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Colorectal cancer (CRC) commonly metastasises to the liver and is a leading cause of cancer-related death. The FOXFIRE trial compared the safety and efficacy of radiosensitising chemotherapy (OxMdG: oxaliplatin, 5-fluorouracil and folic acid) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited) to OxMdG alone as first-line management for liver-dominant metastatic CRC. In patients downsized to potentially-curative hepatic resection, we explored survival, safety, and histopathological findings.

Background Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival. Methods FOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global). Findings Between Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group. Interpretation Addition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.

Charles Dearman,1 Esme J Hill,1 Jamie M Franklin,1 Greg P Sadler,2 Lai Mun Wang,3 Michael A Silva,3 Ricky A Sharma41Department of Oncology, 2Department of Endocrine Surgery, 3Department of Histopathology and Hepatobiliary Surgery, 4CRUKMRC Oxford Institute for Radiation Oncology, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, University of Oxford, Oxford, UK Abstract: The routine use of 18F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography scans for staging and assessment of treatment response for cancer has resulted in a large number of thyroid abnormalities being detected as incidental findings (“incidentalomas”). Since most PET/CT scans are performed in the setting of a known nonthyroid malignancy, the need for “incidentalomas” to be further investigated and managed depends on the stage, prognosis, and current treatment plan for the known malignancy. We present a case describing the management of an incidental F-fluorodeoxyglucose-avid thyroid nodule detected in a patient with known metastatic colorectal cancer. On the basis of this case, we discuss the management of incidental PET-detected thyroid nodules in patients with metastatic cancer. Thyroid “incidentalomas” must be seen in the context of the prognosis and treatment plan for the known malignancy.Keywords: cancer, imaging, metastasis, morbidity, surgery, PET

In survival analyses, competing risks are encountered where the subjects under study are at risk for more than one mutually exclusive failure event [1]. Competing risks are often analysed using either cause-specific or subdistribution (cumulative incidence) proportional hazards models. Cause-specific hazards model the rate of occurrence of an event, whereas subdistribution hazards model the risk of failure of a specific event. Results of competing risks analyses are being presented more frequently in the medical literature, but the difference in the interpretation of various estimates, compared to standard Cox hazard ratios, is rarely considered.

The cellular genome is constantly subject to DNA damage caused by endogenous factors or exogenously by damaging agents such as ionizing radiation or various anticancer agents. The base excision repair (BER) enzyme, DNA polymerase β, and the polymerases involved in translesion synthesis (TLS) have been shown to contribute to cellular tolerance and repair of DNA lesions by anticancer treatments, particularly the platinum cytotoxic drugs. Moreover, there is robust preclinical evidence linking alterations in DNA pol β and TLS polymerase levels to cancer. DNA polymerases may therefore be potential targets to increase the sensitivity of cancer cells to chemotherapy drugs. In this article, the physical and chemical properties of DNA polymerase β and the translesion synthesis polymerases are reviewed with a view to identifying how they may act as targets for anticancer treatment. The potential clinical role of new DNA polymerase inhibitors is discussed and how they may be combined with conventional cytotoxic agents. © 2012 Bentham Science Publishers.

The cellular genome is constantly subject to DNA damage caused by endogenous factors or exogenously by damaging agents such as ionizing radiation or various anticancer agents. The base excision repair (BER) enzyme, DNA polymerase β, and the polymerases involved in translesion synthesis (TLS) have been shown to contribute to cellular tolerance and repair of DNA lesions by anticancer treatments, particularly the platinum cytotoxic drugs. Moreover, there is robust preclinical evidence linking alterations in DNA pol β and TLS polymerase levels to cancer. DNA polymerases may therefore be potential targets to increase the sensitivity of cancer cells to chemotherapy drugs. In this article, the physical and chemical properties of DNA polymerase β and the translesion synthesis polymerases are reviewed with a view to identifying how they may act as targets for anticancer treatment. The potential clinical role of new DNA polymerase inhibitors is discussed and how they may be combined with conventional cytotoxic agents.

AIM: To facilitate implementation of National Institute for Health and Clinical Excellence (NICE) guidelines for urgent colorectal cancer referral, local cancer networks have promoted the use of standardized proformas in primary care. This clinical audit assessed use of the proforma within the Thames Valley Cancer Network (TVCN) to see whether increased proforma use was associated with higher compliance to NICE guidelines and higher cancer detection rates. METHOD: All 2-week wait referrals for lower bowel cancer to the six Acute NHS Trusts in the TVCN received during the month of June 2010 were identified, anonymized and analysed in relation to colorectal cancer detection rates. RESULTS: Of the 586 referrals audited, proforma usage varied significantly across the six Acute NHS Trusts from 18% to 96%. Referral letters from primary care had NICE compliance ranging from 30 to 50%. In those which received a referral protocol, 50-90% were NICE compliant. Proforma use was associated with higher cancer detection rates (P = 0.03). CONCLUSION: These results have wide-ranging implications since they suggest that the adoption of a simple proforma in primary care can improve the effectiveness of referral for suspected cancer.

Background Knowledge that liver tumours preferentially take their blood supply from the arterial blood supply rather than the portal venous system can be used for local delivery of treatment or for embolisation to cut off the blood supply to tumours. Aims To present histological evaluation of malignant and non-malignant hepatic tissue of one such therapy, selective internal radiation therapy (SIRT) with yttrium-90 microspheres, to decipher its principal mechanism of action. Methods The H&E stained sections of hepatic resection specimens from three patients with liver metastases from colorectal (CRC) cancer, who underwent hepatic surgery 4–9 months following SIRT, were examined and the pathological changes documented. Results Resin microspheres were identified in the vascular tumour bed and vessels within the portal tracts of the background liver parenchyma. Microspheres were usually associated with giant cell reaction or histiocytes. In the tumour bed, tumour necrosis, mucinous alteration, collections of foamy histiocytes, ectatic vessels, calcification and fibrosis were observed. There was minimal cellular inflammatory response observed, suggestive of direct radiation injury as a non-immune mediated process. Conclusions We describe in detail the spectrum of histopathological changes in malignant tissue and liver parenchyma in patients with metastatic CRC treated with SIRT. Our findings are consistent with the hypothesis that the principal mechanism of action of SIRT appears to be via arterially directed delivery of highly radioactive microspheres in and around the vascular tumour bed rather than by micro-arterial embolisation.

Objective: Estimation of total phenol, flavonoid and antioxidant activity of various plant parts (leaves, stem, root, flower and fruit) of Ailanthus excelsa Roxb. methanolic extracts.Methods: Different plant parts were extracted with methanol, then the total phenol content was calculated by using Folin–Ciocalteu reagent, total flavonoid content was estimated by using Aluminum Chloride Colorimetric Method and the antioxidant activity was measured by DPPH (1,1-diphenyl-2-picrylhydrazyl radical) assay.Results: The highest total phenolic content (48.38 mg GAE/gdw) was observed in flower and lowest phenolic content in root (28.56 mg GAE/gdw). The highest total flavonoidal content (21.5 mg QE/gdw) was found in leaf and lowest in root (1.11 mg QE/gdw). The highest radical scavenging activity was found in flower extracts with the IC50 value of 36.85 µg/ml and the lowest scavenging activity was observed in root extract that was found to be 1493.46µg/ml.Conclusion: According to the results of present investigation the plant showed significant antioxidant activity that can be used for medical purpose for the treatment of various diseases.Keywords: Antioxidant activity, Ailanthus excelsa Roxb., Total phenolic content, Total flavonoid content, DPPH (2, 2- diphenyl- 1- picryl hydrazyl), Scavenging activity.