Radiotherapy & Oncology - Articles in Press

Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004–03 - Corrected Proof

2012-02-02

Abstract: Background and purpose: In 2003, the French Authority for Health (HAS) recommended the use of intensity modulated radiotherapy (IMRT) in prospective trial before its routine use. The Oncology and Radiotherapy Group for Head and Neck Cancer (GORTEC) proposed to evaluate prospectively acute and late toxicities, locoregional control and overall survival for patients treated for head and neck cancer (HNC) with IMRT and bilateral neck irradiation.Materials and methods: Between 2002 and 2008, 208 patients with HNC were treated with IMRT in 8 centres. There were 38 nasopharynx, 117 oropharynx, 25 pharyngo-larynx, 24 oral cavity and 4 unknown primary (28.5% stage I–II and 71% Stage III–IV). Ninety-three patients (46%) had postoperative IMRT and 78 patients (37.5%) received concurrent chemotherapy. The doses were 70Gy to the gross tumour, 66Gy to the high-risk postoperative sites and 50Gy to the subclinical disease. Toxicities were graded according to the RTOG–EORTC scales.Results: The median follow-up was 25.3months (range: 0.4–72months). There were 29 local–regional failures: 24 were in-field, three were marginal and one was out-field. The two-year loco-regional control and overall survival were 86% and 86.7%, respectively. At 18months, grade ⩾2 xerostomia was 16.1%. A mean dose to the spared parotid below 28Gy led to significantly less grade ⩾2 xerostomia (8.5% vs 24%) with a relative risk of 1.2 [95% CI: 1.02–1.41, p=0.03]. Grade ⩾2 xerostomia increased by approximately 3% per Gy of mean parotid dose up to 28, Gy then 7% per Gy above 33Gy.Conclusions: IMRT for HN cancer seems to reduce late toxicities without jeopardising local control and overall survival.

Urinary morbidity after permanent prostate brachytherapy – Impact of dose to the urethra vs. sources placed in close vicinity to the urethra - Corrected Proof

2012-02-02

Abstract: Background and purpose: The impact of the dose to the urethra and sources placed close to the urethra on urinary morbidity after permanent prostate brachytherapy (PPB) is not well known.Materials and methods: Fifty-nine patients were surveyed prospectively before treatment (A), 1month after (B) and >1year after PPB (C) using a validated questionnaire (Expanded Prostate Cancer Index Composite). Computed tomography (CT) postimplant scans were performed at days 1 (Foley catheter in situ) and 30 after PPB and sources within 5mm of the urethra at day 1 were identified.Results: As opposed to the urethral dose–volume histogram, a larger number of sources within 5mm of the urethra at day 1 predicted significantly larger urinary bother score changes at times B and C – with an impact on incontinence and frequency (e.g. moderate/big problem with leaking urine in 25% vs. 3%, p=0.02; moderate/big problem with frequent urination in 33% vs. 7%, p<0.01, at time C with vs. without ⩾3 sources in a single strand placed close to the urethra).Conclusions: Placement of sources with a minimum distance of a few mm to the urethra should be a major aim to avoid urinary morbidity irrespective of the urethral dose–volume histogram.

Prognostic significance of the total dose of cisplatin administered during concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma - Corrected Proof

2012-02-02

Abstract: Background and purpose: Concurrent chemoradiotherapy (CRT) confers survival benefit over radiotherapy (RT) alone in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). This study explored the prognostic significance of the total dose of cisplatin delivered during CRT.Materials and methods: A retrospective analysis was performed in patients with stage II to IVB NPC (AJCC 6th edition) who participated in 3 prospective studies. All patients received cisplatin at a fixed dose of 40mg/m2/week during a 6–7-weeks course of CRT. Chi-square test was used in the univariate analysis. Relationship between prognostic factors, the total dose of cisplatin administered and time-to-event endpoints were analyzed with the Cox Hazards model.Results: Two hundred and forty-one patients were identified with the following stage distribution: Stage II=13.7%, III=45.2%, IV=41.1%. The median total number of cycles of cisplatin administered per patient was 5 cycles (range 1–8 cycles). At a median follow-up of 56.5months (range 4.2–200.2months), 93 patients (38.6%) had relapsed and 85 patients (35.2%) died. For all patients, the total number of cycles of cisplatin delivered was significantly associated with survival in the univariate but not the multivariate analysis. In a sub-group analysis of 142 patients with stage II and III NPC, patients who received more than 5 cycles of cisplatin had significantly better overall survival than those who did not (hazard ratio 0.44; 95% confidence interval, 0.23–0.85; p=0.02).Conclusion: Number of cycles of cisplatin delivered is an independent prognostic factor in patients with stage II–III NPC undergoing CRT with weekly cisplatin.

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy - Corrected Proof

2012-02-02

Abstract: The GYN GEC-ESTRO working group issued three parts of recommendations and highlighted the pivotal role of MRI for the successful implementation of 3D image-based cervical cancer brachytherapy (BT). The main advantage of MRI as an imaging modality is its superior soft tissue depiction quality. To exploit the full potential of MRI for the better ability of the radiation oncologist to make the appropriate choice for the BT application technique and to accurately define the target volumes and the organs at risk, certain MR imaging criteria have to be fulfilled. Technical requirements, patient preparation, as well as image acquisition protocols have to be tailored to the needs of 3D image-based BT. The present recommendation is focused on the general principles of MR imaging for 3D image-based BT.Methods and parameters have been developed and progressively validated from clinical experience from different institutions (IGR, Universities of Vienna, Leuven, Aarhus and Ljubljana) and successfully applied during expert meetings, contouring workshops, as well as within clinical and interobserver studies.It is useful to perform pelvic MRI scanning prior to radiotherapy (“Pre-RT-MRI examination”) and at the time of BT (“BT MRI examination”) with one MR imager. Both low and high-field imagers, as well as both open and close magnet configurations conform to the requirements of 3D image-based cervical cancer BT. Multiplanar (transversal, sagittal, coronal and oblique image orientation) T2-weighted images obtained with pelvic surface coils are considered as the golden standard for visualisation of the tumour and the critical organs. The use of complementary MRI sequences (e.g. contrast-enhanced T1-weighted or 3D isotropic MRI sequences) is optional. Patient preparation has to be adapted to the needs of BT intervention and MR imaging. It is recommended to visualise and interpret the MR images on dedicated DICOM-viewer workstations, which should also assist the contouring procedure. Choice of imaging parameters and BT equipment is made after taking into account aspects of interaction between imaging and applicator reconstruction, as well as those between imaging, geometry and dose calculation.In a prospective clinical context, to implement 3D image-based cervical cancer brachytherapy and to take advantage of its full potential, it is essential to successfully meet the MR imaging criteria described in the present recommendations of the GYN GEC-ESTRO working group.

Managing a national radiation oncologist workforce: A workforce planning model - Corrected Proof

2012-02-02

Abstract: Purpose: The specialty of radiation oncology has experienced significant workforce planning challenges in many countries. Our purpose was to develop and validate a workforce-planning model that would forecast the balance between supply of, and demand for, radiation oncologists in Canada over a minimum 10-year time frame, to identify the model parameters that most influenced this balance, and to suggest how this model may be applicable to other countries.Methods: A forward calculation model was created and populated with data obtained from national sources. Validation was confirmed using a historical prospective approach.Results: Under baseline assumptions, the model predicts a short-term surplus of RO trainees followed by a projected deficit in 2020. Sensitivity analyses showed that access to radiotherapy (proportion of incident cases referred), individual RO workload, average age of retirement and resident training intake most influenced balance of supply and demand. Within plausible ranges of these parameters, substantial shortages or excess of graduates is possible, underscoring the need for ongoing monitoring.Conclusions: Workforce planning in radiation oncology is possible using a projection calculation model based on current system characteristics and modifiable parameters that influence projections. The workload projections should inform policy decision making regarding growth of the specialty and training program resident intake required to meet oncology health services needs. The methods used are applicable to workforce planning for radiation oncology in other countries and for other comparable medical specialties.

A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis - Corrected Proof

2012-02-02

Abstract: Purpose: We conducted the study to assess the feasibility and efficacy of gemcitabine-concurrent proton radiotherapy (GPT) for locally advanced pancreatic cancer (LAPC).Materials and methods: Of all 50 patients who participated in the study, 5 patients with gastrointestinal (GI)-adjacent LAPC were enrolled in P-1 (50Gy equivalent [GyE] in 25 fractions) and 5 patients with non-GI-adjacent LAPC in P-2 (70.2GyE in 26 fractions), and 40 patients with LAPC regardless of GI-adjacency in P-3 (67.5GyE in 25 fractions using the field-within-a-field technique). In every protocol, gemcitabine (800mg/m2/week for 3weeks) was administered concurrently. Every patient received adjuvant chemotherapy including gemcitabine after GPT within the tolerable limit.Results: The median follow-up period was 12.5months. The scheduled GPT was feasible for all except 6 patients (12%) due to acute hematologic or GI toxicities. Grade 3 or greater late gastric ulcer and hemorrhage were seen in 5 patients (10%) in P-2 and P-3. The one-year freedom from local-progression, progression-free, and overall survival rates were 81.7%, 64.3%, and 76.8%, respectively.Conclusion: GPT was feasible and showed high efficacy. Although the number of patients and the follow-up periods are insufficient, the clinical results seem very encouraging.

Out-of-field contributions for IMRT and volumetric modulated arc therapy measured using gafchromic films and compared to calculations using a superposition/convolution based treatment planning system - Corrected Proof

Frank Van den Heuvel, Gilles Defraene, Wouter Crijns, Ria Bogaerts — 2012-02-02

Abstract: Purpose: To quantify the whole-body-dose delivered during the application of new techniques and compare them to the results obtained by treatment planning systems. The ultimate goal being the use of planning data in combination with complication data to assess the impact of low doses of ionizing radiation.Methods: A film technique using gafchromic films to assess low doses was used on simplified phantoms and compared to data from treatment planning systems as well as a simplified whole body dose calculation system (Peridose). The types of treatment include open fields, intensity modulated radiation therapy (IMRT) and volumetric arc treatments. The film measurements were confirmed using TLDs in Alderson phantoms. In addition neutron contributions were measured as these are not taken into account in the current modern treatment planning systems, but can add significantly to the patient’s whole body dose.Results: Dose outside of the treatment plane diminished to 1% of the prescribed dose, this for open fields, IMRT and rotational treatments alike. Noteworthy was an increase at about 20cm from the central plane in IMRT, and in a more limited fashion for volumetric modulated arc treatment. In open fields this was not observed. Treatment planning systems were good at determining the out-of-field doses of single field treatments. In complex plans the TPS underestimated the dose to the patient. At distances greater than 20cm from the field edge, these systems did not predict any dose. The Peridose program performed well in the case of classical treatments. In the case of IMRT treatments, the overall evolution of the dose as a function of the distance to the field was well-modeled. However, an over estimation of the order of 60–80% was observed, leaving the possibility for a corrective factor based on a point measurement. Dose levels over the whole body were of the order 100mGy or higher over a complete treatment for the more complex treatments. Neutron dose levels were of the order single digit mSv for 10MV treatments. For 18MV the level of neutron contribution was in agreement with recent publications, corroborating reports that the dose from neutrons is lower than previously reported.

Locoregional failures following thoracic irradiation in patients with limited-stage small cell lung carcinoma - Corrected Proof

2012-01-30

Abstract: Purpose: To determine the patterns of loco-regional (LR) and distant failure in patients with limited-stage small cell lung carcinoma (LS-SCLC) treated with curative intent.Methods: From 1997 to 2008, 253 LS-SCLC patients were treated with curative intent chemo-radiation at our institution. A retrospective review identified sites of failure. The cumulative LR failure (LRF) rate was calculated. Distant failure-free survival (FFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Volumetric images of LR failures were delineated and registered with the original radiation treatment plans if available. Dosimetric parameters for the delineated failure volumes were calculated from the original treatment information.Results: The median follow-up was 19months. The site of first failure was LR in 34, distant in 80 and simultaneous LR and distant in 31 patients. The cumulative LRF rate was 29% and 38% at 2 and 5years. OS was 44% at 2years. Seventy patients had electronically archived treatment plans of which there were 16 LR failures (7 local and 39 regional failure volumes). Of the local and regional failure volumes 29% and 31% were in-field, respectively.Conclusions: The predominant pattern of LR failure was marginal or out-of-field. LR failures may be preventable with improved radiotherapy target definition.

Radiotherapy in small cell lung cancer: Limited volumes in limited disease and adding thoracic radiotherapy in extended disease? - Corrected Proof

Lucyna Kepka, Michael Baumann — 2012-01-30

Improving the outcome of treatment of lung cancer remains a formidable and multidisciplinary task . Although distant metastases occur early and frequently in lung cancer it is important to realize that failure to achieve loco-regional control is an equally important reason for todays’ overall poor outcome in this disease . Therefore considerable recent research in the field of radiotherapy has been directed towards technological improvements in target identification by advanced imaging, conformal and motion corrected treatment planning methodologies, more precise as well as better monitored radiotherapy application, and bioimaging for individualized and adaptive treatment approaches . In parallel a large number of retrospective and prospective studies have addressed optimization of total dose, dose per fraction, and overall treatment time, identification of dose–volume constraints for normal tissues, and integration of radiotherapy with chemotherapy . From this research improved loco-regional tumor control, reduced normal tissue toxicity and better survival is expected.

Fat necrosis in women with early-stage breast cancer treated with accelerated partial breast irradiation (APBI) using interstitial brachytherapy - Corrected Proof

2012-01-27

Abstract: Purpose: To report the incidence of clinical, pathological and radiological fat necrosis (FN) in women treated with accelerated partial breast irradiation (APBI) using interstitial brachytherapy (BRT) for early-stage breast cancer and to study certain variables associated with it.Methods and materials: Between May 2000 and August 2008, 171 women were treated with APBI using high dose rate (HDR) BRT. Patients were treated to a dose of 34Gy/10 fractions/1week with two fractions/day after intraoperative/postoperative placement of catheters.Results: At a median follow up of 48months (SD: 28) 20 women developed FN with median time to detection being 24months (range: 4–62months, SD: 20). Actuarial 5 and 7year FN rate was 18% and 23%, respectively. Grade 1 FN was seen in 4, grade 2 in 8 and grade 4 in 8 women. Additional investigations such as aspiration/biopsy were done in 9 patients. Volume of excision was the only significant factor affecting FN (p=0.04).Conclusions: Actuarial FN rate of 18% at 5years in our study was comparable to other reported series of FN. Median time of detection of FN was 24months. Higher volume of excision resulted in an increased incidence of fat necrosis.

Adaptive radiation therapy for breast IMRT-simultaneously integrated boost: Three-year clinical experience - Corrected Proof

2012-01-27

Abstract: Purpose: It has been shown that seroma volumes decrease during breast conserving radiotherapy in a significant percentage of patients. We report on our experience with an adaptive radiation therapy (ART) strategy involving rescanning and replanning patients to take this reduction into account during a course of intensity-modulated radiation therapy with simultaneously integrated boost (IMRT-SIB).Materials: From April 2007 till December 2009, 1274 patients eligible for SIB treatment were enrolled into this protocol. Patients for which the time between the initial planning CT (CT1) and lumpectomy was less than 30days and who had an initial seroma volume >30cm3 were rescanned at day 10 of treatment (CT2) and replanned when significant changes were observed by the radiation oncologist. Patients received 28 fractions of 1.81Gy to the breast and 2.30Gy to the boost volume.Results: Nine percent (n=113) of the 1274 patients enrolled met the criteria and were rescanned. Of this group, 77% (n=87) of treatment plans were adapted. Time between surgery and CT1 (20days versus 20days for adapted and non-adapted plans, p=0.89) and time between CT1 and CT2 (21days versus 22days for adapted and non-adapted plans, p=0.43) revealed no procedural differences which might have biased our results. In the adapted plans, seroma decreased significantly from 60 to 27cm3 (p<0.001), TBV from 70 to 45cm3 (p<0.001) and PTVboost from 277 to 220cm3 (p<0.001). The volume receiving more than 95% of the boost dose (V95%(total-dose)) could be reduced by 19% (linear fit, R2=0.73) from on average 360 to 292cm3 (p<0.001). Delay in treatment and the use of a prolonged treatment schedule with different fractionation for patients with seroma could thus be prevented.Conclusion: The adaptive radiation therapy IMRT-SIB procedure has proven to be efficient and effective, leading to a clinically significant reduction of the high dose volume. Seroma present in a subgroup of patients referred for breast radiation therapy does not hamper the introduction of highly conformal IMRT-SIB techniques.

FDG–PET–CT reduces the interobserver variability in rectal tumor delineation - Corrected Proof

2012-01-27

Abstract: Background and purpose: Previously, we showed a good correlation between pathology and an automatically generated PET-contour in rectal cancer. This study analyzed the effect of the use of PET–CT scan on the interobserver variation in GTV definition in rectal cancer and the influence of PET–CT on treatment volumes.Materials and methods: Forty two patients diagnosed with rectal cancer underwent an FDG–PET–CT for radiotherapy planning. An automatic contour was created on PET-scan using the source-to-background ratio. The GTV was delineated by 5 observers in 3 rounds: using CT and MRI, using CT, MRI and PET and using CT, MRI and PET auto-contour. GTV volumes were compared and concordance indices (CI) were calculated. Since the GTV is only a small portion of the treatment volume in rectal cancer, a separate analysis was performed to evaluate the influence of PET on the definition of the CTV used in daily clinical practice and the caudal extension of the treatment volumes.Results: GTV volumes based on PET were significantly smaller. CIs increased significantly using PET and the best interobserver agreement was observed using PET auto-contours. Furthermore, we found that in up to 29% of patients the CTV based on PET extended outside the CTV used in clinical practice. The caudal border of the treatment volume can be tailored using PET-scan in low seated tumors. Influence of PET on the position of the caudal border was most pronounced in high seated tumors.Conclusion: PET–CT increases the interobserver agreement in the GTV definition in rectal cancer, helps to avoid geographical misses and allows tailoring the caudal border of the treatment volume.

Phase II study of hypofractionated image-guided radiotherapy for localized prostate cancer: Outcomes of 55Gy in 16 fractions at 3.4Gy per fraction - Corrected Proof

2012-01-27

Abstract: Purpose: To estimate the late morbidity of a novel, hypofractionated external beam radiotherapy schedule of 55Gy in 16 fractions (4 fractions/week, 3.4Gy per fraction) for localized prostate cancer.Methods and materials: A multi-center phase 2 study enrolled seventy-three patients between September 2004 and June 2006. After insertion of fiducial gold markers, they were treated with image-guidance (IGRT) using conformal techniques with intensity-modulation, if necessary, and then followed every 6months for toxicity rating and PSA. Patient reported outcomes were collected yearly. Median follow up was 4.6years.Results: At 4years post-radiotherapy, the cumulative incidence of combined urinary and bowel grade 3 toxicity was 7% (95% CI 3–16%) and grade 2+ was 33% (95% CI 24–46%). All except two patients recovered from their grade 3 events. Patient-reported reduction of function was most pronounced at year two for urinary function (mean −7, SD 16), and at year one for bowel function (mean −7, SD 21). The cumulative incidence of biochemical (PSA nadir+2) or biopsy-proven relapse at 4years was 9% (95% CI 4–18%).Conclusions: Hypofractionated radiotherapy is clinically feasible and more convenient than conventional schedules for patients with localized prostate cancer. Phase 3 multicenter studies are on-going (NCT00126165).

Dose–response analysis of acute oral mucositis and pharyngeal dysphagia in patients receiving induction chemotherapy followed by concomitant chemo-IMRT for head and neck cancer - Corrected Proof

2012-01-27

Abstract: Dose–response curves (DRCs) and the quantitative parameters describing these curves were generated for grade 3 oral mucositis and dysphagia in 144 patients using individual patient DVHs. Curve fits to the oral mucositis clinical data yielded parameter values of mean dose in 2Gy equivalent, MD50=51Gy (95% CI 40–61), slope of the curve, k=1(95% CI 0.6–1.5). R2 value for the goodness of fit was 0.80. Fits to the grade 3 dysphagia clinical data yielded parameter values of MD50=44.5Gy (95% CI 36–53), k=2.6 (95% CI 0.8–4.5). R2 value for the goodness of fit was 0.65. This is the first study to derive DRCs in patients receiving induction chemotherapy followed by chemo-radiation (IC-C-IMRT) for head and neck cancer. The dose–response model described in this study could be useful for comparing acute mucositis rates for different dose–fractionation schedules when using IMRT for head and neck cancer.

Late toxicities after conventional radiation therapy alone for nasopharyngeal carcinoma - Corrected Proof

2012-01-27

Abstract: Background and purpose: We sought to evaluate the nature and frequency of late toxicities in a cohort of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy alone.Methods and materials: Seven-hundred and ninety-six consecutive NPC patients treated using conventional radiotherapy at a single center from 1992 to 1995 were retrospectively analyzed. Patients with histology proven, completely staged, Stage I–IVB World Health Organization Type I–III NPC and completed radical radiotherapy were included. Patients with incomplete staging investigations, distant metastases at diagnosis, previous treatment, and incomplete radiotherapy were excluded. Radiotherapy-related complications were categorized using the RTOG Late Radiation Morbidity Scoring Criteria.Results: Median follow-up was 7.2years. The 5-year overall survival and disease free survival were 69% and 56%, respectively, and the corresponding 10-year rates were 52% and 44%. Among 771 patients with at least 3months of follow-up post treatment, 565 (73%) developed RT-related complications. Diagnosed neurological complications were cranial nerve palsies (n=70; 9%), temporal lobe necrosis (n=37; 5%), Lhermitte’s syndrome (n=7; 1%), and brachial plexopathy (n=2; 0.3%). Non-neurological complications included xerostomia (n=353; 46%), neck fibrosis (n=169; 22%), hypo-pituitarism (n=48; 6%), hearing loss (n=120; 16%), dysphagia (n=116; 15%), otorrhea (n=101; 13%), tinnitus (n=94; 12%), permanent tube feeding (n=61; 8%), trismus (n=45; 6%), second malignancies within treatment field (n=17; 2%), and osteo-radionecrosis (n=13; 2%).Conclusions: While radiotherapy is curative in NPC, many patients suffer significant late treatment morbidities with conventional radiotherapy techniques.

Multivariate modeling of complications with data driven variable selection: Guarding against overfitting and effects of data set size - Corrected Proof

2012-01-24

Abstract: Purpose: Multivariate modeling of complications after radiotherapy is frequently used in conjunction with data driven variable selection. This study quantifies the risk of overfitting in a data driven modeling method using bootstrapping for data with typical clinical characteristics, and estimates the minimum amount of data needed to obtain models with relatively high predictive power.Materials and methods: To facilitate repeated modeling and cross-validation with independent datasets for the assessment of true predictive power, a method was developed to generate simulated data with statistical properties similar to real clinical data sets. Characteristics of three clinical data sets from radiotherapy treatment of head and neck cancer patients were used to simulate data with set sizes between 50 and 1000 patients. A logistic regression method using bootstrapping and forward variable selection was used for complication modeling, resulting for each simulated data set in a selected number of variables and an estimated predictive power. The true optimal number of variables and true predictive power were calculated using cross-validation with very large independent data sets.Results: For all simulated data set sizes the number of variables selected by the bootstrapping method was on average close to the true optimal number of variables, but showed considerable spread. Bootstrapping is more accurate in selecting the optimal number of variables than the AIC and BIC alternatives, but this did not translate into a significant difference of the true predictive power. The true predictive power asymptotically converged toward a maximum predictive power for large data sets, and the estimated predictive power converged toward the true predictive power. More than half of the potential predictive power is gained after approximately 200 samples. Our simulations demonstrated severe overfitting (a predicative power lower than that of predicting 50% probability) in a number of small data sets, in particular in data sets with a low number of events (median: 7, 95th percentile: 32). Recognizing overfitting from an inverted sign of the estimated model coefficients has a limited discriminative value.Conclusions: Despite considerable spread around the optimal number of selected variables, the bootstrapping method is efficient and accurate for sufficiently large data sets, and guards against overfitting for all simulated cases with the exception of some data sets with a particularly low number of events. An appropriate minimum data set size to obtain a model with high predictive power is approximately 200 patients and more than 32 events. With fewer data samples the true predictive power decreases rapidly, and for larger data set sizes the benefit levels off toward an asymptotic maximum predictive power.

The effect of hormonal treatment on conspicuity of prostate cancer: Implications for focal boosting radiotherapy - Corrected Proof

2012-01-24

Abstract: Background and purpose: For focal boosting of prostate tumors, three questions are important regarding the use of hormonal therapy. Does prolonged hormonal treatment affect the conspicuity of tumor tissue on diffusion weighted imaging (DWI) and dynamic contrast-enhanced (DCE-MRI) images? Is tumor delineation possible in patients using hormonal treatment? Can we identify specific imaging thresholds for tumor delineation in patients after prolonged androgen deprivation?Materials and methods: Ninety-six patients were included. Using multivariate linear regression analyses, we investigated if DWI and DCE-MRI parameter maps are different in patients receiving hormonal treatment for 0–3 or >3months. Furthermore, logistic regression was performed to obtain specific imaging thresholds for tumor tissue for the two patient groups.Results: We found a significantly higher diffusion and lower perfusion of tumor tissue in the >3months hormonal treatment group compared to the 0–3 group. This resulted in lower tumor conspicuity. Nevertheless, in 18/21 of the patients in the >3months treatment group, a suspicious lesion could be defined based on the MR images. Based on logistic regression, different imaging thresholds should be set for tumor detection in the two treatment groups.Conclusions: Prolonged androgen deprivation decreases tumor conspicuity. Different imaging thresholds need to be set to delineate tumor in patients who have had prolonged hormonal treatment.

Evaluating FDG uptake changes between pre and post therapy respiratory gated PET scans - Corrected Proof

2012-01-24

Abstract: Purpose: Whole body (3D) and respiratory gated (4D) FDG-PET/CT scans performed pre-radiotherapy (pre-RT) and post-radiotherapy (post-RT) were analyzed to investigate the impact of 4D PET in evaluating 18F-fluorodeoxyglucose (FDG) uptake changes due to therapy, relative to traditional 3D PET.Methods and materials: 3D and 4D sequential FDG-PET/CT scans were acquired pre-RT and approximately one month post-RT for patients with non-small cell lung cancer (NSCLC). The lesions of high uptake targeted with radiotherapy were identified on the pre-RT scan of each patient. Each lesion on the 3D and each of the five phases of the 4D scan were analyzed using a region of interest (ROI). For each patient the ROIs of the pre-RT scans were used to locate the areas of initial FDG uptake on the post-RT scans following rigid registration. Post-RT ROIs were drawn and the FDG uptake was compared with that of the pre-RT scans.Results: Sixteen distinct lesions from 12 patients were identified and analyzed. Standardized uptake value (SUV) maxima were significantly higher (p-value <0.005) for the lesions as measured on the 4D compared to 3D PET. Comparison of serial pre and post-RT scans showed a mean 62% decrease in SUV with the 3D PET scan (range 36–89%), and a 67% decrease with the 4D PET scan (range 30–89%). The mean absolute difference in SUV change on 3D versus 4D scans was 4.9%, with a range 0–15% (p-value=0.07).Conclusions: Signal recovery with 4D PET results in higher SUVs when compared to standard 3D PET. Consequently, differences in the evaluation of SUV changes between pre and post-RT plans were observed. Such difference can have a significant impact in PET-based response assessment.

Incidence of skin recurrence after breast cancer surgery - Corrected Proof

2012-01-24

In a study of interobserver variations in delineating the breast for treatment planning, Reed et al. reported that interobserver differences were smallest at the breast skin surface, owing to the use of an automatically generated external skin contour . Accordingly, the RTOG breast atlas extends the breast/chest wall CTV to the skin . However, including the skin into the breast CTV is in discrepancy with planning studies that reported cropping CTV or PTV to 5mm or 6mm under the skin surface . On one hand, including the skin can impact on the need to use a bolus or a skin flash technique , with consequently increased risk of skin toxicity. On the other hand, excluding the skin could cause an unwanted underdosage. There is a need to discuss whether the breast’s skin should be a treatment target or not.

Reducing interobserver variation of boost-CTV delineation in breast conserving radiation therapy using a pre-operative CT and delineation guidelines - Corrected Proof

2012-01-24

Abstract: Aims: To investigate whether using a pre-operative CT scan (Preop-CT) (1) decreases interobserver variation of boost-CTV delineation in breast conserving therapy (BCT), and (2) influences the size of the delineated volumes.Patients and methods: Thirty cT1-2N0-1 breast cancer patients underwent a CT-scan in radiation treatment position, prior to and after lumpectomy. Five observers delineated a boost-CTV, both with and without access to the Preop-CT. For each patient and for each observer pair, the conformity index (CI) and the distance between the centres of mass (COMd) for both boost volumes were calculated. In addition, all delineated volumes including the standard deviation (SD) with respect to the median delineation were calculated.Results: Using a Preop-CT reduced the mean COMd of the boost-CTV from 1.1cm to 1.0cm (p<0.001). No effect was seen on the CI, but the boost-CTV volume reduced from 42cc to 36cc (p=0.005), implying a reduction of interobserver variation. We saw no significant change in the SD.Conclusion: Use of a Preop-CT in BCT results in a modest but statistically significant reduction in interobserver variation of the boost-CTV delineations and in a significant reduction in the boost-CTV volume.

Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors - Corrected Proof

2012-01-24

Abstract: Purpose: To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest.Methods: Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9Gy (n=6), then 5 fractions of 10Gy (n=15), and finally 5 fractions of 12Gy (n=22).Results: Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100Gy compared to 60% for tumors treated with a BED ⩽100Gy. No grade 4 or 5 toxicity was observed. Acute grade 1–2 esophagitis was observed in 11% of patients.Conclusion: SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions.

Hypofraction radiotherapy of liver tumor using cone beam computed tomography guidance combined with active breath control by long breath-holding - Corrected Proof

2012-01-20

Abstract: Background and purpose: To evaluate the feasibility and validity of cone beam computed tomography (CBCT) and active breath control (ABC) by long breath-holding in hypofraction radiotherapy of liver tumor.Methods and materials: Twenty-four patients received hypofraction radiotherapy of liver tumor with long breath-holding at end-inhale; four prescriptions were used: 6Gy×7 (n=8), 10Gy×4 (n=7), 5Gy×9 (n=6), 4Gy×10 (n=3). For each fraction, all patients received pre-correction CBCT scans with ABC, some patients received post-correction and post-treatment CBCT. The interfraction and intrafraction liver positioning errors on medial–lateral (ML), cranial–caudal (CC) and anterior–posterior (AP) directions were obtained. The theoretic margin from clinical target volume (CTV) to planning target volume (PTV) was calculated based on post-treatment error. The dosimetric parameters of PTV and normal tissue were compared between ABC and free breathing (FB).Results: The interfraction error in liver positioning showed system errors (Σ) of 3.18mm (ML), 6.80mm (CC) and 3.05mm (AP); random error (σ) of 3.03mm (ML), 6.78mm (CC) and 3.62mm (AP). These errors were significantly reduced with CBCT guided online correction. The intrafraction systematic error was 0.72mm (ML), 2.21mm (CC), 1.49mm (AP), and random error was 2.30mm (ML), 3.58mm (CC), 2.49mm (AP). Dosimetric parameters such as PTV, the liver’s volume included by 23, 30Gy isodose curve (V23, V30), mean dose to normal liver (MDTNL) and mean dose to cord were significantly larger for FB (P<0.05).Conclusion: Liver radiotherapy with long time breath-holding at end-inhale is an effective method to reduce liver motion, PTV and dose to normal tissue. Interfraction and intrafraction liver positioning errors were substantial. CBCT guided online correction of positioning error is recommended for liver radiotherapy with end-inhale ABC.

Bone marrow transplantation enhances trafficking of host-derived myelomonocytic cells that rescue intestinal mucosa after whole body radiation - Corrected Proof

2012-01-19

Abstract: Background: Bone marrow (BM)-derived cells were demonstrated within intestines after radiation damage and were reported to be responsible for intestine repair. However, there was a discrepancy between intestine epithelial clonogenic regeneration, and mouse survival after BM transplantation (BMT) and radiation. The contribution of BM to acute intestine repair after radiation needed further investigation.Methods: Mouse survival, intestine microcolony assay, immunohistochemical studies of both intestine and BM were evaluated in mice after whole body irradiation (WBI) and BMT. Immunoblotting, flowcytometry, and double immunostaining were used to evaluate the amount and the character of stroma cells within intestines of recipient mice after receiving gender-mismatched BMT or BMT from green fluorescence donors.Results: Stromal cell proliferation within the lamina propria correlated with the beneficial effect of BMT to intestine recovery and day-8 survival of mice. Few donor-derived cells were found before the completion of intestine repair. The number of host but not donor-derived myelomonocytic and stromal cells increased dramatically within one week after radiation and BMT. Depletion of myelomonocytic cells of recipient mice abolished the mitigating effect of BMT.Conclusions: Besides rescuing injured BM from aplasia, BMT triggers trafficking of host CD11b(+) myelomonocytic cells from the host marrow to the radiation-injured intestinal mucosa, enhancing the proliferation of intestinal stroma cells, leading secondarily to epithelial regeneration.

Whole-brain irradiation with concomitant daily fixed-dose Temozolomide for brain metastases treatment: A randomised phase II trial - Corrected Proof

Carlos Gamboa-Vignolle, Tabaré Ferrari-Carballo, Óscar Arrieta, Alejandro Mohar — 2012-01-18

Abstract: Background and purpose: This randomised phase II study evaluated the use of Temozolomide (TMZ) concomitant with 30Gray (Gy) of Whole-brain irradiation (WBI) for 2weeks without adjuvant TMZ vs. WBI alone in patients with Brain metastases (BM) from solid tumours.Materials and methods: Fifty-five patients were randomised into the following groups: 28 patients received WBI (30Gy in 10 fractions over 2weeks) concomitant with once-daily 200mg TMZ on Mondays, Wednesdays, and Fridays, and 300mg TMZ on Tuesdays and Thursdays (TMZ plus WBI arm). Twenty-seven patients received the same schedule of WBI alone (control arm).Results: The objective response (OR) was 78.6% for the TMZ plus WBI arm, (95% confidence interval [CI], 63.4–93.8%) and 48.1% (29.3–66.9%) for the control arm (p=0.019). Median Progression-free survival (PFS) of BM was 11.8months (CI, 4.7–8.9months) and 5.6months (4.9–6.2months) for the TMZ plus WBI and control arms, respectively, (Hazard ratio [HR], 0.24; CI, 0.09–0.65; p=0.005). Overall survival (OS) of 8.0 Months for the TMZ plus WBI arm and 8.1months for the control arm, were not significantly different.Conclusion: A daily fixed dose of TMZ during WBI without adjuvant TMZ was well tolerated and significantly improved local control of BM compared with WBI alone. These findings require confirmation in a phase III trial (ClinicalTrials.gov number, NCT01038271).

Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery - Corrected Proof

2012-01-16

Abstract: Purpose: To evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms (XRCC1, TP53, MSH2, MSH3, XPD), oxidative stress response (GSTP1, GSTA1, eNOS, SOD2) and fibroblast proliferation (TGFβ1) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy.Material and methods: Skin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery. Genotyping was conducted by PCR-RFLP analysis and real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood.Results: In the multivariate analysis, nominally significant associations, before multiple testing corrections, were found between XRCC1 T-77C (T carriers vs. CC, OR: 2.240, 95% CI: 1.015–4.941, P=0.046), eNOS G894T polymorphisms (TT vs. G carriers, OR: 2.473, 95% CI: 1.220–5.012, P=0.012), breast diameter (OR: 1.138, 95% CI: 1.001–1.293, P=0.048), boost dose-fractionation (3Gy vs. no boost, OR: 4.902, 95% CI: 1.458–16.483, P=0.010) and ⩾grade 2 acute radiation skin toxicity in breast cancer patients.Conclusions: As our exploratory study suggests that XRCC1 T-77C and eNOS G874T may confer an increased risk of acute skin reactions to radiotherapy in breast cancer patients, further confirmatory studies are warranted to determine the clinical significance.

Stereotactic body radiation therapy in the treatment of multiple primary lung cancers - Corrected Proof

2012-01-16

Abstract: Background and purpose: Patients with multiple primary lung cancers (MPLC) present a therapeutic dilemma, particularly when they are at high risk for surgical resection. We evaluated the role of stereotactic body radiation therapy (SBRT) in the treatment of MPLC.Materials and methods: A prospective thoracic SBRT registry was explored for patients with either synchronous or metachronous MPLC treated with SBRT for one or both of their tumors. Sixty-three patients were identified and clinical data were analyzed.Results: Fifteen patients had synchronous lesions and 48 patients had metachronous lesions. Seventy-six lesions were treated with SBRT. Median follow-up was 24months for living patients. Median progression-free survival (PFS) and overall survival (OS) for the entire cohort was 15.5 and 20months, respectively. Patients with metachronous MPLC had a significantly higher 2year PFS (53.3% vs. 0%, p=0.0466) compared to patients with synchronous MPLC. Likewise, 2year OS was also superior for patients with metachronous versus synchronous MPLC (68.1% vs. 27.5%, p=0.0014). Six tumors (7.9%) recurred within the radiation field. There were no grade ⩾3 toxicities.Conclusions: SBRT for patients with MPLC appears to be a safe and effective local treatment alternative to surgery, particularly for medically inoperable patients. Patients with metachronous MPLC have encouraging survival rates, and thus local therapy appears justified. However, patients with synchronous MPLC have poor OS and PFS despite having excellent local control, and thus the utility of local therapy in this population requires further study.

Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma - Corrected Proof

2012-01-16

Abstract: Purpose: To investigate threshold dose (TD) of focal liver reaction (FLR) following stereotactic body radiotherapy (SBRT) for patients with hepatocellular carcinoma (HCC) and liver cirrhosis.Materials and methods: In consecutive 50 patients receiving SBRT for small HCC, 38 patients receiving SBRT and follow up >6months, FLR on follow-up CT had been previously studied. Patients with good concordance between FLR and highly irradiated area were eligible. Dose volume histogram (DVH) was used to identify TDs for FLR. Clinical factors were analyzed for correlation with TDs.Results: Of 24 eligible patients, 23 had Child–Pugh score A and 1 scored B. Presence of FLR peaked at a median of 6 (range; 3–12) months. The median and 95% confidential intervals of TDs of pre-contrast and portal-venous phase CT were 32.4Gy (30.3–35.4) and 34.4Gy (31.9–36.0), respectively. Each median coefficient representing the concordance was 74.9% (range; 55.8–98.0%) and 80.5% (range; 70.8–92.4%), respectively. No clinical factors significantly correlated with the TDs.Conclusion: We proposed 30Gy/5 fractions as TD of FLRs following SBRT for patients with HCC and liver cirrhosis. This TD will enable us to predict injured liver volume and to avoid complication beforehand from toxicity. Further pathological and clinical studies, in addition to more practical and precise data of DVH, are needed to clarify the significance of FLRs.

Repeat CT assessed CTV variation and PTV margins for short- and long-course pre-operative RT of rectal cancer - Corrected Proof

2012-01-12

Abstract: Purpose: To quantify the inter-fraction shape variation of the CTV in rectal-cancer patients treated with 5×5 (SCRT) and 25×2Gy (LCRT) and derive PTV margins.Methods and materials: Thirty-three SCRT with daily repeat CT scans and 30 LCRT patients with daily scans during the first week followed by weekly scans were included. The CTV was delineated on all scans and local shape variation was calculated with respect to the planning CT. Margin estimation was done using the local shape variation to assure 95% minimum dose for at least 90% of patients.Results: Using 482 CT scans, systematic and random CTV shape variation was heterogeneous, ranging from 0.2cm close to bony structures up to 1.0cm SD at the upper-anterior CTV region. A significant reduction in rectal volume during LCRT resulted in an average 0.5cm posterior shift of the upper-anterior CTV. Required margins ranged from 0.7cm close to bony structures up to 3.1 and 2.3cm in the upper-anterior region for SCRT and LCRT, respectively.Conclusions: Heterogeneous shape variation demands anisotropic PTV margins. Required margins were substantially larger in the anterior direction compared to current clinical margins. These larger margins were, however, based on strict delineated CTVs, resulting in smaller PTVs compared to current practice.

Control chart analysis of data from a multicenter monitor unit verification study - Corrected Proof

2012-01-12

Abstract: Background and purpose: This study aims to investigate the process of monitor unit verification using control charts. Control charts is a key tool within statistical process control (SPC), through which process characteristics can be visualized, usually chronologically with statistically determined limits.Material and methods: Our group has developed a monitor unit verification software that has been adopted at several Swedish institutions for pre-treatment verification of radiotherapy treatments. Deviations between point dose calculations using the treatment planning systems and using the independent monitor unit verification software from 9219 treatment plans and five different institutions were included in this multicenter study. The process of monitor unit verification was divided into subprocesses. Each subprocess was analyzed using probability plots and control charts.Results: Differences in control chart parameters for the investigated subprocesses were found between different treatment sites and different institutions, as well as between different treatment techniques. 19 of 37 subprocesses met the clinical specification (±5%), i.e. process capability index was equal to or above one.Conclusions: Control charts were found to be a useful tool for continuous analysis of data from the monitor unit verification software for patient specific quality control, as well as for comparisons between different institutions and treatment sites. The derived control chart limits were in agreement with AAPM TG114 guidelines on action levels.

Volumetric modulated arc therapy for nasopharyngeal carcinoma: A dosimetric comparison with TomoTherapy and step-and-shoot IMRT - Corrected Proof

2012-01-11

Abstract: Purpose: Volumetric modulated arc therapy (VMAT), a novel technique, employs a linear accelerator to conduct dynamic modulation rotation radiotherapy. The goal of this study was to compare VMAT with helical tomotherapy (HT) and step-and-shoot intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with regard to the sparing effect on organs at risk (OARs), dosimetric quality, and efficiency of delivery.Materials and methods: Twenty patients with NPC treated by HT were re-planned by VMAT (two arcs) and IMRT (7–9 fields) for dosimetric comparison. The target area received three dose levels (70, 60, and 54Gy) in 33 fractions using simultaneous integrated boosts technique. The Philips Pinnacle Planning System 9.0 was adopted to design VMAT, using SmartArc as the planning algorithm. For a fair comparison, the planning target volume (PTV) coverage of the 3 plans was normalized to the same level. Dosimetric comparisons between VMAT, HT, and IMRT plans were analyzed to evaluate (1) coverage, homogeneity, and conformity of PTV, (2) sparing of OARs, (3) delivery time, and (4) monitor units (MUs).Results: The VMAT, HT, and IMRT plans had similar PTV coverage with an average of 96%. There was no significant difference between VMAT and HT in homogeneity, while the homogeneity indices of VMAT (1.06) and HT (1.06) were better than IMRT plans (1.07, p<0.05). HT plans provided a better conformity index (1.17) than VMAT (1.28, p=0.01) and IMRT (1.36, p=0.02). When compared with IMRT, VMAT and HT had a better sparing effect on brain stem and spinal cord (p<0.05). The effect of parotid sparing was similar between VMAT (mean=26.3Gy) and HT (mean=27.5Gy), but better than IMRT (mean=31.3Gy, p<0.01). The delivery time per fraction for VMAT (5.7min) were much lower than for HT (9.5min, p<0.01) and IMRT (9.2min, p<0.01).Conclusions: Our results indicate that VMAT provides better sparing of normal tissue, homogeneity, and conformity than IMRT, and shorter delivery time than HT.

Ionizing radiation regulates the expression of AMP-activated protein kinase (AMPK) in epithelial cancer cells: Modulation of cellular signals regulating cell cycle and survival - Corrected Proof

2012-01-09

Abstract: Purpose: To analyze the (i) expression of AMPK in a variety of epithelial cancer cells, (ii) regulation of AMPK subunit expression by ionizing radiation (IR) and (iii) impact of AMPK on signaling pathways regulating cell cycle and survival.Methods and materials: Human lung, prostate, and breast normal and cancer cells were treated with 0 or 8Gy IR and mRNA and protein levels of AMPK were evaluated by RT-PCR and immunoblotting 24 or 48h later. Untreated and radiated wild type (WT) and AMPKα−/− mouse embryonic fibroblasts (MEFs) were analyzed by immunoblotting using total- and phosphorylation-specific antibodies. Histone H2Ax was examined by fluorescence microscopy. The cell cycle and survival of WT and AMPKα−/− MEFs was also evaluated following 8Gy by IR.Results: AMPK subunits were found widely expressed in normal and cancer epithelial cells. IR increased subunit protein levels and stimulated gene transcription in cancer cells. AMPKα−/−-MEFs showed enhanced basal total levels of ATM and phosphorylation of its substrates histone H2Ax, but inhibited response of these markers and of checkpoint kinase Chk2 phosphorylation to IR. AMPKα−/−-MEFs showed increased basal levels of p53 and cyclin-dependent kinase inhibitors p21cip1, but lack of response of both genes to IR. These cells had increased basal levels and activation of the Akt-mTOR-p70S6K/4-EBP1 signalling pathway. IR increased Akt, p70S6K and 4-EBP1 phosphorylation in WT-MEFs, but this was reduced in AMPKα−/−-MEFs. AMPKα−/−-MEFs failed to arrest at the G2-M checkpoint after IR and showed a trend for radio-resistance in proliferation assays.Conclusions: AMPK is widely expressed in human normal and cancer epithelial cells and its gene transcription, protein levels, and enzymatic activity is stimulated by IR. Work with AMPKα knockout cells suggests that AMPK (i) may mediate a suppressive regulation on basal expression and activity of ATM and its downstream effector pathways Chk2/p53-p21cip1 and Akt-mTOR, (ii) facilitates the normal response of these pathways to IR and, (iii) mediates the IR-induced G2-M checkpoint.

Cone beam CT for organs motion evaluation in pediatric abdominal neuroblastoma - Corrected Proof

Mohamed Soliman Nazmy, Yasser Khafaga, Amr Mousa, Ehab Khalil — 2011-12-26

Abstract: Background and purpose: To quantify the organ motion relative to bone in different breathing states in pediatric neuroblastoma using cone beam CT (CBCT) for better definition of the planning margins during abdominal IMRT.Methods and materials: Forty-two datasets of kV CBCT for 9 pediatric patients with abdominal neuroblastoma treated with IMRT were evaluated. Organs positions on planning CT scan were considered the reference position against which organs and target motions were evaluated. The position of the kidneys and the liver was assessed in all scans. The target movement was evaluated in four patients who were treated for gross residual disease.Results: The mean age of the patients was 4.1±1.6years. The range of target movement in the craniocaudal direction (CC) was 5mm. In the CC direction, the range of movement was 10mm for the right kidney, and 8mm for the left kidney. Similarly, the liver upper edge range of motion was 11mm while the lower edge range of motion was 13mm.Conclusions: With the use of daily CBCT we may be able to reduce the PTV margin. If CBCT is not used daily, a wider margin is needed.

Assessment of hypoxia and radiation response in intramuscular experimental tumors by dynamic contrast-enhanced magnetic resonance imaging - Corrected Proof

Kirsti Marie Øvrebø, Tord Hompland, Berit Mathiesen, Einar K. Rofstad — 2011-12-26

Abstract: Background and purpose: Studies of intradermal melanoma xenografts have suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful method for assessing the extent of hypoxia in tumors. Because the microvascular network of tumors is influenced significantly by the site of growth, we challenged this possibility in the present work by studying relationships between DCE-MRI-derived parameters and hypoxia in intramuscular melanoma xenografts.Materials and methods: Intramuscular R-18, U-25, and V-27 tumors were subjected to DCE-MRI and measurement of the fraction of radiobiologically hypoxic cells (HFRad). Parametric images of Ktrans and ve were produced by pharmacokinetic analysis, and Ktrans and ve were related to HFRad in individual tumors.Results: Ktrans decreased with increasing HFRad. The correlations between Ktrans and HFRad were similar for the three tumor lines and were highly significant (P<0.00001). There was no correlation between ve and HFRad. However, ve decreased significantly with increasing cell survival after single dose irradiation.Conclusion: Intramuscular melanoma xenografts show similar inverse correlations between Ktrans and HFRad as intradermal tumors, which support the current clinical attempts to establish DCE-MRI as a method for detecting hypoxia and defining therapeutic targets in tumors.

Urethra sparing – potential of combined Nickel–Titanium stent and intensity modulated radiation therapy in prostate cancer - Corrected Proof

Jakob Borup Thomsen, Dennis Tideman Arp, Jesper Carl — 2011-12-26

Abstract: Background and purpose: To investigate a novel method for sparing urethra in external beam radiotherapy of prostate cancer and to evaluate the efficacy of such a treatment in terms of tumour control using a mathematical model.Materials and methods: This theoretical study includes 20 patients previously treated for prostate cancer using external beam radiotherapy. All patients had a Nickel–Titanium (Ni–Ti) stent inserted into the prostate part of urethra. The stent has been used during the treatment course as an internal marker for patient positioning prior to treatment. In this study the stent is used for delineating urethra while intensity modulated radiotherapy was used for lowering dose to urethra. Evaluation of the dose plans were performed using a tumour control probability model based on the concept of uniform equivalent dose.Results: The feasibility of the urethra dose reduction method is validated and a reduction of about 17% is shown to be possible. Calculations suggest a nearly preserved tumour control probability.Conclusions: A new concept for urethra dose reduction is presented. The method relies on the use of a Ni–Ti stent as a fiducial marker combined with intensity modulated radiotherapy. Theoretical calculations suggest preserved tumour control.

A new lung stent tested as fiducial marker in a porcine model - Corrected Proof

2011-12-23

Abstract: Introduction: The aim of the present study was to test the feasibility of a Nickel–Titanium (Ni–Ti) stent technique (Memocore™) in a porcine model. The stent is intended as a new fiducial for gated image guided radiotherapy in the lung. The study included test of an improved insertion system and respiratory gated treatments with this new technique.Methods and materials: Tests were carried out in a porcine model using Göttingen mini-pigs. The study included 10 animals. Planning CT was performed as 4 dimensional CT (4DCT) using the Varian RPM system. Respiratory gated radiotherapy treatments were simulated using the Brainlab ExacTrac system. Reproducibility of stent position during treatment was analyzed off-line using an experimental version of the ExacTrac software. The experimental version has a dedicated algorithm for segmentation of the stent in the planning CT and subsequent registration to X-ray position images.Results: A total of 23 stents were inserted in the 10 animals. Stents could be placed in all parts of the lungs. No stent migrated within the four weeks the experiment lasted. Stent trajectories in the lung were not reproducible, even though respiration was highly standardized using a respirator. The best accuracy of stent position in the gating window was obtained using gating at the half_max amplitude as reference level. The smallest stent movement within the gating window was observed in the exhale phase. Further success of human application will depend on the possibility to insert the stent within or close to lung tumors.Conclusions: This new technique based on the Memocore™ lung stent used in connection with respiratory gated radiotherapy was demonstrated to be feasible in a porcine model. The study demonstrated lack of reproducibility in lung trajectories of inserted stents. The technique gave the best accuracy when applied to the exhale phase of respiration.

Feasibility of using anatomical surrogates for predicting the position of lung tumours - Corrected Proof

2011-12-23

Abstract: We studied the use of internal anatomical surrogates (carina and diaphragm) for the purpose of predicting the 3D position of lung tumours in 41 patients, in whom repeat 4DCT scans were available. Despite using two surrogates, significant prediction errors were observed, which varied depending on tumour position, baseline tumour motion and respiratory phase.

A dual centre study of setup accuracy for thoracic patients based on Cone-Beam CT data - Corrected Proof

Tine B. Nielsen, Vibeke N. Hansen, Jonas Westberg, Olfred Hansen, Carsten Brink — 2011-12-23

Background and purpose: To compare setup uncertainties at two different institutions by using identical imaging and analysis techniques for thoracic patients with different fixation equipments.Methods and materials: Patient registration results from Cone-Beam CT (CBCT) scans of 174 patients were evaluated (1068 CBCT scans). Patients were fixated using a standard or custom made fixation at Royal Marsden Hospital and Odense University Hospital, respectively. Five imaging protocols were retrospectively simulated to compare the fixation equipments. Systematic and random setup uncertainties were calculated to estimate sufficient treatment margins.Results: The setup uncertainties are of similar sizes at the two institutions and there is no observable drift in the precision of the fixation equipments during the treatment course. When a correcting imaging protocol is performed there is a significant increase of the systematic setup uncertainties in between imaging fractions. A margin reduction of ⩾0.2cm can be achieved for patients with peak-to-peak respiration amplitudes of ⩾1.2cm when changing from 4D-CT to Active Breathing Coordinator™ (ABC).Conclusions: The setup uncertainties at the two institutions are the same despite different fixation equipments. Hence margins cannot be reduced by changing fixating equipment.

A practical technique to avoid the hippocampus in prophylactic cranial irradiation for lung cancer - Corrected Proof

2011-12-22

Abstract: A practical technique is presented to deliver hippocampus avoiding prophylactic cranial irradiation for lung cancer patients, using two lateral fields. For a prescribed dose of 12×2.5Gy, sparing of the hippocampi to 6.1Gy was achieved with a V95% of the brain of 81.7%.

Vertebral metastases reirradiation with volumetric-modulated arc radiotherapy - Corrected Proof

2011-12-22

Abstract: Purpose: To assess the feasibility, acute toxicity, clinical improvement, local control and survival for spinal metastatic patients re-irradiated using volumetric-modulated-arc-radiotherapy (VMAT).Methods and materials: Between February 2009 and November 2010, 31 patients were treated. Surgery was performed in six before re-irradiation. The clinical target volume (CTV) was defined as the whole vertebrae with recurrence excluding the central section of spinal canal. Planning target volume was defined as CTV+0–5mm in the three directions. Dose was prescribed in order to have biological equivalent dose to the spinal cord from the two courses lower than 120Gy2 to 1cc of the volume. Clinical improvement, toxicity and recurrence were evaluated. All patients had back pain before treatment and 15 (48%) neurological deficit.Results: Clinical remission of pain was obtained in 29 patients (93%). Neurological improvement was observed in 73% of patients. No acute or late toxicities were recorded. No recurrence occurred. Median survival was 10months (range 6–24). At the last follow-up 19 patients (61%) were alive and 12 (39%) dead from systemic disease progression. The 1 and 2year survival were 55% and 35%, respectively.Conclusion: In patients with spinal metastases recurrence re-irradiation with VMAT is feasible and provides clinical benefit in most patients.

The International Atomic Energy Agency (IAEA): An active role in the global fight against cancer - Corrected Proof

2011-12-14

The International Atomic Energy Agency (IAEA) is an independent, intergovernmental science and technology-based organization, in the United Nations, that serves as the global focal point for nuclear cooperation. Article II of the IAEA Statute states: “The Agency shall seek to accelerate and enlarge the contribution of atomic energy to peace, health and prosperity throughout the world. It shall ensure, so far as it is able, that assistance provided by it or at its request or under its supervision or control is not used in such a way as to further any military purpose” .

The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells - Corrected Proof

2011-12-14

Abstract: Purpose: To examine direct and bystander radiation-induced effects in normal umbilical-cord stromal stem cell (HCSSC) lines and in human cancer cells.Materials and methods: The UCSSC lines used in this study were obtained in our laboratory. Two cell lines (UCSSC 35 and UCSSC 37) and two human melanoma skin-cancer cells (A375 and G361) were exposed to ionizing radiation to measure acute radiation-dosage cell-survival curves and radiation-induced bystander cell-death response.Normal cells, although extremely sensitive to ionizing radiation, were resistant to the bystander effect whilst tumor cells were sensitive to irradiated cell-conditioned media, showing a dose–response relationship that became saturated at relatively low doses.We applied a biophysical model to describe bystander cell-death through the binding of a ligand to the cells. This model allowed us to calculate the maximum cell death (χmax) produced by the bystander effect together with its association constant (KBy) in terms of dose equivalence (Gy). The values obtained for KBy in A375 and G361 cells were 0.23 and 0.29Gy, respectively.Conclusion: Our findings help to understand how anticancer therapy could have an additional decisive effect in that the response of sub-lethally hit tumor cells to damage might be required for therapy to be successful because the survival of cells communicating with irradiated cells is reduced.

External validation of three dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among patients treated with intensity modulated radiotherapy - Corrected Proof

2011-12-14

Abstract: Purpose: The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER6M) and sticky saliva (STIC6M) at 6months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT).Methods and materials: Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER6M consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC6M consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit).In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R2 Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer–Lemeshow “goodness-of-fit” test.Results: Overall model performance of the 3D-CRT based predictive models for XER6M and STIC6M was significantly worse in terms of the Brier score and R2 Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer–Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome.Conclusion: 3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or chemoradiation turned out to be less valid for patients treated with IMRT. The main message from these findings is that models developed in a population treated with a specific technique cannot be generalised and extrapolated to a population treated with another technique without external validation.

Does IGRT ensure target dose coverage of head and neck IMRT patients? - Corrected Proof

Pierre Graff, Weigang Hu, Sue S. Yom, Jean Pouliot — 2011-12-07

Abstract: Purpose: To determine if image-guided radiotherapy (IGRT) ensures dose coverage to the target, and to assess the dosimetric impact of anatomic changes using megavoltage cone-beam CT (MVCBCT) for patient positioning during head and neck IMRT.Methods and materials: Forty-eight MVCBCT from 10 head and neck IMRT/IGRT patients were analyzed off-line. Target volumes and organs at risk (OARs) contours delineated on CT were transferred and adjusted on MVCBCT images. Each MVCBCT was processed to allow dose recalculation, resulting in 469 dose–volume histograms (DVHs). The concept of dosimetric latitude was introduced to provide a clinical perspective.Results: MVCBCT target DVHs showed a moderate level of difference in D95 (dose to ⩾95% of volume), generally less than a 5% difference from the planned dose. Delivered-dose increases to the spinal cord and brainstem showed no apparent time trend. The 4mm margin around OARs was a useful precaution to prevent exceeding critical dose thresholds. The parotid glands showed progressive increases in mean dose related to shrinkage of the external contours.Conclusion: IGRT repositioning ensured target volume coverage, but significant dose variations were observed for OARs. The dosimetric impact of anatomic changes during radiotherapy was of lesser importance than the effects of IGRT repositioning.

Multimodality functional imaging of spontaneous canine tumors using 64Cu-ATSM and 18FDG PET/CT and dynamic contrast enhanced perfusion CT - Corrected Proof

2011-11-28

Abstract: Purpose: To compare the distribution and uptake of the hypoxia tracer 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) PET/CT, FDG PET/CT and dynamic contrast enhanced perfusion CT (DCE-pCT) in spontaneous canine tumors. In addition 64Cu-ATSM distribution over time was evaluated.Methods and materials: Nine spontaneous cancer-bearing dogs were prospectively enrolled. FDG (1h pi.) and 64Cu-ATSM (3 and 24h pi.) PET/CT were performed over three consecutive days. DCE-pCT was performed on day 2. Tumor uptake of FDG and 64Cu-ATSM was assessed semi-quantitatively and the distribution of FDG, 64Cu-ATSM and CT perfusion parameters correlated.Results: 64Cu-ATSM distribution on scans performed 24h apart displayed moderate to strong correlation; however, temporal changes were observed. The spatial distribution pattern of 64Cu-ATSM between scans was moderately to strongly positively correlated to FDG, whereas the correlation of CT perfusion parameters to FDG and to 64Cu-ATSM yielded more varying results.Conclusions: 64Cu-ATSM uptake was positively correlated to FDG. 64Cu-ATSM was found to be relatively stable between PET scans performed at different time points, important temporal changes were however observed in hypo-perfused regions. These findings potentially indicate that prolonged uptake periods for 64Cu-ATSM imaging may be needed. Although a moderate to strong correlation between 64Cu-ATSM and FDG PET/CT is observed, the two tracers provide different biological information with an overlapping spatial distribution.

Parameters for the Lyman Kutcher Burman (LKB) model of Normal Tissue Complication Probability (NTCP) for specific rectal complications observed in clinical practise - Corrected Proof

2011-11-28

Abstract: Background and purpose: The Normal Tissue Complication Probability (NTCP) for rectum is usually defined for late rectal bleeding. This study calculates NTCP parameter values for additional rectal toxicity endpoints observed in clinical practise.Materials and methods: 388 patients from the multicentre MRC-RT01 prostate conformal radiotherapy trial (ISRCTN 47772397) were used to derive independent Lyman Kutcher Burman model (LKB) parameters for five late rectal toxicity endpoints: rectal bleeding, proctitis, stool frequency, loose stools and rectal urgency. The parameters were derived using maximum likelihood estimation. Bootstrap and leave-one-out methods were employed to test the generalisability of the results for use in a general population.Results: A consistent pattern of increasing value of TD50(1) for Grade 2 toxicity only compared to Grades 1 and 2 toxicity was observed for all endpoints. Parameter values varied between endpoints (particularly for the volume parameter n). TD50(1), m and n were 68.5Gy (95% CI)(66.8–70.8), 0.15 (0.13–0.17) and 0.13 (0.10–0.17), respectively, for G2 rectal bleeding. Bootstrap and leave-one-out results showed that the rectal bleeding and proctitis parameter fits were extremely robust.Conclusions: The variation between the values derived for different endpoints may indicate different patho-physiological responses of the rectum to radiation. Therefore different parameter sets would be required to predict specific rectal toxicity endpoints.

Combination of quercetin with radiotherapy enhances tumor radiosensitivity in vitro and in vivo - Corrected Proof

Chenghe Lin, Yan Yu, Hong-guan Zhao, Aimin Yang, Hong Yan, Yali Cui — 2011-11-28

Abstract: Purpose: Quercetin (3, 3,′ 4′, 5, 7 – five-flavonoids) is one of the main components of flavonoids, with multifunctions on immune function, anti-oxidation, anti-viral, anti-inflammatory, and cardiovascular protection. We hypothesize that a combination of quercetin with radiation would increase tumor radiosensitivity. To test this hypothesis, we conducted in vitro and in vivo studies.Methods and materials: The in vitro radio-sensitization activity of quercetin was tested in DLD1, HeLa and MCF-7 tumor cell lines by colony formation assays. The in vivo activity was assessed in the DLD-1 human colorectal cancer xenograft model in nude mice. Mechanistic studies were conducted in several cell lines using Western blot analysis and immunofluorescence microscopy.Results: We found that quercetin can significantly increase tumor radiosensitivity both in vitro and in vivo. The in vitro Sensitizing Enhancement Ratios in DLD1, HeLa and MCF-7 cells were 1.87, 1.65, and 1.74, respectively. The mean doubling time of tumor xenografts was significantly increased in irradiated mice treated with quercetin. At the cellular level, exposure to quercetin resulted in prolonged DNA repair. The mechanistic studies demonstrated that quercetin induced radio-sensitization is through inhibiting the ATM kinase, one of the critical DNA damage response proteins.Conclusion: We demonstrate both in vitro and in vivo evidence that combination of quercetin with radiotherapy can enhance tumor radiosensitivity by targeting the ATM-mediated pathway in response to radiation.

Salvage radiotherapy after prostatectomy – What is the best time to treat? - Corrected Proof

2011-11-28

Abstract: Purpose: Salvage radiotherapy (SRT) is applied routinely in patients with biochemical relapse after radical prostatectomy (RP). However, only ∼30% of these patients achieve a durable response after 10years. As a standard, 66Gy are given, ideally with a PSA below 0.5ng/ml. We tried to determine more precisely the optimal PSA for starting SRT.Material and methods: In 301 prostate cancer patients without hormonal treatment, we analysed the impact on the biochemical response (bNED) to SRT of two pre-SRT PSA levels, namely below or above the median of 0.28ng/ml.Results: The median follow-up time for the entire group was 30months. In 151 patients, SRT commenced at a PSA ⩽0.28ng/ml, in 150 at >0.28ng/ml. Eighty-two patients (27%) developed biochemical progression during follow up. The calculated two-year bNED was 74% for the entire group, 78% versus 61% for a PSA⩽or >0.28ng/ml, respectively. In multivariate analysis, pT3b, resection status, pre-SRT PSA dichotomized at median, PSA post-SRT undetectable, and PSA doubling time were statistically significant independent predictors of progression after SRT.Conclusions: Our findings suggest that a PSA of ⩽0.28ng/ml improves bNED compared with a PSA before SRT of >0.28ng/ml.

Clinical impact of margin reduction on late toxicity and short-term biochemical control for patients treated with daily on-line image guided IMRT for prostate cancer - Corrected Proof

2011-11-28

Abstract: To evaluate the impact of PTV reduction when delivering image-guided IMRT (IG-IMRT) for patients with prostate cancer. Between 2001 and 2007, 165 men were treated with daily IG-IMRT using a 3D ultrasound-based system. Median dose prescribed to the prostate was 78Gy [74Gy–78Gy]. Patients were stratified regarding the CTV to the PTV margin: group A (n=87)=5mm or group B (n=78)=10mm. Late toxicity was scored using the CTC v3.0 scale. Biochemical progression-free survival (bPFS) was calculated using the Phoenix definition. Grade 2 genitourinary toxicity was 7.0% for group A and 6.6% for group B (p=1.00). Grade 2 gastrointestinal toxicity was 1.2% and 2.6% (p=0.38). With a median follow-up of 38.3months [5.25–87.3], bPFS at 3years was 92.5% [82.4%–96.9%] in group A and 94.3% [85.5%–97.8%] in group B (p=0.84). IG-IMRT yielded very low rates of late toxicity. Margin had impact neither on short-term bPFS nor late toxicity.

Accuracy of self-reported tobacco assessments in a head and neck cancer treatment population - Corrected Proof

2011-11-28

Abstract: Prospective analysis was performed of self-reported and biochemically confirmed tobacco use in 50 head and neck cancer patients during treatment. With 93.5% compliance to complete weekly self-report and biochemical confirmatory tests, 29.4% of smokers required biochemical assessment for identification. Accuracy increased by 14.9% with weekly vs. baseline self-reported assessments. Data confirm that head and neck cancer patients misrepresent true tobacco use during treatment.

In-gantry or remote patient positioning? Monte Carlo simulations for proton therapy centers of different sizes - Corrected Proof

2011-11-28

Abstract: Purpose: We estimated the potential advantage of remote positioning (RP) vs. in-room positioning (IP) for a proton therapy facility in terms of patient throughput.Materials and methods: Monte Carlo simulations of facilities with one, two or three gantries were performed. A sensitivity analysis was applied by varying the imaging and setup correction system (ICS), the speed of transporters (for RP) and beam switching time. Possible advantages of using three couches (for RP) or of switching the beam between fields was also investigated.Results: For a single gantry facility, an average of 20% more patients could be treated using RP: ranging from +45%, if a fast transporter and slow ICS were simulated, to −14% if a slow transporter and fast ICS was simulated. For two gantries, about 10% more patients could be treated with RP, ranging from +32% (fast transporter, slow ICS) to −12% (slow transporter, fast ICS). The ability to switch beam between fields did not substantially influence the throughput. In addition, the use of three transporters showed increased delays and therefore a slight reduction of the fractions executables. For three gantries, RP and IP showed similar results.Conclusions: The advantage of RP vs. IP strongly depends on ICS and the speed of the transporters. For RP to be advantageous, reduced transport times are required. The advantage of RP decreases with increasing number of gantries.