Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.

/pdf/targeting-cancer-metabolism-a-therapeutic-window-opens-4eayk4wjss.pdf

Targeting cancer metabolism: a therapeutic window opens

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m−2, day 1; folinic acid, 200 mg m−2; and 5-fluorouracil: as a 400 mg m−2 bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m−2, from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.

/pdf/final-analysis-of-colorectal-cancer-patients-treated-with-11j15gdmnf.pdf

Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases

Colorectal cancer (CRC) caused over 500 000 deaths worldwide in 2002. Recent advances in the treatment of advanced disease include the incorporation of two new cytotoxic agents, irinotecan and oxaliplatin, into first-line regimens. The concept of planned sequential therapy involving three active agents during the course of a patient's treatment is evolving. Coupled with the integrated use of targeted monoclonal antibodies, we can now expect overall survival rates for advanced disease to exceed 20 months. This review considers current treatments and suggests where future progress may occur.

/pdf/management-of-advanced-colorectal-cancer-state-of-the-art-2y51jj8wgm.pdf

Management of advanced colorectal cancer: state of the art.

The CpG island methylator phenotype (CIMP+) of colorectal cancer (CRC) occurs predominantly in the proximal colon and is characterized by frequent hypermethylation of gene promoter regions. In this review, we present evidence suggesting CIMP+ represents the subgroup of colon cancers that are responsive to 5-fluorouracil (5-FU)-based treatments. CIMP+ has been associated with survival benefit from 5-FU in a clinical study of CRC, with additional evidence coming from studies on gastric cancer and tumor cell lines. Elevated concentrations of 5-10-methylene tetrahydrofolate (CH2FH4) occur in CIMP+ tumors and are probably due to low expression levels for γ-glutamyl hydrolase (GGH). Clinical and in vitro work has previously shown that high CH2FH4 and low GGH expression levels correlate with good response to 5-FU. Methylation-induced silencing of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU degradation, may also provide a link between CIMP+ and good response to 5-FU. The CIMP+-related phenotype referred to as microsatellite instability (MSI+) has been widely investigated as a predictive marker of response to 5-FU, with contradictory results. The interpretation of these studies is likely to be confounded by the fact that some MSI+ tumors occur in the background of CIMP+, but a significant proportion of others do not. Further studies on tumors from randomized clinical trials are required to confirm the value of CIMP+ and associated molecular features for the prediction of clinical outcome to 5-FU-based chemotherapy.

/pdf/predicting-clinical-outcome-of-5-fluorouracil-based-2ocb5q11l8.pdf

Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup?

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20 mg m−2, respectively) (n=59) or the daily × 5 Mayo Clinic schedule (425 and 20 mg m−2, respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79–1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71–1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred.

/pdf/a-meta-analysis-of-two-randomised-trials-of-early-2lp4vhs4q5.pdf

A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer

7233 Background: Several groups are assessing the feasibility of increasing the radiobiological impact of 3-D radiation for NSCLC by using high dose per fraction dose escalation. We report the most mature data of any trial using 3Gy /fraction (72 Gy/24 fractions). Methods: 30 pts with NSCLC with KPS>70% and wt loss =25 Gy (V25) and the max. dose to the cord was < 61%. No oesophageal dose limits were used. Results: 8 CR and 11 PR in 27 evaluable pts. Median time to local progression, progression and survival: 18.6, 17.3 and 12.6 months. No grade-4 acute toxicity occurred. 2 pts had grade-3 acute oesophageal toxicity and 1 pt a grade 3 acute lung toxicity. 26 pts were evaluable for long-term toxicity (median follow-up 9.5 months). Late grade-1 lung toxicity occurred in 5 pts. Late oesophageal toxicity was clinically...

Intensity modulated radiation therapy (IMRT) may reduce the oesophageal toxicity of hypofractionated accelerated 3-D radiation for non small cell lung carcinoma

7527 Background: Dose escalation and RT intensification may improve local control in NSCLC but may potentially increase late toxicity. We postulated that accelerated hypofractionated RT is safe and...

Hypofractionated accelerated high-dose radiotherapy (RT) in non-small cell lung cancer (NSCLC)

Rationale: The HFSA 2019 nutrition consensus statement recommends “All patients with HF should be offered at least 1 evaluation and counselling session as an outpatient or inpatient from a Registered Dietitian Nutritionist (RDN)”. This audit aims to compare the current services in an Irish tertiary hospital Heart Failure (HF) Service to this consensus statement. 

A Retrospective Audit Of Dietetic Services Within An Irish Tertiary Hospital Heart Failure Service, In Comparison To The Heart Failure Society Of America (Hfsa) 2019 Nutrition Consensus Statement.

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Intensity modulated radiation therapy (IMRT) may reduce the oesophageal toxicity of hypofractionated accelerated 3-D radiation for non small cell lung carcinoma

Hypofractionated accelerated high-dose radiotherapy (RT) in non-small cell lung cancer (NSCLC)

A Retrospective Audit Of Dietetic Services Within An Irish Tertiary Hospital Heart Failure Service, In Comparison To The Heart Failure Society Of America (Hfsa) 2019 Nutrition Consensus Statement.