Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases. METHODS: For this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and - 16.3% for SUVmax, and 21.2% and - 17.5% for SULpeak. 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak. CONCLUSION: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients with bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases.In this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified as the maximum tumor voxel normalized by dose and body weight (SUVmax) and the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals of SUVmax and SULpeak were used to determine limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax in 38 bone tumors of the first cohort was 4.3%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and -16.3%, respectively. The 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria changed the status of 3 patients compared to standard the standard Positron Emission Tomography Response Criteria in Solid Tumors of ±30% SULpeak. CONCLUSIONS: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG uptake, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions from these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer.

PURPOSE: To investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer. METHODS: Patients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated. RESULTS: Thirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31-66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS. CONCLUSION: Mid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

Tumour volume and radiotherapy prolongation in locally advanced head and neck cancer patients treated with radical IMRT.

AIMS: The relationship of tumour volume, radiotherapy treatment time and other prognostic factors affecting prognosis was evaluated. METHODS: 184 patients with locally advanced head and neck cancer were treated with radical intensity modulated radiotherapy (IMRT) and compared retrospectively. RESULTS: In the multivariate analysis the overall survival was dependent on gross tumour volume (GTV), clinical stage (CS), radiotherapy treatment time (RTT) and p16 status. Local control was influenced by GTV, overall RTT and age. DFS was significantly affected by GTV, CS, RTT, p16 status and concomitant chemotherapy (CHT). CONCLUSIONS: The tumour volume and the radiotherapy treatment time were the most significant prognostic factors with the best outcomes in patients with GTV ≤ 55 cc and RTT ≤ 48 days (mean LC 8.1, DFS 7.1 and OS 6.4 years) and worst outcomes with GTV > 55 cc and RTT >48 days (mean LC 4.4, mean DFS 3.2 and mean OS 2.6 years).

18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study.

PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. METHODS: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. RESULTS: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. CONCLUSIONS: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

Determining priority risk groups for compensation of treatment breaks in radical radiotherapy in patients with locally advanced head and neck cancer.

PURPOSE: Prolongation of radiotherapy worsens the results of treatment of head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to identify the prognostic factors most affected by the prolongation of treatment. METHODS: 184 patients with locally advanced HNSCC were treated with curative chemo-radiation using SIB-IMRT from 2008 to 2016 and the influence of radiotherapy time (RTT) in groups of patients according to prognostic factors was retrospectively evaluated. RESULTS: Median overall survival (OS) was 45 months, median disease-free survival (DFS) was 41 months and median local control (LC) was not reached (mean LRC 68 months). In the multivariate analysis the radiotherapy prolongation negatively affected the LC in stage IV patients, T3/T4, in neck nodes positive disease, in oropharyngeal and oral cavity cancers, after neoadjuvant chemotherapy and in men. The RTT effect on DFS was significant in stage IV patients, patients with neck nodes positive disease and oropharyngeal cancer. RTT prolongation decreased OS within the groups of stage IV and grade 3 tumours. CONCLUSION: Prolonged RTT was associated with worsened OS and LRC, especially in stage IV patients and/or neck node positive disease and/or oropharyngeal cancer and we recommend that these patients should be prioritized in treatment gap compensation in radical radiotherapy for locally advanced HNSCC.

Radiotherapy dose limit for uterus fertility sparing in curative chemoradiotherapy for rectal cancer.

AIMS: Curative sphincter sparing radiotherapy is a treatment option for early rectal cancer. There are many methods developed for fertility preservation in young patients treated with pelvic radiotherapy. Pregnancy rates after radiotherapy are dependent on the radiation dose to ovaries and uterus. Data on outcomes of total body irradiation suggest a pregnancy is possible following 12-14 Gy TBI, despite elevated rates of preterm deliveries and other complications. METHODS: We report a case of full-term delivery of twins after curative chemoradiotherapy for anorectal adenocarcinoma T2 N0 M0 with the total dose 58.6 Gy. The patient underwent laparoscopic laterocranial ovarian transposition before radiotherapy. RESULTS: Long term complete remission was achieved after treatment. Although a spontaneous conception was not successful, the patient underwent an in vitro fertilisation procedure with donor eggs and conceived twins 10 years after the radiotherapy treatment. The mean dose to the uterus was 16 Gy and to the uterine cervix 35 Gy. She reached a full-term pregnancy and delivered two healthy babies by caesarean section at a gestational age of 38 weeks, weighing 2420 g and 2220 g. CONCLUSION: This is the first case report of the successful pregnancy following sphincter sparing curative pelvic radiotherapy for rectal cancer. Furthermore it allows us to propose an increased limit dose to the uterus enabling fertility sparing beyond the limits achieved from total body irradiation series with 12-14 Gy and accept 16 Gy as uterine body (35 Gy for uterine cervix) limit for IMRT treatment planning in young patients asking for maintaining fertility potential.

Regorafenib for Metastatic Colorectal Cancer: An Analysis of a Registry-Based Cohort of 555 Patients.

PURPOSE: Regorafenib is an oral multikinase inhibitor approved for the therapy of previously treated metastatic colorectal carcinoma (mCRC). The aim of the present study was to analyze the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry. METHODS: The CORECT registry, the Czech non-interventional database of patients with mCRC treated with targeted agents, searched for patients with metastatic CRC treated with regorafenib. In total, 555 evaluable patients were identified. RESULTS: The median age at diagnosis was 61.7 years. All patients had disease progression on or after previous systemic treatment. Most patients were treated with an initial dose of 160 mg daily (n = 463; 83.6%). The median duration of treatment was 2.7 months (range 0.0-23.4 months). By the data cut-off date, 472 patients (85%) had completed treatment with regorafenib and were evaluable for treatment response evaluation. Partial response was reported in 13 patients (2.8%) and disease stabilization in 130 patients (27.5%). Median progression-free survival (PFS) and overall survival (OS) were 3.5 months (95% confidence interval [CI] 3.2-3.7 months) and 9.3 months (95% CI 8.3-10.3 months), respectively. The 6-month OS rate was 67.7% (95% CI 63.4-72.1%). Multivariable analysis showed that female gender, longer interval from diagnosis of metastatic disease, M0 stage at diagnosis, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 were associated with longer PFS, while higher body-mass index (BMI), longer interval from diagnosis of metastatic disease, and ECOG PS of 0 were associated with longer OS. CONCLUSION: OS of patients treated with regorafenib in the real-world clinical practice in this cohort exceeded that reported in randomized trials. Regorafenib is a safe and active treatment option for a subgroup of patients with mCRC who are progressing after other systemic therapies and maintain good performance status.

Test-Retest Reproducibility of 18F-FDG PET/CT Uptake in Cancer Patients Within a Qualified and Calibrated Local Network.

Calibration and reproducibility of quantitative 18F-FDG PET measures are essential for adopting integral 18F-FDG PET/CT biomarkers and response measures in multicenter clinical trials. We implemented a multicenter qualification process using National Institute of Standards and Technology-traceable reference sources for scanners and dose calibrators, and similar patient and imaging protocols. We then assessed SUV in patient test-retest studies. Methods: Five 18F-FDG PET/CT scanners from 4 institutions (2 in a National Cancer Institute-designated Comprehensive Cancer Center, 3 in a community-based network) were qualified for study use. Patients were scanned twice within 15 d, on the same scanner (n = 10); different but same model scanners within an institution (n = 2); or different model scanners at different institutions (n = 11). SUVmax was recorded for lesions, and SUVmean for normal liver uptake. Linear mixed models with random intercept were fitted to evaluate test-retest differences in multiple lesions per patient and to estimate the concordance correlation coefficient. Bland-Altman plots and repeatability coefficients were also produced. Results: In total, 162 lesions (82 bone, 80 soft tissue) were assessed in patients with breast cancer (n = 17) or other cancers (n = 6). Repeat scans within the same institution, using the same scanner or 2 scanners of the same model, had an average difference in SUVmax of 8% (95% confidence interval, 6%-10%). For test-retest on different scanners at different sites, the average difference in lesion SUVmax was 18% (95% confidence interval, 13%-24%). Normal liver uptake (SUVmean) showed an average difference of 5% (95% confidence interval, 3%-10%) for the same scanner model or institution and 6% (95% confidence interval, 3%-11%) for different scanners from different institutions. Protocol adherence was good; the median difference in injection-to-acquisition time was 2 min (range, 0-11 min). Test-retest SUVmax variability was not explained by available information on protocol deviations or patient or lesion characteristics. Conclusion:18F-FDG PET/CT scanner qualification and calibration can yield highly reproducible test-retest tumor SUV measurements. Our data support use of different qualified scanners of the same model for serial studies. Test-retest differences from different scanner models were greater; more resolution-dependent harmonization of scanner protocols and reconstruction algorithms may be capable of reducing these differences to values closer to same-scanner results.

Prospective Study of Serial 18F-FDG PET and 18F-Fluoride PET to Predict Time to Skeletal-Related Events, Time to Progression, and Survival in Patients with Bone-Dominant Metastatic Breast Cancer.

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP). 18F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested 18F-FDG PET and 18F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Methods: Patients with bone-dominant MBC were imaged with 18F-FDG PET and 18F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUVmax) and lean body mass adjusted standardized uptake (SULpeak) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18F-FDG PET and 18F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher 18F-FDG SULpeak at scan2 predicted shorter time to tSRE (P = <0.001) and TTP (P = 0.044). Higher 18F-FDG SUVmax at scan2 predicted a shorter time to tSRE (P = <0.001). A multivariable model using 18F-FDG SUVmax of the index lesion at scan1 plus the difference in SUVmax of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) (P = 0.007, 0.028, respectively), with a trend toward improved survival (P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18F-NaF PET was associated with longer OS (P = 0.027). Conclusion: Changes in 18F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC.

Changes in expression of injury after irradiation of increasing volumes in rat lung.

PURPOSE: To improve the cure rates of thoracic malignancies by radiation dose escalation, very accurate insight is required in the dose delivery parameters that maximally spare normal lung function. Radiation-induced lung complications are classically divided into an early pneumonitic and a late fibrotic phase. This study investigated the relative dose-volume sensitivity, underlying pathologic findings, and consequentiality of early to late pathologic features. METHODS AND MATERIALS: We used high-precision, graded dose-volume lung irradiations and followed the time dependency of the morphologic sequelae in relation to overall respiratory function. RESULTS: Two distinct pathologic lesions were identified in the early postirradiation period (6-12 weeks): vascular inflammation and parenchymal inflammation. Vascular inflammation occurred at single doses as low as 9 Gy. This translated into early respiratory dysfunction only when a large lung volume had been irradiated and was reversible with time. Parenchymal inflammation was seen after higher doses only (onset at 16 Gy), progressed into later fibrotic remodeling but did not translate into dysfunction at a 25% lung volume even after single doses up to 36 Gy. CONCLUSION: Our data imply that a low dose scattered over a large lung volume causes more early toxicity than an extreme dose confined to a small volume. Such findings are crucial for clinical treatment planning of dose escalations and choices for modern radiotherapy techniques.

Relation between radiation-induced whole lung functional loss and regional structural changes in partial irradiated rat lung.

PURPOSE: Radiation-induced pulmonary toxicity is characterized by dose, region, and time-dependent severe changes in lung morphology and function. This study sought to determine the relation between the structural and functional changes in the irradiated rat lung at three different phases after irradiation. MATERIALS AND METHODS: Six groups of animals were irradiated to 16-22 Gy to six different lung regions, each containing 50% of the total lung volume. Before and every 2 weeks after irradiation, the breathing rate (BR) was measured, and at Weeks 8, 26, and 38 CT was performed. From the computed tomography scans, the irradiated lung tissue was delineated using a computerized algorithm. A single quantitative measure for structural change was derived from changes of the mean and standard deviation of the density within the delineated lung. Subsequently, this was correlated with the BR in the corresponding phase. RESULTS: In the mediastinal and apex region, the BR and computed tomography density changes did not correlate in any phase. After lateral irradiation, the density changes always correlated with the BR; however, in all other regions, the density changes only correlated significantly (r(2) = 0.46-0.85, p < 0.05) with the BR in Week 26. CONCLUSION: Changes in pulmonary function correlated with the structural changes in the absence of confounding heart irradiation.

Radiation damage to the heart enhances early radiation-induced lung function loss.

In many thoracic cancers, the radiation dose that can safely be delivered to the target volume is limited by the tolerance dose of the surrounding lung tissue. It has been hypothesized that irradiation of the heart may be an additional risk factor for the development of early radiation-induced lung morbidity. In the current study, the dependence of lung tolerance dose on heart irradiation is determined. Fifty percent of the rat lungs were irradiated either including or excluding the heart. Proton beams were used to allow very accurate and conformal dose delivery. Lung function toxicity was scored using a breathing rate assay. We confirmed that the tolerance dose for early lung function damage depends not only on the lung region that is irradiated but also that concomitant irradiation of the heart severely reduces the tolerance of the lung. This study for the first time shows that the response of an organ to irradiation does not necessarily depend on the dose distribution in that organ alone.

Pulmonary radiation injury: identification of risk factors associated with regional hypersensitivity.

Effective radiation treatment of thoracic tumors is often limited by radiosensitivity of surrounding tissues. Several experimental studies have suggested variations in radiosensitivity of different pulmonary regions. Mice and rat studies in part contradict each other and urge for a more detailed analysis. This study was designed to obtain a more comprehensive insight in radiation injury development, expression, and its regional heterogeneity in lung. The latter is obviously highly critical for optimization of radiotherapy treatment plans and may shed light on the mechanisms of lung dysfunction after irradiation. Six different but volume-equal regions in rat lung were irradiated. Whereas the severity of damage, as seen in histologic analysis, was comparable in all regions, the degree of lung dysfunction, measured as breathing rates, largely varied. During the pneumonitic phase (early: 6-12 weeks), the most sensitive regions contained a substantial part of alveolar lung parenchyma. Also, a trend for hypersensitivity was observed when the heart lay in the irradiation field. In the fibrotic phase (late: 34-38 weeks), lung parenchyma and heart-encompassing regions were the most sensitive. No impact of the heart was observed during the intermediate phase (16-28 weeks). The severity of respiratory dysfunction after partial thoracic irradiation is likely governed by an interaction between pulmonary and cardiac functional deficits. As a repercussion, more severe acute and delayed toxicity should be expected after combined lung and heart irradiation. This should be considered in the process of radiotherapy treatment planning of thoracic malignancies.

Transforming growth factor-beta plasma dynamics and post-irradiation lung injury in lung cancer patients.

PURPOSE: To investigate the relevance of transforming growth factor-beta (TGF-beta) dynamics in plasma for identification of patients at low risk for developing pneumonitis as a complication of thoracic radiotherapy (RT). PATIENTS AND METHODS: Non-small cell lung cancer patients undergoing conventional RT were included in the prospective study. Concentrations of TGF-beta were measured in the patients' plasma prior to and weekly during 6 weeks of RT. The incidence of symptoms of early post-irradiation lung injury, i.e. symptomatic radiation pneumonitis, was correlated with TGF-beta parameters. RESULTS: Forty-six patients were included in the study. Eleven patients (24%) developed symptomatic radiation pneumonitis. Absolute TGF-beta plasma levels did not differ between the groups of patients without or with pneumonitis. However, patients who developed pneumonitis tended to show increases in TGF-beta levels in the middle of the RT course relative to their pre-treatment levels while TGF-beta plasma levels of patients who did not develop pneumonitis tended to decrease over the RT treatment. The difference in the relative TGF-beta dynamics between the groups reached marginal significance in the third week of the treatment (P = 0.055) but weakened towards the end of the RT course. The utility of TGF-beta testing was evaluated at each RT week based on the test's ability to yield more accurate estimate of complication probability in an individual patient compared to empirically expected probability in similar group of patients. The ratio of TGF-beta level at week 3/week 0 being <1 showed an ability to improve the prediction of freedom from pneumonitis, yet with a large degree of uncertainty (wide confidence intervals). The accuracy of prediction deteriorated at later time points (weeks 4, 5 and 6) rendering the end-RT ratios without predictive power. CONCLUSIONS: We observed a trend of plasma TGF-beta concentration to decrease below the pre-treatment value during the RT treatment in patients who did not develop pulmonary complications after the RT treatment. However, this trend was not consistent enough to warrant safe decision-making in clinical setting.