Nicholas J Slevin

Relation of a Hypoxia Metagene Derived from Head and Neck Cancer to Prognosis of Multiple Cancers

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.

Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers

PURPOSE Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. METHODS AND MATERIALS Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at > or = 2 years, Pc, were analyzed by log linear models, and Cox proportional hazard models were used to model the disease-free period. RESULTS T stage, nodal involvement, and site of the tumor were important determinants of the disease-free interval, as was the radiation schedule used. Elongation of the treatment time by 1 day, or a gap of 1 day, was associated with a decrease in Pc of 0.68% per day for Pc = 0.80, with a 95% confidence interval of (0.28, 1.08)%. An increase of 5 days was associated with a 3.5% reduction in Pc from 0.80 to 0.77. At Pc = 0.60 an increase of 5 days was associated with an 7.9% decrease in Pc. The time factor in the Linear Quadratic model, gamma/alpha, was estimated as 0.89 Gy/day, 95% confidence interval (0.35, 1.43) Gy/day. CONCLUSIONS Any gaps (public holidays are the majority) in the treatment schedule have the same deleterious effect on the disease free period as an increase in the prescribed treatment time. For a schedule, where dose and fraction number are specified, any gap in treatment is potentially damaging.

Clinico-pathological and treatment-related factors influencing survival in parotid cancer

SummaryOne hundred and three patients with primary parotid cancer treated surgically at the Christie Hospital, Manchester (1952–1992), were analysed to assess the influence on survival of prognostic and treatment-related factors. Thirty-seven patients were treated by surgery alone (SG), 66 received post-operative radiation (SG+RT). Median follow-up was 12 years, minimum 5 years. The 10-year disease-specific survival rates for stage I, II and III/IV were 96%, 61% and 17% respectively (P < 0.0001). The various histological types segregated into three survival patterns: low-, intermediate-and high-grade with 10-year survival rates of 93%, 41% and 50% respectively (P < 0.0001). On multivariate analysis, the factors influencing risk of cancer death in order of importance were: tumour size > 4 cm (P < 0.001), presence of nodes (P = 0.001), histology of adenoid cystic carcinoma (P = 0.01), high-tumour grade (P = 0.02) and perineural involvement (P = 0.01). Neither the extent of surgery nor the operator influenced outcome. Overall, adjuvant RT significantly reduced locoregional recurrence (SG+RT 15% vs SG 43%; P = 0.002) but not survival, although on subanalysis, there was a trend to improved survival with large cancers and high-grade tumours. Long-term survival is determined primarily by tumour characteristics, namely clinical stage and grade. Post-operative RT contributes significantly to locoregional control and probably confers some survival advantage in high-risk patients.

A systematic review of honey uses and its potential value within oncology care.

AIM To synthesise the evidence regarding honeys role in health care and to identify whether this evidence applies more specifically to cancer care. DESIGN Systematic review. METHODS The inclusion and exclusion criteria were agreed by two reviewers and a keyword strategy was developed. EMBASE, CINAHL, AMED, MEDLINE, COCHRANE and PUBMED databases were screened to identify suitable articles. The citation list from each included study was also screened for potentially suitable papers. The key findings from each study were entered onto a data extraction sheet. RESULTS In total, 43 studies were included in the systematic review, which included studies in relation to wounds (n = 19), burns (n = 11), skin (n = 3), cancer (n = 5) and others (n = 5). In addition, a systematic review regarding honey use in wound care was also included. While the majority of studies noted the efficacy of honey in clinical use, five studies found honey to be equally as effective as the comparator and three found honey to be less effective than the comparator treatment. Other research did not illustrate any significant difference between standard treatment regimes vs. honey treatment. Studies were generally poor in quality because of small sample sizes, lack of randomisation and absence of blinding. CONCLUSIONS Honey was found to be a suitable alternative for wound healing, burns and various skin conditions and to potentially have a role within cancer care. RELEVANCE TO CLINICAL PRACTICE In the cancer setting, honey may be used for radiation-induced mucositis, radiotherapy-induced skin reactions, hand and foot skin reactions in chemotherapy patients and for oral cavity and external surgical wounds.

Radical radiotherapy for carcinoma of the oesophagus: an effective alternative to surgery

BACKGROUND AND PURPOSE Despite advances in operative and postoperative care, long term survival rates following radical oesophagectomy are poor. Surgery remains the mainstay of radical treatment despite various series reporting similar results for treatment with radiotherapy, in particular in the upper third of the oesophagus. We have studied a cohort of patients treated with definitive radiotherapy to examine the influence on survival of changes in diagnostic scanning and radiotherapy computer planning as well as various patient and disease related prognostic factors. PATIENTS AND METHODS From 1985 to 1994, 101 patients with clinically localised carcinoma of the oesophagus were treated at the Christie Hospital with definitive radiotherapy. This included 11 patients with oesophageal adenocarcinoma. Diagnostic and planning techniques changed over the period studied, with increasing use of both diagnostic and radiotherapy planning CT scanning. Radiotherapy doses ranged from 45 to 52.5 Gy in 15 or 16 fractions over 3 weeks. RESULTS The 3- and 5-year survival figures were 27% and 21%, respectively, corrected for intercurrent deaths. Survival was better for adenocarcinoma than squamous cell carcinoma, though not statistically significantly. The only significant prognostic factor (P = 0.01) was the use of diagnostic CT scanning (42% versus 13% 5-year survival with or without diagnostic CT scanning, respectively) which was associated with an increase in field size. Radiotherapy was well tolerated with no acute mortality or significant morbidity. Late stenosis requiring oesophageal was seen in five of 20 patients surviving 3 years or more. CONCLUSIONS Survival following well planned radiotherapy is an effective alternative to surgery for both squamous cell and adenocarcinoma. Advances in staging and three-dimensional planning and the use of multimodality treatment may further improve survival.

Three weeks radiotherapy for T1 glottic cancer: the Christie and Royal Marsden Hospital Experience

BACKGROUND AND PURPOSE Radiotherapy for laryngeal carcinoma is conventionally given over a 6-7-week period. However, in a number of UK centres early lesions are treated over 3 weeks. We review recent results of this policy and discuss the reasons why short treatment times may be advantageous. MATERIALS AND METHODS Two hundred patients (100 from each centre) with T1 glottic invasive squamous cell carcinoma treated with definitive radiotherapy between 1989 and 1997 were analysed. The median age was 68 years. All patients received once daily fractionation, 5 days a week to a total tumour dose of 50.0-52.5 Gy in 16 fractions over 21 days; the fraction size ranged from 3.12 to 3.28 Gy. The median follow-up period was 5 years and 10 months. RESULTS The 5-year local control rates with radiotherapy for the whole group was 93%; there were 14 recurrences of which seven were salvaged by laryngectomy giving an ultimate local control of 96%. The 5-year overall survival was 80% and cause specific survival at 5 years was 97%. Univariate analysis revealed that T1 substaging (P=0.82) and anterior commissure involvement (P=0.47) did not significantly influence local control. A severe late radiation complication was seen in only one patient who continued to smoke heavily after treatment. There were no severe acute complications. CONCLUSIONS Once daily radiotherapy over 3 weeks gives excellent local control in patients with T1 glottic squamous-cell carcinoma and has a low rate of severe complications. The short overall treatment time and large fraction size may be advantageous in radiotherapy of these well-differentiated tumours.

The influence of radiotherapy treatment time on the control of laryngeal cancer: a direct analysis of data from two British Institute of Radiology trials to calculate the lag period and the time factor

This study analyses node-negative laryngeal tumour control data from two clinical trials conducted by the British Institute of Radiology in order to determine the time factors and the presence or absence of a lag period before the time factor takes effect. A direct maximum likelihood approach is used to fit a double-logarithmic model including a repopulation term which commences after an initial lag period, Tk. The analysis yields a time factor of 0.8 Gy per day (95% confidence interval 0.5-1.1 Gy per day) as the extra dose required to counteract the reduction in tumour control probability (TCP) with extension of the treatment time. The latter reduction amounted to between 5 and 12% TCP per week, depending on the stage and time period. With this dataset, where few patients were treated for short times, no statistically significant lag phase can be demonstrated. However, the best estimate of Tk is 21 days (95% confidence interval 0-27 days), which is consistent with estimates from other studies on other datasets. If a lag phase exists, this study would indicate that the duration is less than 27 days. Other studies have used retrospective data and are subject to a number of potential biases. The present study, using data from multicentre prospective randomized clinical trials, is free from some of these sources of bias. The fact that very similar estimates of the radiobiological parameters are obtained lends credence to these other studies and suggests that the potential biases may be small in practice.

Influence of radiotherapy treatment time on control of laryngeal cancer: Comparisons between centres in Manchester, UK and Toronto, Canada

A comparison has been made of the influence of treatment time on tumour control rates for 496 (T2 and T3) larynx cancer cases in Manchester, UK and 1001 (T1-T4) cases in Toronto, Canada. Both series of patients were treated in fairly short overall times, commonly 3 weeks in Manchester and 4-5 weeks in Toronto. All the tumour control data were analysed using the same method to obtain values of fitted dose, fractionation and time parameters. The analysis showed the following. (a) Differences between the total combined (T2 + T3) data sets from the two centres, fitted using direct analysis and the LQ model incorporating a parameter for overall treatment time, were not significant (p = 0.17) and close similarity in control rates was observed using treatment regimens common to both series. (b) The Manchester series over 9-41 days and the Toronto series over 14-84 days are both consistent in showing for (T2 + T3) tumours the presence of a mean time factor of 0.6-0.8 Gy/day required to abrogate the decrease in tumour control concomitant with an increase in overall treatment time from the minimum the maximum employed in each series. (c) When a parameter was included in the model to test for the possible presence of a lag period before the time factor became operative, the lag was not significant for the Toronto data, in contrast to a significant lag for the Manchester data alone (T2 + T3 data).(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitivity to radiation-induced chromosome damage may be a marker of genetic predisposition in young head and neck cancer patients.

We previously showed that levels of chromosome damage induced by ionizing radiation were, on average, higher in G2and G0lymphocytes of breast cancer patients than of normal healthy controls, but that there was no correlation between the results in the two assays. We proposed that enhanced sensitivity to G2or G0irradiation was a marker of low-penetrance predisposition to breast cancer, and have recently demonstrated heritability of sensitivity in families of breast cancer cases. We have now applied these assays to patients with head and neck cancers, for whom there is epidemiological evidence of inherited predisposition in addition to environmental causes. The mean frequency of radiation-induced G2aberrations was higher in the 42 patients than in 27 normal controls, but not significantly so. However, cases less than 45 years old were significantly more sensitive than normals of the same age range (P = 0.046), whereas there was no difference between patients and normals of less than 45 years. Also, there was an inverse correlation between G2sensitivity and age for patients but not for normals. Radiation-induced micronuclei in G0cells were more frequent in 49 patients than in 31 normals (P = 0.056) but, as with the G2assay, the greatest difference was seen between early-onset patients and young normals. Again there was an inverse correlation with age for patients but not for normals. Six patients with enhanced toxicity to radiotherapy were G2tested and four other such patients were G0tested; levels of chromosome damage were not significantly greater than in patients with normal reactions. Both assays were used on 64 individuals (39 patients, 25 normals) and there was no significant correlation between the results. We suggest that a proportion of early-onset head and neck cancer patients are genetically predisposed and that each of the two assays detects a different subset of these cases.

Perfusion estimated with rapid dynamic contrast-enhanced magnetic resonance imaging correlates inversely with vascular endothelial growth factor expression and pimonidazole staining in head-and-neck cancer: A pilot study

PURPOSE To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples taken during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined. RESULTS Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining (r = -0.79, p = 0.03) and VEGF expression (r = -0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia (r = -0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF (r = 0.82, p = 0.02). CONCLUSIONS Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression.