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Supplementary Data from Clinical Benefit of Allogeneic Melanoma Cell Lysate–Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients

Purpose: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)–pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate.Experimental Design: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 × 106 cells per dose) at biweekly intervals.Results: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders.Conclusion: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726–36)

Introduction This study aimed to describe the planning, development and evaluation of the success of the first nationwide, resident-led, large-group teaching programme for medical students - the Singapore Health Services Student Internship Programme (SIP) Bootcamp. Methods This was an initial feasibility study evaluating a half-day teaching boot camp initiated, developed and conducted by the resident educators. A three-month preparation period was required to set up an education subcommittee, liaise with medical student leaders, recruit resident educators, meet all the stakeholders and conduct the boot camp. During the SIP Bootcamp, resident educators conducted clinical case presentations using a question-and-answer format. Audience participation was strongly encouraged. A 15-item questionnaire was distributed to assess the participants' learning experience and the resident educators' teaching performance using a five-point Likert scale. Results Overall, 94.8% (n = 110) of the 116 respondents agreed that the teaching sessions were of high quality and content was relevant to their training. The resident educators appeared well-informed (96.6%, n = 112) and enthusiastic about their respective topics (98.3%, n = 114). However, a few students (9.5%, n = 11) felt that the audio-visual aids and handouts could be improved to better aid their learning process. Conclusion This teaching boot camp for medical students was the first of its kind in Singapore and feedback from medical students showed that it was well-received. Further research using different teaching methods, including small-group discussions and surgical practical sessions by resident educators from different specialties, would be of great value to students.

Aim The survival benefit of using a non-cross resistant second-line chemotherapy in the third-line setting in metastatic gastroesophageal cancer is unproven. We evaluated the utility of third-line chemotherapy in patients treated at a single institution. Methods Between 2010 and 2014, efficacy and toxicity data of patients who received three or more lines of systemic therapies for metastatic gastroesophageal adenocarcinoma at the National Cancer Centre Singapore was retrospectively analyzed. Results Thirty-two (6%) patients received three or more lines of chemotherapy. The median age and ECOG performance status were 59 years (36-82) and 1 (0-2), respectively. Majority of patients (88%) had tumor located in the stomach and 13 patients (41%) had diffuse histology or poorly cohesive or signet ring cells. Four (12%) patients had HER2-positive disease. Prior therapy was platinum (100%), fluoropyrimidine (97%), taxane (63%), irinotecan (28%), anthracycline (13%) and ramucirumab (3%). Third-line therapy consisted of 24 (75%) monotherapy, 6 (19%) doublet, 1 (3%) triplet chemotherapy and 1 (3%) clinical trial. Monotherapy irinotecan (44%) was most common, followed by docetaxel (19%) and paclitaxel (9%). Of 22 patients evaluable for response, there was 1 (5%) partial response, 9 (41%) stable disease. Median overall survival was 18.3 weeks (4.3-65.1). Of 30 patients evaluable for toxicities, 17 (57%) experienced at least one grade 3 or 4 toxicities. Conclusion The benefit of using non-cross resistant second-line regimens as third-line chemotherapy was small with moderate toxicity. Newer agents such as nivolumab or TAS-102 or clinical trial may be preferred.

Introduction: The Academic Medicine Education Institute (AM∙EI), jointly established by Duke-NUS Graduate Medical School (Duke-NUS) and Singapore Healthcare Services (SingHealth), is a newly formed health professions education academy designed to cultivate best education practices and create a community of health professions educators. To achieve the aims of AM∙EI, the needs of SingHealth educators have to be understood. Therefore, this study was carried out to assess educators’ perceptions towards the current education climate and their academic needs. Materials and Methods: A 28-item questionnaire consisting of free-response, Likert-type and ranking questions was developed. The questionnaire was electronically distributed to 200 medical and nursing educators, and made available to attendees of the 2012 Singhealth Duke-NUS Scientific Congress through hardcopies. Results: A total of 150 completed questionnaires were received (94 from electronic survey and 56 from Congress). Five themes emerged from the analysis of responses to free-response questions: 1) faculty development, 2) development of a community of educators, 3) recognition for educational efforts, 4) institutional support, and 5) better communication about SingHealth educational activities. Respondents were in highest agreement with the statements (rating of 3.7 out of 5): “The SingHealth education programmes are high quality”, “New learning or teaching methods are welcomed in this institution/hospital”, and “An academic appointment is important to me”. The competencies that respondents felt to be the most important were facilitating discussions, presentation skills, and providing feedback (respective means = 5.1, 5, 5 of 7). Conclusion: This needs assessment provided us with important insights regarding SingHealth medical educators’ perceptions of their education environment and established key priorities for the AM∙EI’s programming efforts. Key words: Academy, Duke-NUS, Singapore, SingHealth

INTRODUCTION The use of faecal immunochemical occult blood test (FIT) has been reported to decrease mortality from colorectal cancer. The Singapore Cancer Society (SCS) gives out FIT kits to encourage opportunistic screening of colorectal cancer. Any Singapore citizen or permanent resident aged ≥ 50 years is eligible to receive two FIT kits. Participants with at least one positive FIT are referred for further evaluation. We aimed to analyse the results of SCS data from the year 2008. METHODS The factors evaluated included compliance, positive test rate (PR) and positive predictive value (PPV) of FIT. RESULTS 20,989 participants received 41,978 kits in 2008. Compliance was 38.9%, with 8,156 participants returning at least one kit. 8% of participants tested positive, and 75% of these test-positive participants agreed to undergo further investigations. 33 participants had colorectal cancers, 45 had advanced polyps (≥ 1 cm) and 90 had polyps < 1 cm. Histologically, 114 polyps were adenomatous, 20 were hyperplastic and 1 was serrated. PPV of colorectal neoplasia for those who underwent further colonoscopy was 34%. Over half of the participants who had only one positive test had colorectal neoplasia. CONCLUSION PR and PPV of FIT in our study were comparable to that in the literature. However, compliance was low and a quarter of all participants who tested positive refused further investigations. Extensive population education programmes are required to improve compliance and tackle inhibitions among the masses. It is also important to take steps to enhance the cost effectiveness of future screening programmes.

Introduction: More than half of all deaths in Singapore occur in hospitals. Little is known about the quality of care received by dying patients in hospitals. The Liverpool Care Pathway (LCP) provides a framework of providing good end-of-life care for dying patients and has been used with success in the United Kingdom (UK). In this study, we investigate whether adoption of a modified LCP in a Singapore hospital translated to better end-of-life care for cancer patients. Materials and Methods: The LCP was adapted and implemented as a pilot project on an oncology ward in Singapore General Hospital. A baseline review of 30 consecutive death records was performed, followed by a 4-month pilot and post-implementation audit of 30 consecutive patients on the adapted LCP. Results: Five types of end-of-life symptoms were analysed. There was only 1 uncontrolled symptom at death in the post-implementation group compared to 24 uncontrolled symptoms in the retrospective audit group. The prescription of breakthrough medications for symptom control increased from 21% in the retrospective audit group to 79% in the post-implementation group. Inappropriate monitoring was discontinued in 25 patients in the post-implementation group compared to none in the retrospective audit group. The documentation of resuscitation status and religion of the patient was improved, achieving full documentation in the post-implementation group. Conclusion: This study shows promising results for improving end-of-life care in cancer patients with a protocol-based pathway in a Singapore hospital. Extension of this care pathway to other settings should be explored to maximise its benefits to patients dying from all causes in hospital. Key words: End-of-life care, Liverpool Care Pathway, Symptom control

Aim: Oxaliplatin-related neurotoxicity is frequently dose-limiting. Following retrospective studies suggesting neuroprotective effects of calcium and magnesium (Ca and Mg), we conducted a prospective study using nerve conduction studies (NCS) to evaluate the effectiveness of such infusions in oxaliplatin-related neuropathy. Methods: Colorectal cancer patients receiving FOLFOX-4 or capecitabine plus oxaliplatin were randomized to (Arm A) calcium gluconate 1g +15% magnesium sulphate 1g diluted in 100 mL of dextrose 5% or (Arm B) placebo. Neuropathy was assessed using the National Cancer Center common toxicity criteria, oxaliplatin-specific scale and NCS. Results: This study was terminated prematurely based on the initial negative results of the CONcePT trial. Median follow up was 8.7 months. Overall 22 out of 27 patients experienced neuropathy. The subjective neuropathy rate was 77% in Arm A and 86% in Arm B, (P = 0.6). At the end of treatment, three patients in Arm A and 0 in Arm B had grade 3 numbness (P = 0.09). There was no significant difference in neuropathy between arms, whether during or at the end of treatment. Median objective neuropathy score was 6 in Arm A and 0 in Arm B, (P = 0.02). Conclusion: Premature closure of this study limits the interpretation of results. While there was a trend towards reduced subjective acute sensory neuropathy with Ca and Mg, this was not significant. Ca and Mg failed to reduce the rate of cumulative sensory neuropathy and instead increased the rate of abnormal NCS, suggesting a significant difference in perceived sensory and objective neuropathy.

Purpose: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)–pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. Experimental Design: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 × 106 cells per dose) at biweekly intervals. Results: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders. Conclusion: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726–36)

Objective This study aims to develop a function for mapping the English and Chinese versions of the Functional Assessment of Cancer Therapy–General (FACT–G) scores to the EuroQoL Group's EQ-5D utility index and to test whether a single function is sufficient for the two language versions. Methods A baseline survey of 558 cancer patients in Singapore using the FACT–G and EQ-5D was conducted (308 English and 250 Chinese questionnaires). Regression models were used to predict the EQ-5D utility index values based on the FACT–G scores and thus derive a mapping equation. Data from a follow-up survey of the patients were used to validate the results. Results The FACT–G Social/Family scale was not associated with the EQ-5D utility index ( P = 0.701). There was no interaction between language version and the predictors (each P > 0.1). An equation that maps the FACT–G Physical, Emotional, and Functional well-being scales to the EQ-5D utility index was derived. In the validation sample, the mean observed utility values was larger than the mapped by only 0.005 (95% confidence interval [CI] −0.006 to 0.016), but the mean absolute difference was 0.083 (95% CI 0.076 to 0.090). Conclusions At the group level, but not individual level, the equation developed can accurately map the English and Chinese versions of the FACT–G scores to the EQ-5D utility index.

Objective To assess measurement equivalence of the Singaporean English and Chinese versions of the EuroQol Group's 5-domain questionnaire (EQ-5D) in cancer patients. Study Design and Setting Seven hundred and seventy-one ethnic Chinese patients in Singapore were recruited, and they answered either an English or a Chinese version of the EQ-5D. Seven days later, a similar questionnaire in the same language was mailed to the patients. Regression analysis was used to assess equivalence of the mean values obtained by using the two language versions. The validity, responsiveness to change, and reliability of the two versions of the EQ-5D were assessed and compared. Results Based on the prespecified equivalence margin of ±10% for binary outcome, ±0.05 for utility index, and ±5 points in the visual analog scale, the two language versions of the EQ-5D gave equivalent mean values at item and scale levels. They also showed similar characteristics in validity, responsiveness, and reliability. For example, the test–retest reliability values for the EQ-5D utility index in the two language samples were identical in two significant digits: 0.79. Conclusion The Singaporean English and Chinese versions of the EQ-5D were validated in cancer patients and were shown to achieve measurement equivalence.

Introduction: Advanced hepatocellular carcinoma (HCC) has a dismal prognosis and is notoriously chemo-resistant. We conducted a Phase II prospective study to evaluate the activity and tolerability of gemcitabine and cisplatin in chemo-naïve advanced hepatocellular carcinoma. The trial considered a “no further interest” response rate of 10% and a target response rate of 30%. Utilising a Simon’s minimax two-stage design with a type I error of 0.05 and power of 80%, 25 subjects would be required. Fifteen patients would be needed in stage 1 and if fewer than 2 responses were observed, the trial would be stopped and lack of efficacy claimed. Materials and Methods: Patients with advanced HCC, diagnosed based on histology or by World Health Organization (WHO) criteria, were administered gemcitabine 1000 mg/m2 and cisplatin 25 mg/ m2 on day 1 and day 8 of a 21-day schedule. Assessment of response based on computer tomography was performed after every 2 cycles of chemotherapy. Results: The trial was stopped early due to a lack of efficacy. A total of 15 patients were accrued. Twelve patients were hepatitis B positive and the other 3 patients were negative for both hepatitis B and C. Only 1 patient had a history of prior heavy alcohol use. Two patients had Child C liver cirrhosis, 5 patients had Child B cirrhosis, and the remaining 8 patients had Child A cirrhosis. This regime was well tolerated and there was only 1 patient who experienced grade IV toxicities. Only 5 of 15 patients experienced grade III toxicities (nausea and emesis, 1 patient; anemia, 1 patient; thrombocytopenia, 1 patient; and neutropaenia, 2 patients). Only 1 patient experienced a partial response to the combination of gemcitabine and cisplatin. A further 3 patients experienced stable disease and 11 patients progressed on chemotherapy. The median time to progression was 6 weeks. The progression-free curve showed a sharp descent in the initial part of the study, suggesting that many patients had disease progression after enrolment. The median overall survival was 18 weeks. Conclusion: The progression-free survival and overall survival in our study were extremely short. Based on the results of our phase 2 study, we are unable to recommend further studies utilising gemcitabine and cisplatin combination in patients with advanced HCC. Key words: Cisplatin, Gemcitabine, Hepatitis B, Hepatocellular carcinoma

Introduction: The aim of this paper was to study the efficacy, side effects and complications of radiofrequency (RF) ablation of primary and metastatic liver malignancies. Materials and Methods: We retrospectively reviewed 57 patients (39 men, 18 women; mean age, 63 years; age range, 44 to 83 years) who underwent RF ablation for liver malignancies from January 2002 to December 2004. A total of 87 tumours were ablated – 71 (81.6%) hepatocellular carcinomas and 16 (18.4%) metastases (from primaries in the colon, stomach and pancreas). RF ablation was performed either percutaneously (n = 71) under conscious sedation or intraoperatively (n = 16) under general anaesthesia. Follow-up ranged from 1 month to 41 months (mean, 15.2) and included computed tomography (CT) 1 day, 1 month and 3 months after ablation, and half-yearly thereafter. Patients were observed for local tumour progression and for the emergence of new tumours. Results: Four patients with a total of 5 tumours were lost to follow-up. Of the remaining 82 tumours treated, complete ablation was attained in 66 tumours after a single procedure, giving a primary effectiveness rate of 80.5%. Seven (8.5%) required 2 procedures to achieve complete ablation, giving a secondary effectiveness rate of 89% after 2 ablations. One tumour (1.2%) required 3 procedures to achieve complete ablation. One tumour required 4 procedures to date, with the latest follow-up CT still demonstrating incomplete ablation. Two tumours (2.4%) had an initial RF ablation and subsequent transarterial chemoembolisation (TACE). One tumour had an initial RF ablation followed by 32Phosphorus-biosilicon (BrachySil®) injection, the latter as part of a Phase IIA trial. One tumour required 2 RF ablations and a subsequent TACE. Lastly, 3 tumours received initial RF ablation but subsequent local tumour progression was not treated as the patients were deemed unfit for repeat ablation. No procedure-related deaths or major complications were encountered. Minor complications were reported in 2 patients (3.8%) – subcapsular haematoma and thermal injury to the adjacent gastric antrum, both not necessitating surgical intervention. Conclusions: RF ablation is an effective, safe and relatively simple procedure for the treatment of unresectable liver malignancies. Key words: Hepatocellular carcinoma, Liver neoplasms, Radiofrequency ablation, Therapeutic chemoembolisation

Corticosteroids are used in the management of intestinal obstruction (IO) in carcinomatosis peritonei. There is considerable overlap in the symptoms experienced in IO and functional adrenal insufficiency (AI). The success of symptom palliation in IO may be related to the presence of AI. The aim of this preliminary study was to evaluate the incidence of functional adrenal insufficiency in patients with IO and its relation to clinical outcome and symptom control. Twenty-nine consecutive patients with IO and carcinomatosis peritonei from gastrointestinal cancers admitted to our inpatient service between January and October 2002 were analyzed. They were screened for AI using the short corticotropin stimulation test. Thirteen patients (45%) had functional AI. Differences in characteristics of patients with normal adrenal function (Group 1) and adrenal insufficiency (Group 2) were not statistically significant. Time taken to control symptoms in Group 2 was longer. Mean duration of hospitalization per month of survival was two times longer in Group 2 relative to Group 1 (7.9 versus 4.0 days, P=0.011). Functional AI may be caused by cytokines produced in advanced cancer mediating direct adrenal suppression. Prompt corticosteroid therapy in the presence of AI may facilitate IO symptom palliation.

Methodological studies and outcome research often include several health-related quality of life (HRQoL) measurement scales in one questionnaire. Psychological studies have previously demonstrated that changing the sequential order of measurement scales within a questionnaire can alter the pattern of responses. Little is known, however, about whether there are order effects on the assessment of HRQoL in cancer patients. Here we address this issue in a study of 190 Singaporean cancer patients who were assessed using two different HRQoL instruments placed in alternating sequence within a questionnaire package. Measurement properties of the instruments, including the number of missing values, means, variability, known-group validity and internal consistency, were compared in the two samples representing different presentation orders. The HRQoL instruments administered in different sequential orders appeared to be equivalent in several aspects. No major effect of presentation order on outcomes was shown. The reasons and implications of the absence of an order effect are discussed. We conclude that presentation order is unlikely to alter the responses to the two HRQoL instruments.

Importance Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm ( P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance ( P −8 ), including a novel DPYD variant (rs75267292; P = 1.57 × 10 −10 ), and variants in the MACF1 (rs183324967, P = 4.80 × 10 −11 ;rs148221738, P = 5.73 × 10 −10 ) and SPRY2 (rs117876855, P −8 ;rs139544515, P = 1.30 × 10 −8 ) genes involved in wound healing. Conclusions and Relevance Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration clinicaltrials.gov Identifier:NCT00486213

Gastric cancer is a leading cause of cancer-related deaths worldwide. The majority of cases are diagnosed in the advanced stages and prognosis is poor, with 5-year survival rates in the range of 5 to 15% [1]. Clinical trials have consistently supported the role of chemotherapy over best supportive care in the setting of advanced gastric cancer (AGC) [2,3]. In prospective randomised trials, combination chemotherapy with epirubicin, cisplatin and infusional 5-fluorouracil (ECF) has been shown to be superior to 5-fluorouracil, doxorubicin, and methotrexate (FAMTX) [4], improving median survival from 5.7 to 8.9 months. And more recently, Moiseyenko and colleagues [5] have demonstrated superior response rates and improved survival of docetaxel, cisplatin and 5-fluorouracil (DCF) over cisplatin and 5-fluorouracil (CF). However both ECF and DCF are toxic, associated with high rates of neutropenia, thus do not provide ideal palliation to patients with AGC. Oxaliplatin appears to be more effective than cisplatin with regards to DNA inhibition [6] and has a more favourable toxicity profile. In combination with 5-fluorouracil, response rates of 43% and 44.9%, with median survival of 9.6 months and 8.6 months respectively, were achieved in studies by AlBatran and Louvet [7,8]. Capecitabine is a novel oral fluoropyrimidine carbamate that generates 5-FU selectively in tumor tissue. Preliminary data from the REAL-2 study suggests that in patients with AGC, substitution of capecitabine for 5-fluorouracil does not compromise outcomes when used in combination with an anthracycline and platinum [9]. Therefore it is conceivable that the combination capcitabine-oxaliplatin (XELOX) given 3-weekly, may be efficacious in AGC. This regimen is attractive, as it is well tolerated, does not require a central venous catheter (CVC), and convenient, only requiring a short duration intravenous treatment every 3 weeks. Thus we undertook a retrospective study of all patients with AGC treated with XELOX regimen in our centre from June 2003 to March 2006. The objectives were to study the response rates and overall survival of patients and safety of this regimen. Thirty-five patients with metastatic gastric cancer who received XELOX regimen were identified. Tumor lesions were measured using the Response Evaluation Criteria in Solid Tumors criteria. Adverse events were graded according to National Cancer Institute common toxicity criteria. Peripheral sensory neuropathy was graded according to the oxaliplatin-specific scale previously described [10]. Overall survival (OS) was calculated from time of diagnosis to time of death. Median age at diagnosis was 58 years with 20% aged ]70 years. One third of patients have an ECOG performance status of 2 4 (Table I). The median starting doses of capecitabine and oxaliplatin were 1 700 mg/m/day (days 1 14) and 130 mg/m (day 1) respectively. The median number of cycles of chemotherapy was 5. Sixty-nine percent and 23% of patients were treated with XELOX in the first and second line setting respectively.

Cutaneous metastases from colon cancer are uncommon and usually present as nodular lesions. We describe a patient with colonic carcinoma who developed an inflammatory pattern of cutaneous metastases. A review of the literature is also presented. Recognition of this entity is important as it may be mistaken for erysipelas and radiation recall phenomenon. Early treatment with chemotherapy can result in meaningful palliation.

Background Neoadjuvant chemotherapy improves survival of locally advanced gastric cancer patients. However, benefit is limited and the best regimen remains controversial. Objectives Our primary objective of this prospective, multicenter phase 2 study was to evaluate the pathological complete response rate (PCR) with 2 cycles of docetaxel and capecitabine. Methods To be eligible, patients had to have histologically documented gastric cancer, a ECOG performance status 0 or 1, T3or4 Nany M0 staging after oesophagogastroduodenoscopy (OGD), endoscopic ultrasound (EUS), CT scan of thorax and abdomen, and negative laparoscopic examination and peritoneal washing. Eligible patients received two cycles of intravenous docetaxel 60 mg/m2 on day 1 and oral capecitabine 900 mg/m2 two times per day from day 1 to day 14 every 3 weeks. We evaluated the response by CT scan and EUS. The patients underwent curative resection with D2 lymphadenectomy subsequently. Results 18 patients were enrolled in the study: 66% were male and the median age was 60 years. 17 patients had T3 disease at diagnosis. There was no pCR noted. 4 patients had a partial response of 22% (95% CI: 7–42%), 8 patients had stable disease and 3 patients had disease progression. The median survival was 17.1 months with 3 long-term survivors after at least 3 years of follow-up. The treatment was well tolerated with neutropenia being the most common toxicity. We observed 22% grade III and 33% grade IV neutropenia, but no neutropenic fever or death was observed from chemotherapy. Conclusion Neo-adjuvant chemotherapy with docetaxel and capecitabine has limited activity against GC. More effective treatment regimens are needed urgently. Trial registration number NCT00414271.

Well-established clinicopathological variables used in the risk stratification of gastrointestinal stromal tumor (GIST) may not completely predict rectal GIST, an uncommon and poorly studied GIST subset. The aim of the present study was to determine the patterns of relapse and morbidities associated with recurrence in rectal GIST. A single-institution retrospective study between 2002 and 2011 was conducted, identifying 9 patients (8%) with localized rectal GIST, while comparing small intestinal (n=37) and gastric (n=63) GIST (median age, 60 years). Rectal GIST tumors were smaller compared to small intestinal/gastric GIST (P=0.044). The number of mitoses per 50 high-power field (HPF) did not differ by primary site. In general, 73% of patients were high-risk, as defined by the National Institutes of Health (NIH) consensus criteria, however, only 25% received adjuvant imatinib. Fewer rectal GIST patients achieved negative surgical margins compared to small intestinal/gastric GIST (67 vs. 92%; P=0.054). Of the 9 patients with localized rectal GIST 6 had peri-operative tumor rupture, anastomotic breakdown or required anal sphincter-compromising surgery. At the time of the first relapse, 83% of the recurrences were local failures for rectal GIST, compared to 21% for small intestinal/gastric GIST (P=0.005). The median relapse-free survival was 51 months for the entire cohort, and 54, 36 and 56 months for rectal, small intestinal and gastric GIST, respectively (P=0.468). Rectal GIST was found to be associated with high rates of local relapse and significant morbidity, despite being significantly smaller compared to GIST of other sites. A multimodality peri-operative therapeutic approach may be required to improve outcomes.

To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC).Patients (N = 18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100 mg/m(2) on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000 mg) once daily taken at 2400 hours on days 1-5. Each cycle lasted 14 days.The MTD of capecitabine was 4,500 mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3 %, and median overall survival was 16.3 months (95 % CI: 11.2-18.2 months). The maximum plasma concentration (C(max)) and area under plasma concentration-time curve from time 0 to infinity (AUC([0-∞])) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity.Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.

BACKGROUND AND OBJECTIVES The purpose of this study was to confirm our hypothesis that the development of functional intestinal obstruction in carcinomatosis peritonei (CP) is related to cytokine-mediated inhibition of the Akt pathway and to investigate the phenomenon of relative adrenal insufficiency in CP. METHODS Human adrenocortical cells (NCI-H295R) were treated with serum derived from eight cancer patients who had intestinal obstruction and functional adrenal insufficiency. Serum from three normal healthy subjects and three who had CP but without intestinal obstruction or adrenal insufficiency were used as controls. The differential effects of serum on the treated cells were studied using Western blot analysis. Cortisol production of these treated cells was assayed with cortisol ELISA kits. RESULTS Phosphorylation of Akt at Ser473 and Ser308 in cells was significantly reduced when treated with serum from patients with intestinal obstruction but not controls. Phosphorylation of PDK1 at Ser241, mTOR downstream targets like p70S6 at Thr421/Ser424 and Thr389, and lastly 4EBP-1 at Ser70 a downstream target of p70S6 was reduced by approximately 50%, 40%, and 70%, respectively. There was enhanced phosphorylation of eIF4E an initiating factor in protein translation in cells treated with patient serum compared to controls. Cortisol synthesis was stimulated upon treatment with patient serum but not with control serum. CONCLUSION Inhibition of Akt phosphorylation is a mechanism that could play a major role in the development of intestinal obstruction in carcinomatosis peritonei. The identification of the mediating cytokines will lead to the development of cogent targeted therapeutic strategies.

Summary Asia has a disproportionately large share of the world's hepatocellular carcinoma (HCC), mainly because of the endemic status of chronic hepatitis B and C viruses, which leads to liver cirrhosis and an increased risk of HCC. This etiological factor presents important opportunities for prevention, early detection, diagnosis, and treatment of HCC. This consensus statement reviews the available medical evidence for management of HCC in Asia, and gives treatment recommendations that are adapted to resource availability in this diverse region with disparate health-care delivery systems.

The aim of this paper was to study the efficacy, side effects and complications of radiofrequency (RF) ablation of primary and metastatic liver malignancies.We retrospectively reviewed 57 patients (39 men, 18 women; mean age, 63 years; age range, 44 to 83 years) who underwent RF ablation for liver malignancies from January 2002 to December 2004. A total of 87 tumours were ablated - 71 (81.6%) hepatocellular carcinomas and 16 (18.4%) metastases (from primaries in the colon, stomach and pancreas). RF ablation was performed either percutaneously (n = 71) under conscious sedation or intraoperatively (n = 16) under general anaesthesia. Follow-up ranged from 1 month to 41 months (mean, 15.2) and included computed tomography (CT) 1 day, 1 month and 3 months after ablation, and half-yearly thereafter. Patients were observed for local tumour progression and for the emergence of new tumours.Four patients with a total of 5 tumours were lost to follow-up. Of the remaining 82 tumours treated, complete ablation was attained in 66 tumours after a single procedure, giving a primary effectiveness rate of 80.5%. Seven (8.5%) required 2 procedures to achieve complete ablation, giving a secondary effectiveness rate of 89% after 2 ablations. One tumour (1.2%) required 3 procedures to achieve complete ablation. One tumour required 4 procedures to date, with the latest follow-up CT still demonstrating incomplete ablation. Two tumours (2.4%) had an initial RF ablation and subsequent transarterial chemoembolisation (TACE). One tumour had an initial RF ablation followed by 32Phosphorus-biosilicon (BrachySil) injection, the latter as part of a Phase IIA trial. One tumour required 2 RF ablations and a subsequent TACE. Lastly, 3 tumours received initial RF ablation but subsequent local tumour progression was not treated as the patients were deemed unfit for repeat ablation. No procedure-related deaths or major complications were encountered. Minor complications were reported in 2 patients (3.8%) - subcapsular haematoma and thermal injury to the adjacent gastric antrum, both not necessitating surgical intervention.RF ablation is an effective, safe and relatively simple procedure for the treatment of unresectable liver malignancies.

Prospective randomized clinical trials have shown the effectiveness of combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer. To assess toxicity of this therapy, prospective data were collected from 236 Asian rectal cancer patients treated with combined 5-fluorouracil-based chemotherapy and radiotherapy after surgery. Almost 82% of patients completed planned therapy. Grade 3 and 4 diarrhea, stomatitis, and granulocytopenia occurred in approximately 18-21% of patients. There were two treatment-related deaths from granulocytopenia and sepsis. With median follow-up of 3.5 years, median disease-free and overall survival was 75 and 88 months, respectively. In conclusion, combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer is tolerable in Asian patients with moderate toxicity.

14089 Background: Effective 1st line chemotherapy that is easily delivered and tolerable is important in patients with advanced gastric cancer (AGC). This study aimed to evaluate the toxicity and efficacy of combination capecitabine and oxaliplatin (XELOX), given 3 weekly, in patients with AGC. Methods: Twenty-seven patients with AGC, were treated with XELOX at the National Cancer Centre Singapore between June 2003 and December 2005. Capecitabine was given 2000 mg/m2/day, days 1–14, and oxaliplatin was given 130 mg/m2 on day 1, every 21 days. Results: The median age was 61 years with 22% of patients ≥ 70 years. One-third of patients had ECOG 2 - 4, and 33% of patients had signet ring cell histology. Median doses of capecitabine and oxaliplatin achieved were 1500 mg/m2/day (1200 - 2400) and 130mg/m2 (80 - 130) respectively. A median of 5 cycles (range 1 - 8) of XELOX was administered. All 27 patients had toxicity assessment. Toxicities were infrequent and mild. There were 3 cases of grade 3/4 toxicities (thrombocytopenia, neutropenia and fatigue). Twenty-two patients had measurable disease for response evaluation. Complete (CR) and partial (PR) response rates were 9 and 50% respectively. Overall response rate was 59%. Chemo-naïve patients had better responses (80% vs 25%). Four of the remaining 5 patients had reduction in non-measurable disease or in tumor marker levels. Of the 9 patients with ECOG > 1, there was radiological CR in 1 patient and 5 PR; 1 had normalization of CEA, another reversal of disseminated intravascular coagulation and the third decreased ascites. The median time to progression and overall survival were 5.9 months and 7.6 months respectively. Conclusions: XELOX regimen is safe, active and well tolerated in AGC even in patients with poor ECOG status. It is easily administered without requiring a central venous catheter. This regimen should be investigated further in a prospective manner. No significant financial relationships to disclose.