Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study

INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998–2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04–4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes

Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor <it>(VEGF-R</it>) and Transketolase-like-1 (<it>TKTL1</it>) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of <it>VEGFR-1</it>, <it>VEGFR-2 </it>and <it>TKTL1 </it>in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab.</p> <p>Methods</p> <p>Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR.</p> <p>Results</p> <p>Significantly higher expression of <it>VEGFR-1/2 </it>was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High <it>TKTL1 </it>expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers.</p> <p>Conclusion</p> <p>High <it>TKTL-1 </it>expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.</p

Intrafraction motion of the prostate during an IMRT session: a fiducial-based 3D measurement with Cone-beam CT

Background: Image-guidance systems allow accurate interfractional repositioning of IMRT treatments, however, these may require up to 15 minutes. Therefore intrafraction motion might have an impact on treatment precision. 3D geometric data regarding intrafraction prostate motion are rare; we therefore assessed its magnitude with pre- and post-treatment fiducial-based imaging with cone-beam-CT (CBCT). Methods: 39 IMRT fractions in 5 prostate cancer patients after (125)I-seed implantation were evaluated. Patient position was corrected based on the (125)I-seeds after pre-treatment CBCT. Immediately after treatment delivery, a second CBCT was performed. Differences in bone- and fiducial position were measured by seed-based grey-value matching. Results: Fraction time was 13.6 +/- 1.6 minutes. Median overall displacement vector length of (125)Iseeds was 3 mm (M = 3 mm, Sigma = 0.9 mm, sigma = 1.7 mm; M: group systematic error, Sigma: SD of systematic error, sigma: SD of random error). Median displacement vector of bony structures was 1.84 mm (M = 2.9 mm, Sigma = 1 mm, sigma = 3.2 mm). Median displacement vector length of the prostate relative to bony structures was 1.9 mm (M = 3 mm, Sigma = 1.3 mm, sigma = 2.6 mm). Conclusion: a) Overall displacement vector length during an IMRT session is &lt; 3 mm. b) Positioning devices reducing intrafraction bony displacements can further reduce overall intrafraction motion. c) Intrafraction prostate motion relative to bony structures is &lt; 2 mm and may be further reduced by institutional protocols and reduction of IMRT duration

Direct dose correlation of MRI morphologic alterations of healthy liver tissue after robotic liver SBRT

Purpose: For assessing healthy liver reactions after robotic SBRT (stereotactic body radiotherapy), we investigated early morphologic alterations on MRI (magnetic resonance imaging) with respect to patient and treatment plan parameters. Patients and methods: MRI data at 6\u201317&nbsp;weeks post-treatment from 22&nbsp;patients with 42&nbsp;liver metastases were analyzed retrospectively. Median prescription dose was 40\u202fGy&nbsp;delivered in 3\u20135&nbsp;fractions. T2- and T1-weighted MRI were registered to the treatment plan. Absolute doses were converted to EQD2 (Equivalent dose in 2Gy fractions) with \u3b1/\u3b2-ratios of 2&nbsp;and 3\u202fGy for healthy, and 8\u202fGy for modelling pre-damaged liver tissue. Results: Sharply defined, centroid-shaped morphologic alterations were observed outside the high-dose volume surrounding the GTV. On T2-w MRI, hyperintensity at EQD2 isodoses of 113.3\u202f\ub1 66.1\u202fGy2, 97.5\u202f\ub1 54.7\u202fGy3, and 66.5\u202f\ub1 32.0\u202fGy8 significantly depended on PTV dimension (p\u202f= 0.02) and healthy liver EQD2 (p\u202f= 0.05). On T1-w non-contrast MRI, hypointensity at EQD2 isodoses of 113.3\u202f\ub1 49.3\u202fGy2, 97.4\u202f\ub1 41.0\u202fGy3, and 65.7\u202f\ub1 24.2\u202fGy8 significantly depended on prior chemotherapy (p\u202f= 0.01) and total liver volume (p\u202f= 0.05). On T1-w gadolinium-contrast delayed MRI, hypointensity at EQD2 isodoses of 90.6\u202f\ub1 42.5\u202fGy2, 79.3\u202f\ub1 35.3\u202fGy3, and 56.6\u202f\ub1 20.9\u202fGy8 significantly depended on total (p\u202f= 0.04) and healthy (p\u202f= 0.01) liver EQD2. Conclusions: Early post-treatment changes in healthy liver tissue after robotic SBRT could spatially be correlated to respective isodoses. Median nominal doses of 10.1\u201311.3\u202fGy per fraction (EQD2 79\u201397\u202fGy3) induce characteristic morphologic alterations surrounding the lesions, potentially allowing for dosimetric in-vivo accuracy assessments. Comparison to other techniques and investigations of the short- and long-term clinical impact require further research