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
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo, 060-8543, Japan. Cancer Chemotherapy and Pharmacology
(Impact Factor: 2.77).
01/2013; 71(3). DOI: 10.1007/s00280-013-2073-5
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.
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.
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%.
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.
Available from: Jichun Zhou
- "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 "
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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.
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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.
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ABSTRACT: Digestive tract cancers - gastric-, colorectal-, pancreatic-, hepatocarcinoma- and esophageal are some of the most frequent cancers; they are characterized by invasivity, metastatic potential and bad outcomes. This group includes several of the most critical cancers (those ranked 2nd-4th in cancer related mortality), and, despite all efforts, they remain with low survival rates and lack of success of therapies. Discovery of novel biomarkers may improve disease characterization and make optimized or personalized therapies possible. The novel biomarkers are expected to provide, hopefully, less invasive or non-invasive diagnostic tools to make possible earlier detection of disease, and, also, they will provide more reliable selection in the drug discovery process, and provide guidance for personalized medicine. Deregulation of protein expression and genetic alterations were demonstrated in various cancers, including digestive. Investigations in tissue samples provided a considerable amount of knowledge, identifying altered expressions of proteins associated with tumorigenesis and tumour progression. Over-expression of some tumour-inducing or tumour promoting proteins was demonstrated, as well as expression down-regulation of several tumor suppressor genes. Often mutated and polymorphic alleles were demonstrated to occur in various cancers with high incidence. Several protein biomarkers were also demonstrated to be differentially expressed in groups of patients showing different responsivities to therapies. Both individual proteins and sets of multiple proteins were set up as candidate biomarkers for diagnostics or monitoring, offered relevant insights on the tumorigenic mechanisms. Proteins and other molecules (mRNAs, miRNAs, lncRNAs) are also providing potential candidates for multifactorial panels of biomarkers.
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