Fluorouracil-based Chemotherapy Research Articles

Systemic Chemotherapy in Advanced Pancreatic Cancer

Pancreatic cancer remains one of the most lethal cancers. These patients often have multiple symptoms, and integrated supportive care is critical in helping them remain well for as long as possible. Fluorouracil-based chemotherapy is known to improve overall survival (OS) by approximately 3 months, compared to the best supportive care alone. A 1997 study comparing gemcitabine and fluorouracil treatment of advanced pancreatic cancer patients showed an improvement in OS of 1 month in patients receiving gemcitabine. Over the next 10 years, multiple randomized studies compared single-agent gemcitabine with combination chemotherapy and showed no effective survival improvement. However, the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, was associated with a significant improvement in OS of approximately 2 weeks. However, adoption of this regimen has not been widespread because of its limited effect and added toxicity. Two clinical trials have recently prolonged OS in advanced pancreatic cancer patients by almost 1 year. The first compared FOLFIRINOX with gemcitabine alone, and was associated with a significant improvement in median survival. The second compared gemcitabine and nab-paclitaxel with gemcitabine alone, and was associated with improvements in OS. At present, these regimens are considered standard treatment for patients with good performance statuses.

Impact of cytoreductive surgery on survival in gastric cancer patients with peritoneal metastasis

To investigate the survival benefit of cytoreductive surgery in gastric cancer patients with peritoneal metastasis. Clinicopathological data of 151 advanced gastric adenocarcinoma patients with extensive peritoneal metastasis who were identified by surgical exploration between May 2008 and April 2015 in Xijing Hospital of Digestive Diseases were analyzed retrospectively. Of all the patients, 32 cases were treated by cytoreductive surgery with local radical tumor resection and regional lymph node cleaning, combined with fluorouracil-based adjuvant chemotherapy after surgery (cytoreductive surgery combined with chemotherapy group); 39 caseswere only treated by cytoreductive surgery group(cytoreductive surgery group);23 caseswere treated bysurgical exploration combined with fluorouracil-based adjuvant chemotherapy after surgery(surgical exploration combined with chemotherapy group) and 57 cases were only treated bysurgical exploration (surgical exploration group). The overall survival of four groups were analyzed and compared. Among the 151 patients, 148 (98.0%) patients were followed up. The median follow up time was 7.2 months (range 1.4-61.2). The median survival of cytoreductive surgery combined with chemotherapy group, cytoreductive surgery group, surgical exploration combined with chemotherapy group and surgical exploration group was 11.9(95% CI: 8.8-15.1) months, 7.1(95% CI: 3.2-11.1) months, 8.2(95% CI:4.6-11.8) and 5.4(95% CI:4.4-6.4) months, respectively(P < 0.01). Cytoreductive surgery can prolong the survival of gastric adenocarcinoma patients with extensive peritoneal metastasis. Cytoreductive surgery combined with chemotherapy may provide more benefit for patients, and can be used as a choice of treatment in these patients.

Interventions for preventing oral mucositis in patients with cancer receiving treatment: oral cryotherapy.

Interventions for preventing oral mucositis in patients with cancer receiving treatment: oral cryotherapy.

Irinotecan plus fluorouracil-based regimen as second or third-line chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma.

No standard second-line regimen exists for the treatment of advanced esophageal squamous cell carcinoma (ESCC). The aim of this study was to evaluate the efficacy and safety of irinotecan and fluorouracil-based chemotherapy as a second or third-line regimen for advanced ESCC patients. We retrospectively reviewed a cohort of 27 consecutive patients with advanced ESCC in one institute, treated with a combination of irinotecan plus fluorouracil-based regimens after the failure of first-line platinum-based therapy. Nine patients were treated with 150-160 mg/m(2) irinotecan and 400 mg/m(2) fluorouracil (5-FU) on day 1, followed by 2000 mg/m(2) 5-FU during a 48-hour infusion every two weeks. Eighteen patients received 150-160 mg/m(2) irinotecan on day 1 and 80-120 mg/day S-1 on days 1-10 every two weeks. The S-1 dose was based on the patients' body surface area. Twenty-four of the 27 patients were assessable for response. One (3.7%) patient achieved complete response, seven (25.9%) achieved partial response, eight (29.6%) had stable disease, and eight (29.6%) had progressive disease. The median progression-free and overall survival were 4.8 (95% confidence interval [CI]: 1.2-8.4) and 10.5 months (95% CI: 8.4-12.7), respectively. Grade 3 neutropenia and diarrhea were detected in four (15%) and one (4%) patient, respectively. No grade 4 toxicity was noted. Our study indicates that an irinotecan plus 5-FU-based regimen is effective and well-tolerated as a second or third-line chemotherapy for patients with advanced ESCC.

Functional and clinical evaluation of renal injury in patients treated with adjuvant chemoradiotherapy for gastric cancer: Low dose and comorbidity considerations

AimTo analyze the dosimetric factors affecting long-term renal function in patients with gastric cancer following postoperative radiotherapy with concomitant chemotherapy to the upper abdomen. MethodsBetween January 2005 and July 2010, 13 patients treated with three-dimensional conformal radiotherapy and concurrent fluorouracil-based chemotherapy (CRT) were included in this analysis. After a median follow-up of 55 months, creatinine, glomerular filtration rate (GFR), total kidney and left kidney volumes, before and after CRT and mercaptoacetyltriglycine (MAG3) scintigraphy, were used to evaluate the renal function and were correlated with the dosimetrics data. ResultsSignificant correlations were found in the loss of left kidney volume and V35 (20.6%) (p = 0.035) and V40 (15.7%) (p = 0.031) and in the loss of relative functional contribution of the main kidney and V35 Gy (p = 0.027) and V40 Gy (p = 0.019). In patients with a slightly low basal GFR (n = 6), the relative functional contribution of the left kidney significantly decreased, regardless of the dosage. ConclusionFunctional renal impairment without any clinical signs or symptoms can be observed in low doses after radiotherapy. Careful treatment planning and a detailed evaluation of the functional renal capacity before treatment may help to reduce late renal toxicity.

Preventive effects of amino-acid-rich elemental diet Elental® on chemotherapy-induced oral mucositis in patients with colorectal cancer: a prospective pilot study.

PurposeThe prospective pilot study was designed to evaluate the preventive effects of amino-acid-rich elemental diet (ED), Elental®, on chemotherapy-induced oral mucositis in patients with colorectal cancer. The factors influencing its efficacy are also investigated.MethodsA total of 22 eligible patients with colorectal cancer experiencing grade 1–3 oral mucositis during treatment with fluorouracil-based chemotherapy entered the current study. Their average age was 67 years. There were 10 male and 12 female. The PS was 0 in the majority of patients. Patients received two courses of the same chemotherapy regimen and Elental® concurrently after recovery to grade 0 or 1 oral mucositis.ResultsFOLFOX6 + bevacizumab in 8 patients, FOLFIRI + bevacizumab in 8 patients, FOLFIRI + panitumumab in 1 patient, FOLFIRI in 1 patient, XELOX + bevacizumab in 2 patients, and S-1 + cetuximab in 2 patients were used as first-line (16 cases) or as second-line (6 cases) chemotherapy. Dose reduction of 5-fluorouracil (5-FU) or oral fluoropyrimidine was performed in the 2 patients achieving grade 3 oral mucositis and in the 3 patients achieving grade 2 oral mucositis. The maximum grade of oral mucositis decreased in 18 of the 22 patients during the first treatment course with Elental® (p = 0.0002) and in 20 of the 22 patients in the second course (p < 0.0001). Multivariate analyses found that the dose reduction in 5-FU or oral fluoropyrimidine, ED intake, and the prior administration of ED were each a significant factor for the preventive efficacy on oral mucositis.ConclusionThe amino-acid-rich elemental diet Elental® may be useful as a countermeasure for 5-FU-based chemotherapy-induced oral mucositis in patients with colorectal cancer.

Surgical Resection of Primary Tumor in Asymptomatic or Minimally Symptomatic Patients With Stage IV Colorectal Cancer: A Canadian Province Experience

BackgroundSurgical resection of the primary tumor in patients with stage IV colorectal cancer (CRC) remains controversial. Survival benefit reported in the literature has been attributed to the selection of younger and healthier patients with good performance status. We have recently reported that resection of the primary tumor improved survival of patients with stage IV CRC. In this study we examined survival benefit of surgery in patients with asymptomatic or minimally symptomatic primary tumor. Patients and MethodsA cohort of patients with stage IV CRC and asymptomatic or minimally symptomatic primary tumor, who were diagnosed during the period of 1992 to 2005, in the province of Saskatchewan Canada, was evaluated. The Kaplan–Meier method was used to determine survival. A multivariate Cox proportional hazard regression analysis was performed to determine prognostic importance of resection of primary tumor. A test for interaction was performed for resection of primary tumor and other important clinicopathological variables. ResultsA total of 834 patients with a median age of 70 years (range, 22-93) and male:female ratio of 58:42 were identified. Among them 521 (63%) patients underwent surgery and 361 (43.3%) received chemotherapy. Patients who underwent surgery and received any chemotherapy had a median overall survival of 19.7 months (95% confidence interval [CI], 16.9-22.6) compared with 8.4 months (95% CI, 6.9-10.0) if they did not have surgery (P < .0001). In multivariate analysis, 5–fluorouracil-based chemotherapy (hazard ratio [HR], 0.43; 95% CI, 0.36-0.53), surgical resection of the primary tumor (HR, 0.47; 95% CI, 0.39-0.57), metastasectomy (HR, 0.48; 95% CI, 0.38-0.62), and second-line chemotherapy (HR, 0.72; 95% CI, 0.58-0.92) were correlated with superior survival. A test for interaction between ≥ 1 metastatic sites and surgery was significant, which suggests a larger benefit of surgery in patients with stage IVA disease. ConclusionResults of this large population-based cohort study suggest that resection of the primary tumor in asymptomatic or minimally symptomatic patients with stage IV CRC improved survival independent of other prognostic variables. The benefit was more pronounced in stage IVA disease.

PWE-305 Nqo1 is a predictive biomarker and therapaeutic target in metastatic colorectal cancer

<h3>Introduction</h3> A knowledge of the biological phenotype of colorectal liver metastases would be invaluable to inform clinical decision making; however, deriving this information from the metastatic lesions is not feasible until after resection. We aimed to use proteomic analysis to identify biomarkers in the primary tumour which predict response to neoadjuvant chemotherapy in liver metastases. <h3>Method</h3> Fresh tissue from both primary colorectal tumour and liver metastases from 17 patients was subjected to proteomic analysis using isobaric tagging for relative quantification, with stratification of patients into those showing low or high response to chemotherapy permitting the identification of potential predictive biomarkers. These markers were subsequently validated by immunohistochemistry on a tissue microarray of 57 patients and further investigated in an <i><i>in vitro</i></i>model. <h3>Results</h3> We identified 5768 discrete proteins, 5 of which predicted histopathological response to fluorouracil-based chemotherapy regimens. Immunostaining of NQO1 in the metastases was lower in those responding to chemotherapy (p = 0.041), with a significant correlation between primary and metastatic disease sites (r = 0.44, p = 0.001). Knockdown of NQO1 with small interfering RNA followed by treatment with irinotecan and 5FU reduced the IC50 from 100.1µM to 49.8µM and from 200.1µM to 25.0µM respectively. Pre-treating cells with dicoumarol (a known competitive inhibitor) prior to incubation in irinotecan and 5FU reduced the IC50 from 100.0µM to 50.0µM and from 183.7µM to 49.9µM respectively. <h3>Conclusion</h3> These results show that proteomic sequencing of matched metastatic colorectal cancer samples is feasible, with high protein coverage. The high degree of similarity between the primary and secondary proteomes suggests that primary tissue is predictive of the metastatic phenotype. NQO1 expression in the primary tumour predicts response to neoadjuvant chemotherapy in the liver metastases, and inhibition of this protein at both genetic and functional levels improves chemosensitivity. Further validation in an <i><i>in vivo</i></i>model is planned. <h3>Disclosure of interest</h3> P. Sutton Grant/ Research Support from: Cancer Research UK, J. Evans: None Declared, R. Jones: None Declared, C. Goldring: None Declared, D. Palmer: None Declared, N. Kitteringham: None Declared, H. Malik: None Declared, D. Vimalachandran: None Declared.

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial

The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and β error of 0.05 and 0.20, respectively, 262 patients were required. In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.

Transcription Factor AP2ε: A Potential Predictor of Chemoresistance in Patients With Gastric Cancer.

Chemotherapy is a mainstay of therapy for advanced gastric cancer (GC); however, owing to drug resistances, the effectiveness of chemotherapy is not satisfactory for some patients with GC. Therefore, identification of a marker that predicts treatment response is beneficial to patients. Hypermethylation of transcription factor activating enhancer-binding protein 2∊ (TFAP2E) has been implicated in chemotherapy resistance to fluorouracil-based chemotherapy in patients with colorectal cancer, but its role in GC is still unknown. In this study, we investigated TFAP2E as a predictor of treatment response in GC. We used methylation-sensitive high-resolution melting analysis to study the methylation of TFAP2E in 141 GC tissue specimens and 45 adjacent nontumor tissue specimens. In vitro experiments, we analyzed the expression and methylation of TFAP2E and to examine the sensitivity of GC cell lines to 5-fluorouracil (5-FU). The TFAP2E methylation occurred at a significantly higher incidence rate in tumor tissues compared to adjacent nontumor tissues (chi-square [χ2] = 38.919, P < .001). Hypermethylation of TFAP2E occurred more frequently in tumors with lower differentiation grades (P < .001) and was significantly associated with nonresponse to fluorouracil-based chemotherapy (P = .010). Hypermethylation was also associated with decreased expression of TFAP2E (P < .01) and nonresponse to 5-FU exposure in vitro (P < .001). Hypermethylation of TFAP2E was associated with lack of response to fluorouracil-based chemotherapy, indicating that it might be a potential predictor of treatment response in patients with GC.

Sustaining Blood Lymphocyte Count during Preoperative Chemoradiotherapy as a Predictive Marker for Pathologic Complete Response in Locally Advanced Rectal Cancer.

PurposeThe objective of this study was to explore the relationship between the circulating lymphocyte level during preoperative chemoradiotherapy (CRT) and pathologic complete response (pCR) in locally advanced rectal cancer.Materials and MethodsFrom May 2010 to May 2013, 52 patients treated with preoperative CRT followed by surgery, were analysed. Patients received conventional fractionated radiotherapy (50-54 Gy) with fluorouracil-based chemotherapy. Surgical resection was performed at 4 to 8 weeks after the completion of preoperative CRT. Absolute blood lymphocyte counts and their relative percentage in total white blood cell counts were obtained from complete blood count tests performed prior to and after 4, 8, and 12 weeks of CRT. We analysed the association between achieving pCR and change in blood lymphocyte level during CRT, as well as clinical parameters.ResultsAmong 52 patients, 14 (26.9%) had evidence of pCR. Sustaining the blood lymphocyte count during CRT (lymphocyte count at 4 weeks/baseline lymphocyte count > 0.35; odds ratio, 8.33; p=0.02) and initial carcinoembryonic antigen < 4.4 ng/mL (odds ratio, 6.71; p=0.03) were significantly associated with pCR in multivariate analyses.ConclusionSustaining blood lymphocyte count during preoperative CRT was predictive for pCR in rectal cancer. Further studies are warranted to investigate the association between pathologic responses and circulating lymphocyte count with its subpopulation during preoperative CRT.

Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-based chemotherapy for patients with HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma patients: A retrospective study

Trastuzumab with 5-fluorouracil (5-FU) and cisplatin offers prolonged survival in patients with HER2-overexpressing advanced gastric cancer (AGC) and advanced gastro-oesophageal junction cancer (AGOJ). Oxaliplatin in combination with intravenous 5-FU plus leucovorin (LV; modified [m]FOLFOX6) or capecitabine (XELOX) improves tolerability compared with 5-FU/cisplatin regimen. There are few data available on the efficacy and safety of trastuzumab-oxaliplatin-based chemotherapy in previously untreated HER2-positive AGC and AGOJ patients. Clinical data were retrospectively analysed in patients receiving trastuzumab plus mFOLFOX6 or XELOX as first-line therapy between July 2009 and December 2012. Eligible patients had histologically proven AGC or AGOJ, HER2 overexpression, and no prior chemotherapy for metastatic disease. Thirty-four patients met the eligibility criteria. Median age was 63 years, 79% of patients had ECOG PS score of 0-1, and all had metastatic disease. Median duration of treatment was 7.5 months. Overall response rate was 41% (95% CI: 25-56). Median progression-free survival and overall survival were 9.0 months (95% CI: 5.6-12) and 17.3 months (95% CI: 13.5-32.3), respectively. Tolerability was acceptable. The most frequent grade 3-4 toxicities were neutropenia (8.8%) and neuropathy (17.6%). mFOLFOX6-trastuzumab combination is an efficient regimen with an acceptable safety profile for AGC and AGOJ patients. These results warrant further prospective study.

First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a United States-based cost-effectiveness analysis.

The addition of bevacizumab to fluorouracil-based chemotherapy is a standard of care for previously untreated metastatic colorectal cancer. Continuation of bevacizumab beyond progression is an accepted standard of care based on a 1.4-month increase in median overall survival observed in a randomized trial. No United States-based cost-effectiveness modeling analyses are currently available addressing the use of bevacizumab in metastatic colorectal cancer. Our objective was to determine the cost effectiveness of bevacizumab in the first-line setting and when continued beyond progression from the perspective of US payers. We developed two Markov models to compare the cost and effectiveness of fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab in the first-line treatment and subsequent fluorouracil, leucovorin, and irinotecan with or without bevacizumab in the second-line treatment of metastatic colorectal cancer. Model robustness was addressed by univariable and probabilistic sensitivity analyses. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Using bevacizumab in first-line therapy provided an additional 0.10 QALYs (0.14 life-years) at a cost of $59,361. The incremental cost-effectiveness ratio was $571,240 per QALY. Continuing bevacizumab beyond progression provided an additional 0.11 QALYs (0.16 life-years) at a cost of $39,209. The incremental cost-effectiveness ratio was $364,083 per QALY. In univariable sensitivity analyses, the variables with the greatest influence on the incremental cost-effectiveness ratio were bevacizumab cost, overall survival, and utility. Bevacizumab provides minimal incremental benefit at high incremental cost per QALY in both the first- and second-line settings of metastatic colorectal cancer treatment.

Proteomic analysis to identify biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases

BackgroundColorectal cancer is the fourth commonest cancer in the UK, and the second commonest cause of cancer-related death. A knowledge of the biological phenotype of colorectal liver metastases would be invaluable to inform clinical decision making; however, deriving this information from the metastatic lesions is not feasible until after resection. We aimed to use proteomic analysis to identify biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases. MethodsFresh tissue from both primary colorectal tumour and liver metastases from 17 patients was subjected to proteomic analysis using isobaric tagging for relative quantification. Data were analysed with Protein Pilot (Ab Sciex, Framingham, MA, USA), with stratification of patients into those showing low or high response to chemotherapy permitting the identification of potential predictive biomarkers. These markers were subsequently validated by immunohistochemistry on a tissue microarray of 63 patients. FindingsWe identified 5768 discrete proteins. Five of them predicted histopathological response to fluorouracil-based chemotherapy regimens, of which the FAD binding protein NQO1 was subsequently validated by immunohistochemistry. When compared with the chemotherapeutic agent alone, knockdown of the corresponding gene with small interfering RNA decreased cell viability when co-incubated with fluorouracil (77·1% vs 46·6%, p=0·037) and irinotecan (41·7% vs 24·4%, p=0·006). Similar results were also seen after inhibition of protein activity by pretreating cells with dicoumarol. InterpretationThese results show that proteomic sequencing of matched metastatic colorectal cancer samples is feasible, with high protein coverage. The high degree of similarity between the primary and secondary proteomes suggests that primary tissue is predictive of the metastatic phenotype. NQO1 expression in the primary tumour predicts response to neoadjuvant chemotherapy in the liver metastases, and inhibition of this protein at both genetic and functional levels improves chemosensitivity. FundingCancer Research UK.

Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data

The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0.97, 95% CI 0.81-1.17; p=0.775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0.91, 95% CI 0.77-1.07; p=0.230) or distant recurrences (0.94, 0.78-1.14; p=0.523) compared with observation. However, in subgroup analyses, patients with a tumour 10-15 cm from the anal verge had improved disease-free survival (0.59, 0.40-0.85; p=0.005, p(interaction)=0.107) and fewer distant recurrences (0.61, 0.40-0.94; p=0.025, p(interaction)=0.126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10-15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. None.

Differences in attitude toward adjuvant chemotherapy between colorectal cancer survivors and the medical staff of Japanese hospitals.

Adding oxaliplatin to fluorouracil-based chemotherapy can improve the survival of patients with stage III colorectal cancer by approximately 20 %. Reportedly, cancer patients are much more likely to prefer chemotherapy than medical professionals, although there is only a very small chance of achieving benefits from treatment. However, chronic neurotoxicity may be long lasting after the administration of oxaliplatin-based chemotherapy. This study aimed to evaluate potential side effects and differences in attitude between colorectal cancer patients and medical staff regarding the risk-benefit trade-offs of chemotherapy. Relapse-free colorectal cancer patients who received adjuvant chemotherapy, doctors, and nurses were surveyed using a questionnaire regarding the side effects of chemotherapy and hypothetical clinical scenarios to quantify gains in the risk of relapse that were deemed necessary to make chemotherapy worthwhile. Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Of these, 39 % of patients and 85 % of doctors replied that moderate side effects of adjuvant chemotherapy were worthwhile to achieve an absolute gain in the risk of relapse of 10 % from a baseline of 40 %. More severe side effects, as reported by colorectal cancer patients, were not associated with the larger gains necessary to make treatment worthwhile. Seven percent of patients treated with oxaliplatin, 40 % of doctors, and 43 % of nurses replied that side effects associated with oxaliplatin-based chemotherapy were severe. Doctors should consider potential heterogeneity in side effects and attitudes regarding the risk-benefit balance of adjuvant chemotherapy, and that patient perspectives should enhance shared decision-making.

Polymorphism of methylenetetrahydrofolate reductase gene is associated with response to fluorouracil-based chemotherapy in Chinese patients with gastric cancer

Background The importance of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene for the prediction of the response to fluorouracil-based adjuvant chemotherapy in gastric cancer patients remains unclear. The aim of this study is to assess the predictive value of several polymorphisms of the MTHFR gene for clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. Methods Three hundred and sixty-two Chinese patients with gastric cancer were treated with fluorouracil-based adjuvant chemotherapy. DNA samples were isolated from peripheral blood collected before treatment. The three single nucleotide polymorphisms (SNPs) (rs1801131, rs1801133, rs2274976) genotypes of the MTHFR gene were determined by matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results The average response rate for chemotherapy was 46.7%. Homozygous genotypes rs2274976G/G (χ2=22.7, P &lt;0.01) and rs1801131A/A (χ2=14.3, P=0.008) were over-represented in responsive patients. Carriers of the rs2274976A allele genotypes (G/A and A/A) and of the rs1801131C allele genotypes (A/C and C/C) were prevalent in nonresponsive patients. In the haplotype association analysis, there was a significant difference in global haplotype distribution between the groups (χ2=20.69, P=0.000 124). Conclusions These results suggest that polymorphisms of the MTHFR gene may be used as predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of MTHFR gene as clinical markers for predicting the response to fluorouracil-based therapy in gastric cancer patients is warranted.

Locally advanced or metastatic pancreatic cancer in elderly patients: Chemotherapy versus best supportive care

(60.4%) patients received 5-fluorouracil-based adjuvant chemotherapy (30 (46.9%)≥ 75 years old versus 34 (53.1%) b 75 years old). Older patients had similar clinico-pathological characteristics as younger patients. The median follow-up duration was 14.9 months. The 3-year disease-free survival (26.4%≥ 75 years old versus 40% b 75 years old, P = 0.006) was different. Elderly patient received a lower relative dose intensity of Oxaliplatin and 5-fluorouracil (57.7 versus 64.4 (P = 0.418)). Conclusion: Adjuvant fluorouracil-based chemotherapy result in different efficacy without in older patient age ≥ 75 years when compared with best younger patients with curatively resected stage II,III colon cancer. Therefore, for colon cancer patients aged ≥75 years can be recommended to receive a lower relative dose intensity of 5-fluorouracil after curative surgery in Korea. Disclosure of interest: None declared.

P16 Methylation is associated with chemosensitivity to fluorouracil in patients with advanced gastric cancer.

No effective biomarkers have been confirmed to predict chemosensitivity for patients with gastric cancer. The purpose of this study was to investigate whether DNA methylation is associated with chemosensitivity in patients with gastric cancer. Tumors and matched non-tumor biopsy tissues collected from 134 advanced gastric cancer (AGC) patients prior to fluorouracil-based chemotherapy were retrospectively analyzed. The methylation status of p16, E-cadherin (CDH1), MGMT (O-6-methylguanine-DNA methyltransferase), and human mutL homolog 1 (hMLH1) was evaluated using a Methylight assay, and the association between p16 methylation and the sensitivity of 5-fluorouracil in cell lines was determined by in vitro assay. The methylation of p16 (17.9 vs. 0 %, P = 0.002), CDH1 (20.9 vs. 2.2 %, P < 0.001), MGMT (17.9 vs. 0 %, P = 0.052), and hMLH1 (14.9 vs. 2.2 %, P = 0.024) was more common in gastric cancer tissues (n = 134) than in non-tumor tissues (n = 46). For all patients, a reverse correlation was only found between p16 methylation and clinical response (P = 0.017), which suggested that p16 methylation might be associated with chemosensitivity of fluorouracil in gastric cancer patients. Results from in vitro experiments demonstrated that p16 methylation was closely correlated with the sensitivity of 5-fluorouracil in gastric cancer cells. The present results indicated that the methylation of p16, CDH1, MGMT, and hMLH1 was both frequent and specific in gastric cancer tissues. p16 Methylation might be used to predict chemosensitivity of fluorouracil for patients with AGC when validated in large samples in the future.

Phenotypic analysis of primary colorectal cancer to inform management of metastatic disease

BackgroundColorectal cancer is the fourth commonest cancer in the UK, and the second commonest cause of cancer-related death. Liver surgery for colorectal liver metastases is increasing, because neoadjuvant chemotherapy has brought a greater number of patients to resection. A knowledge of the biological phenotype of colorectal liver metastases would be invaluable in informing clinical decision making; however, deriving this information from the metastatic lesions is not feasible until after resection. By contrast, material from the primary tumour is routinely available. We aimed to establish the feasibility of using biological information from a primary colorectal tumour to inform and predict response to neoadjuvant chemotherapy for liver metastases. MethodsFresh tissue from both primary colorectal tumour and liver metastases, and from normal colonic mucosa and liver parenchyma, were acquired at the time of resection in 17 patients and subjected to comparative proteomic analysis using isobaric tagging for relative quantification. Data were analysed with Protein Pilot (Ab Sciex, Framingham, MA, USA); proteins with expression significantly different across the different tissue types were subjected to pathway analysis with Metacore software. Stratification of patients to those showing low or high response to chemotherapy allowed the identification of proteins that were differentially expressed in the two groups and thus represented potential response biomarkers. Findings5768 discrete proteins were identified, with 1814 present in all samples and therefore used for analysis. Principal component analysis of relative protein abundance separated liver parenchyma from other tissue types, but did not separate individual patients. No proteins were significantly different between primary and metastatic tumours. 25 proteins were significantly (p<0·05) differentially expressed in the primary tumour compared with normal colon, whereas 53 were different between the liver metasases and normal colon. Five candidate proteins that predict favourable histopathological response to fluorouracil-based chemotherapy regimens were identified. InterpretationProteomic sequencing of matched metastatic colorectal cancer samples is feasible with high protein coverage. Analysis of dysregulated proteins revealed putative pathways that might be implicated in carcinoma progression and metastasis and identify potential novel drug targets. The high degree of similarity between the primary and secondary proteomes suggests that information from primary tissue is predictive of the metastatic phenotype. Further targeted analysis of proteins involved in drug activation and metabolism, as well as the validation of candidate biomarkers, is underway. FundingCancer Research UK.