After breast-conserving radiation therapy most patients experience acute skin toxicity to some degree. This may impair patients' quality of life, cause pain and discomfort. In this study, we ...investigated treatment and patient-related factors, including genetic polymorphisms, that can modify the risk for severe radiation-induced skin toxicity in breast cancer patients.
We studied 377 patients treated at Ghent University Hospital and at ST.-Elisabeth Clinic and Maternity in Namur, with adjuvant intensity modulated radiotherapy (IMRT) after breast-conserving surgery for breast cancer. Women were treated in a prone or supine position with normofractionated (25 × 2 Gy) or hypofractionated (15 × 2.67 Gy) IMRT alone or in combination with other adjuvant therapies. Patient- and treatment-related factors and genetic markers in regulatory regions of radioresponsive genes and in LIG3, MLH1 and XRCC3 genes were considered as variables. Acute dermatitis was scored using the CTCAEv3.0 scoring system. Desquamation was scored separately on a 3-point scale (0-none, 1-dry, 2-moist).
Two-hundred and twenty patients (58%) developed G2+ dermatitis whereas moist desquamation occurred in 56 patients (15%). Normofractionation (both p < 0.001), high body mass index (BMI) (p = 0.003 and p < 0.001), bra cup size ≥ D (p = 0.001 and p = 0.043) and concurrent hormone therapy (p = 0.001 and p = 0.037) were significantly associated with occurrence of acute dermatitis and moist desquamation, respectively. Additional factors associated with an increased risk of acute dermatitis were the genetic variation in MLH1 rs1800734 (p=0.008), smoking during RT (p = 0.010) and supine IMRT (p = 0.004). Patients receiving trastuzumab showed decreased risk of acute dermatitis (p < 0.001).
The normofractionation schedule, supine IMRT, concomitant hormone treatment and patient related factors (high BMI, large breast, smoking during treatment and the genetic variation in MLH1 rs1800734) were associated with increased acute skin toxicity in patients receiving radiation therapy after breast-conserving surgery. Trastuzumab seemed to be protective.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck ...cancer.
A Phase I clinical trial was designed to escalate the dose limited to the (18)-Ffluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy.
Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p = n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted (18)F-FDG-PET-delineated region.
For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.
Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the ...association of 10 base-excision and nucleotide-excision repair gene polymorphisms (
XRCC1 −77 T/C, Arg194Trp, Arg280His and Arg399Gln;
APE1 Asp148Glu;
OGG1 Ser326Cys;
XPA −4 G/A;
XPC PAT;
XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR–RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the
APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (
p
=
0.001) for the Asp/Glu genotype and 2.39 (
p
=
0.038) for the Glu/Glu genotype. Gene–smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the
XRCC1 Arg399Gln and
XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR
=
4.92,
p
=
0.021 for
XRCC1 399 Gln/Gln; OR
=
3.62,
p
=
0.049 for
XPD 751 Gln/Gln), but not in heavy smokers (≥25 PY; OR
=
0.68,
p
=
0.566 for
XRCC1 399 Gln/Gln; OR
=
0.46,
p
=
0.295 for
XPD 751 Gln/Gln). Both the
XRCC1 Arg194Trp and Arg280His as well as the
OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR
=
0.32,
p
=
0.024; OR
=
0.25,
p
=
0.028; OR
=
0.51,
p
=
0.033, respectively). No associations with lung cancer risk were found for the
XRCC1 −77 T/C, the
XPA −4 G/A and the
XPC PAT polymorphisms. In conclusion, the
APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the
XRCC1 Arg399Gln and the
XPD Lys751Gln polymorphisms and lung cancer risk.
Purpose: In case of a large-scale radiation accident when hundreds of people may be exposed, it is important to distinguish the severely exposed individuals (≥1 gray), who require early medical ...treatment, from those less exposed. The aim of our study was to develop a quick population triage method based on automated micronucleus (MN) scoring.
Materials and methods: Using the MN software module developed by MetaSystems specifically for the Metafer4 platform, about 60 blood samples can be scored in one day. Standard dose response curves were determined for manual and automated MN scoring.
Results: The automated MN assay results were closely correlated with MN yields obtained with the manual procedure. A dose of 1 Gy can be estimated with an uncertainty of 0.2 Gy. Corrections for false positives and false negatives by visual inspection of the image gallery did not result in an improved accuracy or reproducibility. To test the automated MN assay in a multicenter setting, an inter-laboratory comparison was performed whereby irradiated blood samples were processed in Ghent University (Belgium) and BfS (Bundesamt fuer Strahlenschutz; Germany). Both laboratories obtained comparable results.
Conclusions: These results confirm the efficacy of the automated MN assay for fast population triage in a multicenter setting, in the case of large radiation accidents.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Because of the higher radiosensitivity of infants and children compared with adults, there is a need to evaluate the doses delivered to pediatric patients who undergo interventional cardiac ...procedures. However, knowledge of the effective dose in pediatric interventional cardiology is very limited.
For an accurate risk estimation, a patient-specific Monte Carlo simulation of the effective dose was set up in 60 patients with congenital heart disease who underwent diagnostic (n=28) or therapeutic (n=32) cardiac catheterization procedures. The dose-saving effect of using extra copper filtration in the x-ray beam was also investigated. For diagnostic cardiac catheterizations, a median effective dose of 4.6 mSv was found. Therapeutic procedures resulted in a higher median effective dose of 6.0 mSv because of the prolonged use of fluoroscopy. The overall effect of inserting extra copper filtration into the x-ray beam was a total effective dose reduction of 18% with no detrimental effect on image quality. An excellent correlation between the dose-area product and effective patient dose was found (r=0.95). Hence, dose-area product is suitable for online estimation of the effective dose with good accuracy. With all procedures included, the resulting median lifetime risk for stochastic effects was 0.08%.
Because of the high radiation exposure, it is important to monitor patient dose by dose-area product instrumentation and to use additional beam filtration to keep the effective dose as low as possible in view of the sensitivity of the pediatric patients.
Abstract Background and purpose To develop predictive models for late radiation-induced hematuria and nocturia allowing a patient individualized estimation of pre-treatment risk. Materials and ...methods We studied 262 PCa patients treated with curative intensity modulated radiotherapy to the intact prostate or prostate bed. A total of 372 variables were used for prediction modeling, among which 343 genetic variations. Toxicity was scored using an in-house developed toxicity scale. Predictor selection is achieved by the EMLasso procedure, a penalized logistic regression method with an EM algorithm handling missing data and crossvalidation avoiding overfit. Model performance was expressed by the area under the curve (AUC) and by sensitivity and specificity. Results Variables of the model predicting late hematuria (36/262) are bladder volume receiving ⩾75 Gy, prostatic transurethral resection and four polymorphisms. (AUC = 0.80, sensitivity = 83.3%, specificity = 61.5%). The AUC drops to 0.67 when the genetic markers are left out. The model that predicts for late nocturia (29/262) contains the minimal clinical target volume (CTV) dose, the CTV volume and three polymorphisms (AUC = 0.76, sensitivity = 75.9%, specify = 67.4%). This model is a better predictor for nocturia compared to the nongenetic model (AUC of 0.60). Conclusions We were able to develop models that predict for the occurrence of late radiation-induced hematuria and nocturia, including genetic factors which might improve the prediction of late urinary toxicity.
To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, ...c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy.
The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volume histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays.
The mean dose (D(mean)) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%.
The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D(mean) to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.
Predicting Risk of Radiation-Induced Lung Injury Madani, Indira; De Ruyck, Kim; Goeminne, Hannelore ...
Journal of thoracic oncology,
September 2007, 2007-September, 2007-Sep, 2007-09-00, Letnik:
2, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Radiation-induced lung injury (RILI) is the most common, dose-limiting complication of thoracic radio- and radiochemotherapy. Unfortunately, predicting which patients will suffer from this ...complication is extremely difficult. Ideally, individual phenotype- and genotype-based risk profiles should be able to identify patients who are resistant to RILI and who could benefit from dose escalation in chemoradiotherapy. This could result in better local control and overall survival. We review the risk predictors that are currently in clinical use—dosimetric parameters of radiotherapy such as normal tissue complication probability, mean lung dose, V20 and V30—as well as biomarkers that might individualize risk profiles. These biomarkers comprise a variety of proinflammatory and profibrotic cytokines and molecules including transforming growth factor β1 that are implicated in development and persistence of RILI. Dosimetric parameters of radiotherapy show a low negative predictive value of 60% to 80%. Depending on the studied molecule, negative predictive value of biomarkers is approximately 50%. The predictive power of biomarkers might be increased if they are coupled with radiogenomics, e.g., genotyping analysis of single nucleotide polymorphisms in transforming growth factor β1, transforming growth factor β1 pathway genes, and other cytokines. Genetic variability and the complexity of RILI and its underlying molecular mechanisms make identification of biological risk predictors challenging. Further investigations are needed to develop more effective risk predictors of RILI.
Purpose: A minority of patients exhibits severe late normal tissue toxicity after radiotherapy (RT), possibly related to their inherent individual radiation sensitivity. This study aimed to evaluate ...four different candidate in vitro cellular radiosensitivity assays for prediction of late normal tissue reactions, in a retrospective matched case-control set-up of breast cancer patients.
Methods: The study population consists of breast cancer patients expressing severe radiation toxicity (12 cases) and no or minimal reactions (12 controls), with a follow-up for at least 3 years. Late adverse reactions were evaluated by comparing standardized photographs pre- and post-RT resulting in an overall cosmetic score and by clinical examination using the LENT-SOMA scale. Four cellular assays on peripheral blood lymphocytes reported to be associated with normal tissue reactions were performed after in vitro irradiation of patient blood samples to compare case and control radiation responses: radiation-induced CD8+ late apoptosis, residual DNA double-strand breaks, G0 and G2 micronucleus assay.
Results: A significant difference was observed for all cellular endpoints when matched cases and controls were compared both pairwise and grouped. However, it is important to point out that most case-control pairs showed a substantial overlap in standard deviations, which questions the predictive value of the individual assays. The apoptosis assay performed best, with less apoptosis seen in CD8+ lymphocytes of the cases (average: 14.45%) than in their matched controls (average: 30.64%) for 11 out of 12 patient pairs (p < .01). The number of residual DNA DSB was higher in cases (average: 9.92 foci/cell) compared to their matched control patients (average: 9.17 foci/cell) (p < .01). The average dose response curve of the G0 MN assay for cases lies above the average dose response curve of the controls. Finally, a pairwise comparison of the G2 MN results showed a higher MN yield for cases (average: 351 MN/1000BN) compared to controls (average: 219 MN/1000BN) in 9 out of 10 pairs (p < .01).
Conclusion: This matched case-control study in breast cancer patients, using different endpoints for in vitro cellular radiosensitivity related to DNA repair and apoptosis, suggests that patients' intrinsic radiosensitivity is involved in the development of late normal tissue reactions after RT. Larger prospective studies are warranted to validate the retrospective findings and to use in vitro cellular assays in the future to predict late normal tissue radiosensitivity and discriminate individuals with marked RT responses.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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