Recent progress and clinical importance on pharmacogenetics in cancer therapy.

Recent advances have provided unprecedented opportunities to identify prognostic and predictive markers of efficacy of cancer therapy. Genetic markers can be used to exclude patients who will not benefit from therapy, exclude patients at high risk of severe toxicity and adjust dosing. Genomic approaches for marker discovery now include genome-wide association studies and tumor DNA sequencing. The challenge is now to select markers for which there is enough evidence to transition them to the clinic. The hurdles include the inherent low frequency of many of these markers, the lengthy validation process through trials, as well as legislative and economic hurdles. Attempts to answer questions about certain markers more quickly have led to an increased popularity of trials with enrichment design, especially in light of the dramatic phase I results seen in recent months. Personalized medicine in oncology is a step closer to reality.

Longitudinal monitoring reveals dynamic changes in circulating tumor cells (CTCs) and CTC-associated miRNAs in response to chemotherapy in metastatic colorectal cancer patients.

We evaluated the changes in CTC count and CTC-associated miRNAs during the course of chemotherapy in patients with metastatic colorectal cancer. Blood samples were collected from 9 metastatic colorectal cancer patients prior to chemotherapy and at every other chemotherapy session during the course of treatment. CTCs were isolated and enumerated using a size-exclusion method (CellSievo, Singapore). CTC-associated miRNAs were isolated using a paper-based, partitioning method, and analyzed using reverse transcription quantitative real-time PCR (MiRXES, Singapore). CTC count trends generally correlated with disease progression defined by radiological measurements and trends in carcinoembryonic antigen (CEA) levels; hence CTC counts may be useful in cases where CEA is not elevated. CTC-associated miRNAs identified were miR-15b, miR-16, miR-19a, miR-21, miR-25, miR-30d, miR-126, miR-185, miR-221, miR-222, and miR-324-5p. The expression of CTC-associated miRNAs did not appear to correlate with CTC count and exhibited inter-individual heterogeneity. This pilot study suggests that analysis of CTC changes during the course of treatment may be useful in monitoring response to therapy in metastatic colorectal cancer.

Conversion Surgery Post-Intraperitoneal Paclitaxel and Systemic Chemotherapy for Gastric Cancer Carcinomatosis Peritonei. Are We Ready?

Peritoneal metastasis is common in gastric cancer. It is difficult to treat and carries a poor prognosis. Intraperitoneal (IP) delivery of chemotherapy can attain a higher drug exposure in the peritoneal cavity but with reduced systemic toxicity. Therefore, we hypothesized that IP paclitaxel with systemic chemotherapy would be clinically beneficial for gastric cancer with peritoneal metastases. Patients with unresectable and/or recurrent gastric adenocarcinoma with peritoneal dissemination and/or positive peritoneal washing cytology were recruited. They underwent eight cycles of IP paclitaxel and systemic XELOX. The primary endpoint was 1-year overall survival rate and secondary endpoints were safety, response rate, and peritoneal cytological response. Patients who subsequently had no distant metastases and two consecutive negative peritoneal cytologies underwent conversion gastrectomy if there was no macroscopic evidence of peritoneal disease at diagnostic laparoscopy. Twenty-two patients were enrolled, receiving at least one cycle of IP paclitaxel at the time of reporting (data cutoff-March 11, 2016). The median number of cycles was 7.5. The median overall survival was 18.8 months, and the 1-year survival rate was 72.2%. One patient died of neutropenic sepsis. Of 19 evaluable patients with measurable disease, 7 (36.8%) achieved PR, 8 (42.1%) achieved SD, and 4 (21.1%) experienced PD. Peritoneal cytology turned negative in 11 of 17 (64.7%) patients. Six patients underwent conversion gastrectomy (4 R0, 2 R1) with a median survival of 21.6 months (range = 8.7-29.9 months). XELOX and IP paclitaxel appears to be an effective regimen in gastric cancer with peritoneal metastases. Conversion gastrectomy may be considered in patients with a favorable response.

Improving Wait Times for Elective Chemotherapy Through Pre-Preparation: A Quality-Improvement Project at the National University Cancer Institute of Singapore.

PURPOSE: Cancer treatment occurs predominantly in the outpatient setting. Long wait times for chemotherapy lead to increased dissatisfaction, inefficient use of chemotherapy chairs, and compromised safety when delays result in treatment beyond operation hours. For patients who have undergone review with the necessary investigations by their oncologists on a prior day, a long wait time is more frustrating, because the sole purpose of their visit is for chemotherapy (termed elective chemotherapy). PATIENTS AND METHODS: From February 2013 to September 2013, we conducted a clinical practice improvement program project to reduce wait times for elective chemotherapy and identified late submission of prescriptions, long drug preparation time, and pharmacy review of prescriptions as the main causes of delay in our center. We formulated a workflow to pre-prepare selected chemotherapy up to 1 day before appointments. Selection was based on shelf life, cost, recyclability, and need for premedication. Patients were triaged by telephone before their appointment before pre-preparation. Participation was voluntary, with patients required to consent for liability for cost in event of wastage. RESULTS: Average wait time for chemotherapy was significantly improved by 66% from 65.7 (median, 60; range, 5 to 301) to 22.4 minutes (median, 20; range, 0 to 80 minutes; P < .001). There were no wastages during this period, and treatment for elective patients could start as soon as the center opened if their drugs were pre-prepared the day before. CONCLUSION: Pre-preparation of chemotherapy, together with effective phone triaging, is an effective way to reduce chemotherapy wait time.

Targeted therapy at the end of life in advanced cancer patients.

OBJECTIVE: We describe the use of systemic therapy in advanced cancer patients admitted to an acute care hospital, with a focus on targeted therapy. We aim to spotlight the utilization of targeted agents in the last months of life. METHODS: Adult patients (N=252) with advanced solid tumors who died as inpatients in the National University Hospital, Singapore, were included in this retrospective study. Patients' demographic and clinical data were extracted from hospital records. Information on systemic therapy was extracted from the time of diagnosis and all other data limited to the last three months before death. RESULTS: 187 adult patients received palliative systemic therapy from the time of diagnosis, of which 125 (66.8%) received it within three months of death. Of patients receiving only nontargeted systemic treatment (n=106), 60 (56.6%) and 26 (24.5%) received it within three months and one month of death respectively. Comparatively, 81 patients received palliative targeted systemic therapy, of which 65 (80.3%) and 40 (49.4%) had treatment within three months and one month of death respectively (p=0.001 and p<0.001). Targeted therapy was first initiated in the last three months of life in 38 patients. Oral agents targeting epidermal growth factor receptor (lung cancer patients) and vascular endothelial growth factor receptor (non-lung cancer patients) pathways were commonly employed. Lung cancer patients were more likely to have targeted therapy as their last line of systemic therapy: 26/54 lung cancer patients compared with 29/133 non-lung cancer patients (48.1% versus 21.8%, p<0.001). CONCLUSIONS: Targeted therapy is used in more than half of patients who received systemic therapy within three months of death. The degree to which these agents are being utilized near the end of life suggests the need to reexamine the risk/benefit profile of targeted therapy for this population, and the decision-making process around their use.