Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer.

Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation. Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ). Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70). Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).

Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: A TransPORTEC initiative.

BACKGROUND: The morphological classification of high-risk endometrial cancer is of limited prognostic value. Recent attempts to stratify tumours according to molecular signatures have shown considerable promise. Here we attempted to further refine molecular classifications using markers of the p53 pathway. METHODS: We analysed the expression of p53 as well as three downstream markers of the p53 pathway, p21, mdm2 and phospho-p63 (pp63), by immunohistochemistry in a series of 114 endometrial cancers (86 endometrioid, 28 non-endometrioid subtype) with high-risk features (such as high tumour grade and deep myometrial invasion) and correlated results with clinical outcome. The Cancer Genome Atlas (TCGA) data were used to analyse TP63 mutations and copy-number alterations using cBioPortal. TP53 was silenced in two endometrial cancer cell lines to study its effect on p21 and p63. RESULTS: About half of the tumours showed a p53 mutant phenotype and there was a strong negative correlation with p21 expression. Being marker positive for pp63 or mdm2 was associated with a significantly increased likelihood of dying, [hazard ratios 5.93 (95% CI 2.37-7.27) and 7.48 (95% CI 3.04-9.39), respectively]. These findings were seen in both p53 wildtype and p53 mutant tumours. Only 11% of TCGA endometrial cancers had a functional TP63 alteration. Upon silencing of TP53, p21 expression was decreased in one cell line, but no effects on p63 were observed. CONCLUSION: Markers of the p53 pathway improve stratification of endometrial cancers and provide novel insights into the role of this pathway in the disease.

Conformal and intensity-modulated radiotherapy for cervical cancer.

Three-dimensional radiotherapy planning techniques, including conformal radiotherapy and intensity-modulated radiotherapy, have potential for improving outcomes in cervical cancer. Accurate target volume definition is essential in order to maximise normal tissue sparing while minimising the risk of a geographical miss. This reduction in toxicity provides the option of dose escalation, particularly with simultaneous integrated boost intensity-modulated radiotherapy. The evidence for the current use and potential applications of these techniques in the treatment of cervical cancer are discussed.

An atlas of the pelvic lymph node regions to aid radiotherapy target volume definition.

AIMS: The implementation of advanced three-dimensional radiotherapy planning techniques requires accurate target volume localisation. We have previously developed guidelines to aid definition of the pelvic lymph node regions, and the aim of this study was to produce a CT atlas. MATERIALS AND METHODS: The guidelines were applied to a CT scan of a patient to receive adjuvant radiotherapy. RESULTS: Reference CT images of the pelvis were generated, illustrating the nodal regions and a typical target volume for adjuvant pelvic radiotherapy for gynaecological cancer. CONCLUSION: These images can be used as an aid for target volume definition of the pelvic nodal regions.

Human tumor blood flow is enhanced by nicotinamide and carbogen breathing.

Perfusion insufficiency and the resultant hypoxia are recognized as important mechanisms of resistance to anticancer therapy. Modification of the tumor microenvironment to increase perfusion and oxygenation of tumors may improve on the efficacy of these treatments. Using laser Doppler probes to measure microregional RBC flux, this study examines the influence of nicotinamide and carbogen on human tumor perfusion. Ten patients with advanced cancers were studied. Nicotinamide (80 mg/kg) was given p.o., and 60 min later, up to six probes were inserted into the tumor. Readings were taken for 1 h, followed by 10 min of carbogen breathing and 10 additional min of breathing room air. Results were compared with those from a similar group of eight control patients who were not given nicotinamide, but who breathed carbogen. In 44 microregions analyzed, 33 (73%) showed perfusion fluctuations of 50% or more, and 20 (44%) by 100% or more. This compared with the control group in whom 62% and 27% of microregions varied by 50% or more and 100% or more, respectively. Perfusion increases outweighed decreases by 30% with nicotinamide and 20% in the controls. On breathing carbogen, patients pretreated with nicotinamide showed an increase in tumor perfusion of 17% at 5 min and 22% at 10 min, compared with only 0% and 1% in the control group. Pretreatment with nicotinamide made little difference to the random blood flow fluctuations seen in controls. However, when carbogen was introduced, tumor perfusion increased compared with the control group. This may have important therapeutic implications by improving response to treatment and allowing better delivery of systemically administered agents.

Continuous hyperfractionated accelerated radiotherapy (CHART) in localized cancer of the esophagus.

PURPOSE: To assess the efficacy and toxicity of continuous hyperfractionated accelerated radiotherapy (CHART) in locoregional control compared with a historical group of patients treated with conventionally fractionated radical radiotherapy. METHODS AND MATERIALS: Between 1985 and 1994, 54 patients with localized esophageal cancer were treated with CHART. Twenty-eight patients received CHART alone (54 Gy in 36 fractions over 12 consecutive days) and 15 were given intravenous mitomycin C and cisplatin on days 10 and 13, respectively. Eleven patients received 40.5 Gy in 27 fractions over 9 days, followed by a single high-dose-rate intraluminal brachytherapy insertion of 15 Gy at 1 cm. RESULTS: Acute toxicity was well tolerated and dysphagia was improved in 35 patients (65%), with 28 (52%) eating a normal diet by week 12. This compares with an improvement in dysphagia score in 72% of the conventionally treated group. The median duration of relief of dysphagia was 7.8 months (range 0-41.4) in the CHART group compared with 5.5 months (range 0-48) in the controls. Strictures developed in 29 patients (61%) and 18 were confirmed on biopsy to be due to recurrent disease. Median survival was 12 months (range 0.5-112) in the CHART group and 15 months (range 3.6-56) in the control patients. CONCLUSION: CHART is well tolerated and achieves a high rate of local control. Palliation in the short overall treatment time of esophageal cancer is an advantage in these patients whose median survival is only 12 months.

The response of human tumors to carbogen breathing, monitored by Gradient-Recalled Echo Magnetic Resonance Imaging.

PURPOSE: Gradient-Recalled Echo (GRE) Magnetic Resonance Imaging (MRI), which detects changes in blood vessel deoxyhaemoglobin content, has been investigated as a noninvasive monitor of changes in human tumor oxygenation and blood flow, in response to carbogen (95% O2, 5% CO2) breathing. METHODS AND MATERIALS: GRE images (TE = 60 ms, TR = 200 ms, alpha = 40 degrees, 256[2] matrix) were acquired from 31 patients with primary and metastatic disease, prior to and during carbogen breathing. Three patients underwent a follow-up examination after radiotherapy. RESULTS: Seventeen out of 34 tumors showed enhanced image intensity, consistent with an improvement in tumor oxygenation and blood flow, while 11 showed no response; 6 studies were technical failures. In one patient a metastatic node that had eluded orthodox investigation was visualized. A reduction in response was observed in the three patients studied postradiotherapy. CONCLUSION: This method, which can be performed on a standard clinical MRI instrument, provides a noninvasive measurement of tumor response to oxygenation/blood flow modification. In principle, this should enable the clinician to optimize treatment protocols, such as carbogen breathing, for individual radiotherapy patients.

Effect of carbogen breathing on tumour microregional blood flow in humans.

BACKGROUND AND PURPOSE: Carbogen is currently being re-evaluated as a radiosensitiser. It acts primarily by increasing tissue pO2, although there is evidence to suggest that enhanced tumour blood flow may also be a component of its action. MATERIALS AND METHODS: Ten tumours in eight patients with advanced malignant disease were studied. Up to six microprobes, each with an estimated sampling volume of 10(-2) mm3, were inserted into the tumours. Ten min of baseline readings were taken prior to a 10 min carbogen (95% O2/5% CO2) breathing period, measurements were continued for a further 10 min. RESULTS: The results show that in 34 microregions analysed no overall change in tumour perfusion was seen with carbogen breathing. Individual tumour analysis demonstrated variation in response between patients to carbogen-after 6 min of carbogen four tumours showed an increase in blood flow by more than 10% of the pre-breathing value, two a decrease and four no change. The magnitude of change was small, with only two tumours fluctuating by more than 25%. CONCLUSIONS: These findings confirm the presence of transient fluctuations in microregional blood flow in human tumours but suggest that the radiosensitising action of carbogen lies primarily in its effect on increasing the oxygen capacity of blood. This supports the addition of agents such as nicotinamide with carbogen in order to overcome both diffusion and perfusion limited hypoxia.

Improvement in human tumour oxygenation with carbogen of varying carbon dioxide concentrations.

BACKGROUND AND PURPOSE: Carbogen (95%O2, 5%CO2) is being used in clinical trials as a hypoxic radiosensitiser. Tolerance to carbogen can be a problem, this study compares tumour oxygenation during inhalation of hyperoxic gas containing either 2% or 5% CO2. MATERIALS AND METHODS: Tumour pO2 was measured in 16 patients using the Eppendorf pO2 histograph. RESULTS: After breathing gas containing either 5% or 2% CO2 an increase in median pO2 was measured in every tumour, the frequency of low pO2 values ( < or = 10 mmHg) fell from 47% to 29% in the 5% group and from 55% to 17% in the 2% group. CONCLUSIONS: This study confirms that breathing 2% CO2 and 98% O2 is well tolerated and effective in increasing tumour oxygenation.

Accelerated radiotherapy, carbogen and nicotinamide (ARCON) in locally advanced head and neck cancer: a feasibility study.

BACKGROUND AND PURPOSE: ARCON (Accelerated Radiotherapy, CarbOgen, Nicotinamide) achieves a large therapeutic gain in rodents. A phase I/II study was therefore undertaken to determine its feasibility in patients with locally advanced head and neck cancer. MATERIALS AND METHODS: The accelerated regime CHART was used in 35 patients given carbogen and/or nicotinamide with 11 small volume fractions. Eight patients received carbogen, 12 received nicotinamide and 15 were treated with ARCON. Treatment compliance, side-effects and acute mucositis were monitored in all cases. RESULTS: All patients underwent CHART as intended. In the 23 patients receiving carbogen, two failed to complete treatment. Compliance with nicotinamide was much lower. Out of 25 patients, only 52% received 10-11 doses of the 80 mg/kg/day of the drug. The most common side-effect was nausea and vomiting, which responded to standard anti-emetics in almost half of the patients. Historical comparisons with the CHART head and neck trials indicate that there was no increase in the severity of acute mucositis in any of these patients. Although the observation period is not sufficiently long to be definitive (median 20 months) there is no evidence of an increase in late normal tissue reactions. CONCLUSIONS: ARCON using CHART as the radiotherapy protocol is feasible in patients with advanced head and neck cancer. However, we are concerned about the low compliance rate in our patients, which is far lower than that reported elsewhere. The implications are discussed together with identifying strategies for increasing compliance.

Atypical stromal hyperplasia of the prostate gland.

Hyperplastic lesions of the prostatic stroma with atypical changes are presented and discussed. One lesion was a leiomyoma with atypical organization and a limited area of nuclear pleomorphism without mitotic figures. One was a lesion which in many portions was histologically indistinguishable from leiomyosarcoma. It, however, had certain features probably connoting less sinister behavior, and at autopsy 16 months after resection there was no evidence of recurrence or metastasis. One lesion histologically resembled fibroadenoma of the female breast. These three lesions occurred in patients more than 50 years who had symptoms and signs of prostatism. Reference is made to two previously reported lesions reminiscent of cystosarcoma phyllodes of the female breast. All the lesions were located in the craniad prostate, which is estrogen-influenced. A parallel is drawn between these atypical changes in prostatic fibromuscular stroma and atypical changes in the connective tissue stroma of the female breast.

Short communication: a technique for delivering carbogen with high dose rate intraluminal brachytherapy in carcinoma of the oesophagus; early results and toxicity.

A technique to deliver carbogen with high dose rate afterloading therapy to the oesophagus is described. Treatment is given using a standard high dose rate (HDR) afterloading catheter which is passed through the tumour-bearing area of the oesophagus within a nasogastric tube. In order to achieve a gas-tight seal, a standard "oxygen" mask used for delivery of carbogen is modified to incorporate the nasogastric tube allowing the treatment catheter to pass through the mask and be connected to the afterloading machine. The technique has proven to be feasible and well tolerated during treatment in four patients treated in this way. Severe acute radiation toxicity, possibly attributable to the carbogen, has been encountered in these patients receiving 1500 cGy at 1 cm via the HDR catheter after 4050 cGy in 27 fractions in 9 days using CHART external beam. Modifications to the radiation scheduling is recommended to enable carbogen to be incorporated in this way.

Dynamic contrast enhanced magnetic resonance scanning as a predictor of response to accelerated radiotherapy for advanced head and neck cancer.

Tumour perfusion has been assessed in patients with advanced head and neck cancer using dynamic contrast enhanced MRI prior to and at completion of accelerated radiotherapy, and related to local tumour control. Sequential MRI scans, at 3 s intervals after intravenous injection of gadolinium using a dynamic scan sequence through a tumour region of interest (ROI), were performed in 13 patients with advanced head and neck cancer before and on completion of radiotherapy. The scans have been analysed in terms of maximum tumour enhancement (E), slope of the enhancement versus time curve and the time taken to reach maximum tumour enhancement (Tmax), and these parameters related to tumour outcome after radiotherapy. Local tumour control was related to the value of E on a post-radiotherapy scan and the difference in Tmax between a pre- and post-radiotherapy scan. Durable local control was seen in those tumours with a post-radiotherapy value for E of less than 8 and a mean fall in Tmax of 27.3 s. These results imply that tumours with diminished tumour perfusion at the end of radiotherapy are those most sensitive to treatment and that those tumours which show greater tumour enhancement after accelerated radiotherapy are likely to fail locally. This may reflect the persistence of viable perfused tumour at completion of radiotherapy.

Surveillance after treatment for well differentiated thyroid cancer: audit for chest radiography.

Well differentiated thyroid carcinoma has an excellent prognosis, with many patients achieving cure. The incidence of pulmonary metastases is about 11%. When thyroid ablation has been used in the initial treatment, serial thyroglobulin (Tg) levels are a sensitive marker of recurrent disease. Data regarding the usefulness of chest radiography (CXR) in monitoring relapse in these patients does not exist and regular CXRs continue to be performed as routine surveillance. To assess their efficacy we have reviewed all serial CXRs and corresponding Tg levels on every patient with well differentiated thyroid cancer who was treated and followed up at the Royal Marsden Hospital between 1984 and 1987. A total of 369 CXRs were performed on 49 patients, with a median follow-up of 81 months. Of these, only 15% were undertaken for a clinical reason, with 85% being requested as routine. Seven patients developed lung deposits, six of whom had CXR performed because of elevated Tg, abnormal 131I uptake imaging or thoracic symptoms. In no case were lung metastases diagnosed by routine CXR in an asymptomatic patient. The cost of routine chest films for the duration of this study was approximately 13,500 pounds. It is concluded that routine chest radiography is neither cost effective nor a sensitive method of screening for relapse in asymptomatic well differentiated thyroid cancer. It should be reserved for patients with chest symptoms, or those in whom Tg has been shown not to be a useful marker of disease.

Coronary artery brachytherapy.

Coronary artery disease is the leading cause of mortality in the West with over 1.2 million angioplasties performed annually. Despite the introduction of stents, restenosis occurs in 30-40% of vessels, which until recently has only been treated effectively by coronary artery bypass surgery. Coronary artery brachytherapy appears to provide an alternative, less invasive remedy. The mechanisms of restenosis and how these are inhibited by radiation are described here. The practicalities of radiation delivery and the history of the development of intravascular radiation as an effective clinical tool are outlined. Finally, the pitfalls of the current technology and the areas in which future research must be targeted for the field to develop are discussed.

Selected options supporting use of the group embedded figures test in modeling achievement in clinical laboratory science programs.

OBJECTIVE: To identify, in light of predicted future shortages of allied-health personnel, student and curricular characteristics of clinical laboratory science (CLS) programs relevant to recruitment and retention at the baccalaureate level. SETTING: Not applicable. PRACTICE DESCRIPTION: Not applicable. PRACTICE INNOVATION: Options for modeling achievement in CLS programs are developed, and designs and procedures for clarifying procedural questions are considered in a context of delivery of instruction for specialized curricula and skill development. Considerable attention is given to the potential for using the Group Embedded Figures Test (GEFT) in modeling, advising, designing curricula, and monitoring quality improvement of programs and graduates. MAIN OUTCOME MEASUREMENT: Not applicable. RESULTS: Supporting evidence is supplied from the literature for options in developing an appropriate model for examining those salient variables known to have linkages to achievement. CONCLUSION: An argument is presented for better understanding of antecedent variables affecting achievement and retention of CLS students. In addition, a case is made for development of an appropriate model examining variables identified in the literature as being linked to achievement. Dynamic models based on these considerations should be developed chronologically from entry through graduation with emphasis on growth at year-end milestones.

First quinquennial review of intensity-modulated radiotherapy at St Bartholomew's Hospital, London.

Intensity-modulated radiotherapy (IMRT) is a relatively new technique of delivering external beam radiotherapy that is becoming increasingly available in the UK. This paper summarises the introduction and initial clinical work in IMRT over the period 2004-2009. Physics aspects of commissioning are described, including the development of a robust method of quality control using a sweeping gap test. Details of the organisational changes necessary to introduce IMRT are given. The clinical selection and practice in head and neck sites are described, together with promising early results on the maintenance of salivary flow after IMRT. A summary of research into optimal planning for pelvic cancer follows. The controversial areas of breast and paediatric IMRT are discussed with recommendations on practice. The potential for concomitant boost therapy is exemplified in the treatment of brain metastatic disease.