Treatment and long term safety outcomes of Peptide Receptor Radionuclide Therapy for metastatic neuroendocrine tumours: an Asian experience.

Peptide-receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NET). It has been shown to be effective and well-tolerated in patients with metastatic neuroendocrine tumours in several centres in United States (US), Europe and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods One hundred and seven (107) patients with metastatic neuroendocrine tumour who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST1.1 and qualitative analysis were examined. The overall and progression free survival curves were also evaluated. Results The median progression free survival was 49 months. Response assessment after completion of treatment showed that 33(37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion Our results show that PRRT is safe and effective in the treatment of metastatic neuroendocrine tumour in the Asian population. There was a significant difference in the progression free survival curves between low-grade and high-grade NET, and in the progression free and overall survival comparing the number of cycles received.

Potentially functional SNPs (pfSNPs) as novel genomic predictors of 5-FU response in metastatic colorectal cancer patients.

5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.

Postoperative serum methylation levels of TAC1 and SEPT9 are independent predictors of recurrence and survival of patients with colorectal cancer.

BACKGROUND: Serum carcinoembryonic antigen (CEA) is the only marker recommended for surveillance of colorectal cancer (CRC) recurrence; its sensitivity and specificity, however, are suboptimal. This study sought to evaluate the values of postoperative serum methylation levels of 7 genes for prognostication and especially for recurrence detection after curative resection. METHODS: This prospective cohort study included 150 patients with stage I-III CRC from whom 3 consecutive blood sampling was taken 1 week before, and 6 months and 1 year after operation. Methylation levels of 7 genes were evaluated via quantitative methylation-specific polymerase chain reaction. Serum CEA was measured in parallel. Univariate and multivariate survival analyses were followed by construction of receiver operating characteristic curves for recurrence detection. RESULTS: After a median follow-up of 59 months, 43 patients (28.7%) developed recurrent lesions. High serum methylation levels of TAC1 in serum at 6-month follow-up (6M-FU), and SEPT9 at 1-year follow-up (1Y-FU) were independent predictors for tumor recurrence and unfavorable cancer-specific survival (CSS) (P < .05 in all tests). Serum NELL1 methylation levels were significant alone for CSS at both 6M-FU and 1Y-FU, but not for disease-free survival. Dynamic changes of TAC1 and SEPT9 with methylation increment were also independently predictive for recurrence (P < .05 in all tests). More importantly, TAC1 at 6M-FU and SEPT9 at 1Y-FU exhibited earlier detection of potential recurrences compared with concurrent serum CEA. CONCLUSIONS: Levels of TAC1 and SEPT9 methylation detected in postoperative sera of patients with CRC appear to be novel promising prognostic markers and may probably be considered for monitoring of CRC recurrence.

Serum methylation levels of TAC1. SEPT9 and EYA4 as diagnostic markers for early colorectal cancers: a pilot study.

OBJECTIVE: To identify methylated genes in serum with diagnostic potentials for early colorectal cancer (CRC). METHODS: Serum methylation levels of up to 12 genes were measured in two sets of serum samples with the second set from 26 stage I CRC patients and 26 age/gender-matched controls. RESULTS: Serum methylation levels of TAC1, SEPT9, and EYA4 were significant discriminants between stage I CRC and healthy controls. Combination of TAC1 and SEPT9 rendered 73.1% sensitivity with 92.3% specificity. CONCLUSION: Serum methylation levels of TAC1. SEPT9 and EYA4 may be useful biomarkers for early detection of CRC though a validation study is necessary.

Improvements in end-of-life care with a protocol-based pathway for cancer patients dying in a Singapore hospital.

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.

Activity of thalidomide and capecitabine in patients with advanced hepatocellular carcinoma.

BACKGROUND: Thalidomide has shown modest activity in advanced hepatocellular carcinomas (HCCs). Single-agent capecitabine has also been used in patients with HCC, with objective responses being reported. In our study, we review the use of thalidomide and capecitabine combination in advanced HCC. METHODS: From November 2003 and September 2008, 42 patients with advanced HCC who were not eligible for clinical trial or conventional chemotherapy were treated with oral capecitabine (2000 mg/m/d) for 14 days every 3 weeks and oral thalidomide at the doses of 50 to 200 mg/d. RESULTS: Almost 50% of patients had Child-Pugh B or C liver cirrhosis and a history of regional or systemic therapy. Three patients achieved complete responses lasting more than 52 weeks, including 1 patient who achieved pathological complete response and underwent curative resection. There were 3 patients with partial responses and 13 with stable disease. Median overall survival of all 42 patients was 9.9 months. The median progression-free survival was 5.1 months. The presence of ascites, portal vein thrombosis, and poorer Child-Pugh liver cirrhosis status also resulted in significantly poorer survival outcome. Treatment was well tolerated. Fatigue was the most common side effect occurring in 16 (38%) patients, but only 1 patient had grade 3 toxicity and had to stop treatment. Two other patients developed grade 3 palmar-plantar erythrodysesthesia from capecitabine. CONCLUSIONS: The combination of thalidomide and capecitabine has activity in advanced HCC and can result in complete pathological response. Treatment is well tolerated even in less-fit patients who have been pretreated and deserve further study.