The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer.

PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.

Assessment of changes in tumor heterogeneity following neoadjuvant chemotherapy in primary esophageal cancer.

To assess the changes in computed tomography (CT) tumor heterogeneity following neoadjuvant chemotherapy in esophageal cancer. Thirty-one consecutive patients who received neoadjuvant chemotherapy for esophageal cancer were identified. Analysis of primary tumor heterogeneity (texture) was performed on staging and post-chemotherapy CT scans. Image texture parameters (mean grey-level intensity, entropy, uniformity, kurtosis, skewness, standard deviation of histogram) were derived for different levels of image filtration (0-2.5). Proportional changes in each parameter following treatment were obtained. Comparison between pathological tumor response and texture parameters was analyzed using Mann-Whitney U-test. The relationship between CT texture and overall survival) was estimated using the Kaplan-Meier method. Tumor texture became more homogeneous after treatment with a significant decrease in entropy and increase in uniformity (filter 1.0 and 2.5). Pretreatment (filter 1.5, P = 0.006) and posttreatment standard deviation of histogram (filter 1.0, P = 0.009) showed a borderline association with pathological tumor response. A proportional change in skewness <0.39 (filter 1.0) was associated with improved survival (median overall survival 36.1 vs. 11.1 months; P < 0.001). CT tumor heterogeneity decreased following neoadjuvant chemotherapy and has the potential to provide additional information in primary esophageal cancer.

Correlation between Ki-67 immunohistochemistry and 18F-fluorothymidine uptake in patients with cancer: A systematic review and meta-analysis.

BACKGROUND: Positron emission tomography (PET) imaging using the radiotracer 18F-Fluorothymidine (FLT) has been proposed as an imaging biomarker of tumour proliferation. If FLT-PET can be established as such it will provide a non-invasive, quantitative measurement of tumour proliferation across the entire tumour. Results from validation studies have so far been conflicting with some studies confirming a good correlation between FLT uptake and Ki-67 score and others presenting negative results. METHODS: Firstly we performed a systematic review of published studies between 1998 and 2011 that explored the correlation between FLT uptake and Ki-67 score and examined possible variations in the methods used. Studies were eligible if they: (a) included patients with cancer, (b) investigated the correlation between Ki-67 measured by immunohistochemistry and FLT uptake measured with PET scanning, and (c) were published as a full paper in a peer-reviewed scientific journal. Secondly a meta-analysis of the correlation coefficient values reported from each study was performed. Correlation coefficient (r) values were extracted from each study and 95% confidence intervals (CIs) were calculated after applying Fisher's z transformation. For subgroup analysis, studies were classified by the index used to characterise Ki-67 expression (average or maximum expression), the nature of the sample (whole specimen or biopsy) and the cancer type. FINDINGS: Twenty-seven studies were identified as eligible for the meta-analysis. In the studies we examined there were variations in aspects of the methods and reporting. The meta-analysis showed that given an appropriate study design the FLT/Ki-67 correlation is significant and independent of cancer type. Specifically subgroup analysis showed that FLT/Ki-67 correlation was high in studies measuring the Ki-67 average expression regardless of use of surgery or biopsy samples (r=0.70, 95% CI=0.43-0.86, p<0.001). Of the studies that measured Ki-67 maximum expression, only those that used the whole surgical specimen provided a significant r value (r=0.72, 95% CI=0.54-0.84, p<0.001). Studies that used biopsy samples for Ki-67 maximum measurements did not produce a significant r value (r=0.04, 95% CI=-0.18-0.26, p=0.71). In terms of the cancer type subgroup analysis there is sufficient data to support a strong FLT/Ki-67 correlation for brain, lung and breast cancer. No publication bias was detected. INTERPRETATION: This systematic review and meta-analysis highlights the importance of the methods used in validation studies comparing FLT-PET imaging with the biomarker Ki-67. The correlation is significant and independent of cancer type provided a study design that uses Ki-67 average measurements, regardless of nature of sample, or whole surgical samples when measuring Ki-67 maximum expression. Sufficient data to support a strong correlation for brain, lung and breast cancer exist. However, larger, prospective studies with improved study design are warranted to validate these findings for the rest of the cancer types.

Temozolomide in the management of dopamine agonist-resistant prolactinomas.

BACKGROUND: The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment. CASE SERIES: We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16-year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT). LITERATURE REVIEW AND DISCUSSION: A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT-negative staining and a good response to temozolomide (OR 9.35, P = 0.0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.

(Stereotactic) radiosurgery XIX: spinal radiosurgery--two year experience in a UK centre.

INTRODUCTION: Modern radiotherapy image guidance enables the treatment of extracranial targets with the required accuracy for safe delivery of radiosurgical treatments. The first two years' experience of spinal radiosurgery in a UK radiotherapy centre is reported. MATERIALS AND METHODS: Patients with primary or metastatic spinal lesions were treated using the CyberKnife stereotactic radiotherapy system. Xsight Spine (fiducial-free) tumour tracking software was used in all cases. Treatment was delivered using either a single or a three-fraction schedule, between February 2009 and March 2011. RESULTS: Fifty-three spinal lesions were treated, comprising 14 primary lesions in 12 patients, and 39 metastases in 29 patients. The prescription dose ranged from 8 to 30 Gy in 1-3 fractions. Fifty-nine percent of patients experienced no acute side effects from treatment. There were three cases of acute grade 3 back or nerve root pain, all of which responded to a short course of oral corticosteroids. At a median follow-up of 11.1 months, local control and overall survival were 91 and 65%, respectively. Pain improvement was seen in 75% of symptomatic metastases at 6 months post treatment. CONCLUSIONS: Early UK experience confirms that radiosurgery is well tolerated with excellent local control rates. Longer-term prospective data are needed to clarify the role of spinal radiosurgery for patients in this country.

Inter-fraction variations in respiratory motion models.

Respiratory motion can vary dramatically between the planning stage and the different fractions of radiotherapy treatment. Motion predictions used when constructing the radiotherapy plan may be unsuitable for later fractions of treatment. This paper presents a methodology for constructing patient-specific respiratory motion models and uses these models to evaluate and analyse the inter-fraction variations in the respiratory motion. The internal respiratory motion is determined from the deformable registration of Cine CT data and related to a respiratory surrogate signal derived from 3D skin surface data. Three different models for relating the internal motion to the surrogate signal have been investigated in this work. Data were acquired from six lung cancer patients. Two full datasets were acquired for each patient, one before the course of radiotherapy treatment and one at the end (approximately 6 weeks later). Separate models were built for each dataset. All models could accurately predict the respiratory motion in the same dataset, but had large errors when predicting the motion in the other dataset. Analysis of the inter-fraction variations revealed that most variations were spatially varying base-line shifts, but changes to the anatomy and the motion trajectories were also observed.

Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement.

In this overview we review and model how radiotherapy tumour control and complication rates vary with dose, fractionation, schedule duration, irradiated volume and use of chemotherapy for stage III non-small cell lung cancer (NSCLC), and use the modelling to study the effectiveness of different NSCLC dose-escalation approaches being developed in the UK. Data have been collated for pneumonitis, lung fibrosis, early and late oesophagitis, cord and cardiac complications, and local progression-free survival at 30 months. Dependences of the various end points on treatment-related factors are catalogued and analysed using the linear-quadratic incomplete repair model to account for dose and fractionation effects, making linear corrections for differences in schedule duration, and loosely characterising volume effects using parallel- and series-type concepts. Tolerance limits are calculated for the different end points and distilled into ranges of prescribed dose likely to be tolerable when delivered in 2.5 and 4 week radiation and 6 week chemoirradiation schedules using conformal techniques. Worthwhile ( approximately 20%) gains in 30 month local progression-free survival should be achievable at safely deliverable levels of dose escalation. The analysis suggests that longer schedules may be more beneficial than shorter ones, but this finding is governed by the relative rates of tumour and oesophageal accelerated proliferation, which are quite imprecisely known. Consequently escalated 2.5, 4 and 6 week schedules are being developed; each should lead to useful improvements in local control but it is not yet known which schedule will be most effective.

MRI-based measurements of respiratory motion variability and assessment of imaging strategies for radiotherapy planning.

Respiratory organ motion has a significant impact on the planning and delivery of radiotherapy (RT) treatment for lung cancer. Currently widespread techniques, such as 4D-computed tomography (4DCT), cannot be used to measure variability of this motion from one cycle to the next. In this paper, we describe the use of fast magnetic resonance imaging (MRI) techniques to investigate the intra- and inter-cycle reproducibility of respiratory motion and also to estimate the level of errors that may be introduced into treatment delivery by using various breath-hold imaging strategies during lung RT planning. A reference model of respiratory motion is formed to enable comparison of different breathing cycles at any arbitrary position in the respiratory cycle. This is constructed by using free-breathing images from the inhale phase of a single breathing cycle, then co-registering the images, and thereby tracking landmarks. This reference model is then compared to alternative models constructed from images acquired during the exhale phase of the same cycle and the inhale phase of a subsequent cycle, to assess intra- and inter-cycle variability ('hysteresis' and 'reproducibility') of organ motion. The reference model is also compared to a series of models formed from breath-hold data at exhale and inhale. Evaluation of these models is carried out on data from ten healthy volunteers and five lung cancer patients. Free-breathing models show good levels of intra- and inter-cycle reproducibility across the tidal breathing range. Mean intra-cycle errors in the position of organ surface landmarks of 1.5(1.4)-3.5(3.3) mm for volunteers and 2.8(1.8)-5.2(5.2) mm for patients. Equivalent measures of inter-cycle variability across this range are 1.7(1.0)-3.9(3.3) mm for volunteers and 2.8(1.8)-3.3(2.2) mm for patients. As expected, models based on breath-hold sequences do not represent normal tidal motion as well as those based on free-breathing data, with mean errors of 4.4(2.2)-7.7(3.9) mm for volunteers and 10.1(6.1)-12.5(6.3) mm for patients. Errors are generally larger still when using a single breath-hold image at either exhale or inhale to represent the lung. This indicates that account should be taken of intra- and inter-cycle respiratory motion variability and that breath-hold-based methods of obtaining data for RT planning may potentially introduce large errors. This approach to analysis of motion and variability has potential to inform decisions about treatment margins and optimize RT planning.

An audit of indications and techniques for supraclavicular fossa irradiation in early breast cancer in the United Kingdom.

This article describes an audit of the indications and techniques used by clinical oncologists in the United Kingdom (UK) in the delivery of adjuvant radiotherapy to the supraclavicular fossa (SCF) in patients with early breast cancer. A postal questionnaire was sent to one consultant clinical oncologist in each UK radiotherapy centre in November 1999. These were the same individuals listed in the Maher Committee Report as providing breast cancer services. Forty-one out of 51 completed forms were returned. The results show significant variation in the indications for SCF irradiation and for the definition of the radiotherapy target volume. We discuss the possible basis for the variations found in the audit. There was broad agreement on technique, in particular on the need for matching the tangential and SCF fields and maintaining patient position between fields, factors that are likely to minimize serious morbidity, including brachial plexus injury.