Validation of an updated evidence-based protocol for proactive gastrostomy tube insertion in patients with head and neck cancer.

BACKGROUND/OBJECTIVES: Evidence-based practice guidelines are available to assist in the decision making for nutrition interventions in patients with head and neck cancer. Re-assessment of guideline recommendations is important with changing demographics, new treatment regimens, advancing radiotherapy techniques, such as helical intensity-modulated radiotherapy, and the emergence of new literature. The aim of this study was to validate the updated high-risk category definition in our local hospital protocol for the swallowing and nutrition management of patients with head and neck cancer to determine the ongoing predictive ability for identifying proactive gastrostomy requirement in a new cohort. SUBJECTS/METHODS: Patients attending a major tertiary hospital for head and neck cancer treatment from 2010 to 2011 were included (n=270). Data were collected on patient demographics (age and gender), clinical factors (tumour site, staging and treatment), nutrition outcome measures (weight, enteral feeding) and protocol adherence. Sensitivity and specificity were calculated and compared with the original validation study. RESULTS: Proactive gastrostomy tubes were inserted in 86 patients. Overall protocol adherence was 93%. Sensitivity improved to 72% (increase of 18%) and specificity improved to 96% (increase of 3%) compared with the original validation study where patients received three-dimensional (3-D) conformal radiotherapy. CONCLUSIONS: The results of this study confirm that the updated high-risk category in the protocol for the swallowing and nutrition management of patients with head and neck cancer remains valid to predict proactive gastrostomy in a mixed population receiving helical intensity-modulated radiotherapy and 3-D conformal radiotherapy. The protocol has an improved sensitivity and specificity and hence remains just as relevant for advanced techniques of radiation treatment delivery.

New radiotherapy techniques do not reduce the need for nutrition intervention in patients with head and neck cancer.

BACKGROUND/OBJECTIVES: Since 2007, our institution has used validated guidelines for the insertion of proactive gastrostomy feeding tubes in patients with head and neck cancer. Helical intensity-modulated radiotherapy (H-IMRT) delivered by Tomotherapy, is an advanced radiotherapy technique introduced at our centre in 2010. This form of therapy reduces long-term treatment-related toxicity to normal tissues. The aim of this study is to compare weight change and need for tube feeding following H-IMRT (n=53) with patients that would have previously been treated with three-dimensional conformal radiotherapy (n=134). SUBJECTS/METHODS: Patients with head and neck cancer assessed as high nutritional risk with recommendation for proactive gastrostomy were identified from cohorts from 2007 to 2008 and 2010 to 2011. Retrospective data were collected on clinical factors, weight change from baseline to completion of treatment, incidence of severe weight loss (⩾ 10%) and tube feeding. Statistical analyses to compare outcomes between the two treatments included χ(2)-test, Fisher's exact and two-sample Wilcoxon tests (P<0.05). RESULTS: The H-IMRT cohort had higher proportions of patients with definitive chemoradiotherapy (P=0.032) and more advanced N stage (P<0.001). Nutrition outcomes were not significantly different between H-IMRT and conformal radiotherapy, respectively: need for proactive gastrostomy (n=49, 92% versus n=115, 86%, P=0.213), median percentage weight change (-7.2% versus -7.3%, P=0.573) and severe weight loss incidence (28% versus 27%, P=0.843). CONCLUSIONS: Both groups had median weight loss >5% and high incidences of tube feeding and severe weight loss. Nutrition intervention remains critical in this patient population, despite advances in radiotherapy techniques, and no changes to current management are recommended.

The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment.

FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that γH2AX foci, indicative of DNA double-strand breaks (DSBs), accumulate in a time-dependent manner in the drug-sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and DSB repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and γH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and γ-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines harbouring an integrated direct repeat green fluorescent protein reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin-immunoprecipitation assay. In agreement, depletion of FOXM1 expression by small interfering RNA downregulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin-resistant MCF-7 Epi(R) cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance.

Quantification of intra-tumour cell proliferation heterogeneity using imaging descriptors of 18F fluorothymidine-positron emission tomography.

Intra-tumour heterogeneity is a characteristic shared by all cancers. We explored the use of texture variables derived from images of [(18)F]fluorothymidine-positron emission tomography (FLT-PET), thus notionally assessing the heterogeneity of proliferation in individual tumours. Our aims were to study the range of textural feature values across tissue types, verify the repeatability of these image descriptors and further, to explore associations with clinical response to chemotherapy in breast cancer patients. The repeatability of 28 textural descriptors was assessed in patients who had two FLT-PET scans prior to therapy using relative differences and the intra-class correlation coefficient (ICC). We tested associations between features at baseline and clinical response measured in 11 patients after three cycles of chemotherapy, and explored changes in FLT-PET at one week after the start of therapy. A subset of eight features was characterized by low variations at baseline (<±30%) and high repeatability (0.7 ≤ ICC ≤ 1). The intensity distribution profile suggested fewer highly proliferating cells in lesions of non-responders compared to responders at baseline. A true increase in CV and homogeneity was measured in four out of six responders one week after the start of therapy. A number of textural features derived from FLT-PET are altered following chemotherapy in breast cancer, and should be evaluated in larger clinical trials for clinical relevance.

Positron emission tomography imaging of cell proliferation in oncology.

Tumour-cell proliferation is a hallmark of the malignant phenotype. Positron emission tomography (PET) offers a unique method of imaging biological and biochemical changes in vivo. Radiolabelled thymidine and thymidine analogues are currently in development as PET tracers. By studying the uptake and kinetics of such compounds using PET, a measure of DNA synthesis and hence cell proliferation can be obtained. Molecular imaging of cellular proliferation with PET is now possible, and has the potential to play an important role in the evaluation of efficacy of new anti-cancer agents.