy in several human solid cancers132133134, including GAC. Thus, patients with advanced GAC treated with 5-FU/oxaliplatin and without ERCC1 expression had a significantly longer overall survival [102]; high ERCC1 tumor expression was associated with decreased overall survival in a subgroup of patients with gastric adenocarcinoma who received chemotherapy with a platinum agent such as cisplatin or oxaliplatin along with resection [103], and patients with locally advanced GAC with a high expression of damaged DNA-binding protein complex subunit 2, (DDB2)/ERCC1, showed a higher resistance to combined chemotherapy with docetaxel, cisplatin and S-1 [135]. "
    [Show abstract] [Hide abstract] ABSTRACT: Although surgical resection is the standard curative therapy for gastric cancer, these tumors are often diagnosed at an advanced stage, when surgery is not recommended. Alternative treatments such as radiotherapy and chemotherapy achieve only very modest results. There is therefore an urgent need to advance in this field of oncologic gastroenterology. The poor response of gastric cancer to chemotherapy is usually due to a combination of mechanisms of chemoresistance (MOC), which may include a reduction in drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), a reduced proportion of active agents in tumor cells due to a reduction in pro-drug activation or an enhancement of drug inactivation (MOC-2), changes in the expression/function of the molecular targets of anticancer drugs (MOC-3), an enhanced ability of cancer cells to repair anticancer drug-induced DNA damage (MOC-4), and decreased expression/function of pro-apoptotic factors or up-regulation of anti-apoptotic genes (MOC-5). Two major goals of modern pharmacology aimed at overcoming this situation are the prediction of a lack of response to chemotherapy and the identification of the underlying mechanisms accounting for primary or acquired refractoriness to anticancer drugs. These are important issues if we are to select the best pharmacological regime for each patient and develop novel strategies to overcome chemoresistance. The present review reports updated information regarding the mechanisms of chemoresistance (from MOC-1 to MOC-5) in gastric cancer, the advances made in the prediction of the failure of chemotherapeutic treatment, and novel strategies based on gene therapy currently being developed to treat these tumors.
    Article · Aug 2015
    • "However, there may be risk in delaying surgery in unresponsive cases. Several studies2,3 have found biomarkers in patients that can predict the chemotherapy response before chemotherapy, but there are still limitations of these for clinical use. Lin28 is a highly conserved RNA-binding protein4 that has been shown to participate in inducing pluripotent stem cells and to the maintenance of stem cell-like cells in cancer.5 "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of the study reported here was to identify whether a stem cell biomarker, Lin28, may predict the pathologic tumor response to neoadjuvant chemotherapy for patients with locally advanced gastric cancer. The study enrolled 47 patients with gastric cancer who underwent neoadjuvant chemotherapy followed by surgery between July 2004 and March 2012. Cancer tissue was biopsied by gastroscopy and Lin28 expression in the tissue was measured by immunohistochemistry. Statistical analyses were performed to identify the relationship between Lin28 expression and tumor regression grade. Of the 47 cases, pathologic nonresponse was observed in 29 (61.7%) and pathologic response in 18 (38.3%). Receiver-operating characteristic curve analysis showed that the histoscore of Lin28 expression with 0.325 as a cutoff value could differentiate between pathologic response and nonresponse. Multivariable analysis showed that Lin28 expression was an independent predictive factor for pathologic response to neoadjuvant chemotherapy (P = 0.006). Lin28 expression was associated with pathologic tumor response in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. This may suggest that Lin28 can serve as a predictive biomarker for neoadjuvant chemotherapy in patients with gastric cancer.
    Full-text · Article · Sep 2013
    • "The prognostic impact of response to neoadjuvant therapy was first published by Lowy et al. [7], including both histopathological and clinical response. Since then most studies have been based on histopathological response because it was estimated to be more objective than the evaluation of clinical response by endoscopy, endoluminal ultrasound, and computed tomography (CT) scan [2, 8, 9] . However, data of clinical response after the end of neoadjuvant treatment also appear promising in respect to association with histopathological response as well as prognosis1011121314. "
    [Show abstract] [Hide abstract] ABSTRACT: Neoadjuvant chemotherapy for locally advanced gastric cancer leads to major histopathological response in less than 30 % of patients. Data on interim endoscopic response assessment do not exist. This exploratory prospective study evaluates early endoscopy after 50 % of the chemotherapy as predictor for later response and prognosis. Forty-seven consecutive patients were included (45 resected; 33 R0 resections). All patients received baseline endoscopy and CT scans, after 50 % of their chemotherapy (EGD-1, CT-1) and after completion of chemotherapy (EGD-2, CT-2). Interim endoscopic response (EGD-1) was assessed after having received 50 % (6 weeks) of the planned 12 weeks of neoadjuvant chemotherapy. Post-chemotherapy response was clinically assessed by a combination of CT scan (CT-2) and endoscopy (EGD-2). Histopathological response was determined by a standardized scoring system (Becker criteria). Endoscopic response was defined as a reduction of >75 % of the tumor mass. Twelve patients were responders at EGD-1 and 13 at EGD-2. Nine patients (19.1 %) were clinical responders and 7 patients (15.6 %) were histopathological responders after chemotherapy. Specificity, accuracy, and negative predictive value of the interim EGD-1 for subsequent histopathological response were 31/38 (82 %), 36/47 (76 %), and 31/33 (93 %); and for recurrence or death, 28/30 (93.3 %), 38/47 (80.9 %), and 28/35 (80.0 %). Response at EGD-1 was significantly associated with histopathological response (p = 0.010), survival (p < 0.001), and recurrence-free survival (p = 0.009). Interim endoscopy after 6 weeks predicts response and prognosis. Therefore, tailoring treatment according to interim endoscopic assessment could be feasible, but the findings of this study should be validated in a larger patient cohort.
    Full-text · Article · Sep 2013
Show more