Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between ...zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer.
For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship.
The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy.
In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three-dimensional inhomogenous dose distribution, cancer risk can be compared by computing OED using the coefficients obtained in this work.
Patients with biochemical failure (BF) after radical prostatectomy may benefit from dose-intensified salvage radiation therapy (SRT) of the prostate bed. We performed a randomized phase III trial ...assessing dose intensification.
Patients with BF but without evidence of macroscopic disease were randomly assigned to either 64 or 70 Gy. Three-dimensional conformal radiation therapy or intensity-modulated radiation therapy/rotational techniques were used. The primary end point was freedom from BF. Secondary end points were acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and quality of life (QoL) according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and PR25.
Three hundred fifty patients were enrolled between February 2011 and April 2014. Three patients withdrew informed consent, and three patients were not eligible, resulting in 344 patients age 48 to 75 years in the safety population. Thirty patients (8.7%) had grade 2 and two patients (0.6%) had grade 3 genitourinary (GU) baseline symptoms. Acute grade 2 and 3 GU toxicity was observed in 22 patients (13.0%) and one patient (0.6%), respectively, with 64 Gy and in 29 patients (16.6%) and three patients (1.7%), respectively, with 70 Gy (P = .2). Baseline grade 2 GI toxicity was observed in one patient (0.6%). Acute grade 2 and 3 GI toxicity was observed in 27 patients (16.0%) and one patient (0.6%), respectively, with 64 Gy, and in 27 patients (15.4%) and four patients (2.3%), respectively, with 70 Gy (P = .8). Changes in early QoL were minor. Patients receiving 70 Gy reported a more pronounced and clinically relevant worsening in urinary symptoms (mean difference in change score between arms, 3.6; P = .02).
Dose-intensified SRT was associated with low rates of acute grade 2 and 3 GU and GI toxicity. The impact of dose-intensified SRT on QoL was minor, except for a significantly greater worsening in urinary symptoms.
Purpose: Determine the time-dependent magnitude of intrafraction prostate displacement and a cutoff for the tracking decision. Methods: Nine patients with localized prostate cancer were treated with ...ultra-hypofractionated radiotherapy (CyberKnife) with fiducial markers. Exact tract kV/kV imaging was used with an average interval of 19−92 s. A Gaussian distribution was calculated for the x-, y-, and z-directions (σx,y,z). The variation of prostate motion (μσ) was obtained by averaging the patients’ specifics, and the safety margin was calculated to be MAB = WYm + WBSs. Results: The calculated PTV safety margins were as follows: at 40 s: 0.55 mm (L/r), 0.85 mm (a/p), and 1.05 mm (s/i); at 60 s: 0.9 mm (L/r), 1.35 mm (a/p), and 1.55 mm (s/i); at 100 s: 1.5 mm (L/r), 2.3 mm (a/p), and 2.6 mm (s/i); at 150 s: 1.9 mm (L/r), 3.1 mm (a/p), and 3.6 mm (s/i); at 200 s: 2.2 mm (L/r), 3.8 mm (a/p), and 4.2 mm (s/i); and at 300 s: 2.6 mm (L/r), 5.3 mm (a/p), and 5.6 mm (s/i). A tracking cutoff of 2.5 min seemed reasonable. In order to achieve an accuracy of < 1 mm, tracking with < 50 s intervals was necessary. Conclusions: For ultra-hypofractionated radiotherapy of the prostate with treatment times > 2.5 min, intrafraction motion management is recommended.
For the epidemiological evaluation of long-term side effects of radiotherapy patients, it is important to know the doses to organs and tissues everywhere in the patient. Computed tomography (CT) ...images of the patients which contain the anatomical information are sometimes available for each treated patient. However, the available CT scans usually cover only the treated volume of the patient including the target and surrounding anatomy. To overcome this limitation, in this work we describe the development of a software tool using the Varian Eclipse Scripting API for extending a partial-body CT to a whole-body representation in the treatment planning system for dose calculation. The whole-body representation is created by fusing the partial-body CT with a similarly sized whole-body computational phantom selected from a library containing 64 phantoms of different heights, weights, and genders. The out-of-field dose is calculated with analytical models from the literature and merged with the treatment planning system-calculated dose. To test the method, the out-of-field dose distributions on the computational phantoms were compared to dose calculations on whole-body patient CTs. The mean doses, D2% and D98% were compared in 26 organs and tissues for 14 different treatment plans in 5 patients using 3D-CRT, IMRT, VMAT, coplanar and non-coplanar techniques. From these comparisons we found that mean relative differences between organ doses ranged from −10% and +20% with standard deviations of up to 40%. The developed method will help epidemiologists and researchers estimate organ doses outside the treated volume when only limited treatment planning CT information is available.
Cancer induction after radiation therapy is known as a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the patient to be treated including ...breast cancer.
In this work a dose-response relationship for breast cancer is derived based on(i) the analysis of breast cancer induction after Hodgkin's disease,(ii) a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and(iii) the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy,(iv) the breast cancer induction of the A-bomb survivor data.
The fitted model parameters for an α/β = 3 Gy were α = 0.067Gy-1 and R = 0.62. The risk for breast cancer is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 20 Gy and drops off only slightly at larger doses. The predicted EAR for breast cancer after radiotherapy of Hodgkin's disease is 11.7/10000PY which can be compared to the findings of several epidemiological studies where EAR for breast cancer varies between 10.5 and 29.4/10000PY. The model was used to predict the impact of the reduction of radiation volume on breast cancer risk. It was estimated that mantle field irradiation is associated with a 3.2-fold increased risk compared with mediastinal irradiation alone, which is in agreement with a published value of 2.7. It was also shown that the modelled age dependency of breast cancer risk is in satisfying agreement with published data.
The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients.
In patients presenting with limited nodal recurrence following radical prostatectomy (RP), stereotactic body radiotherapy (SBRT) results might improve with a better case selection.
Single-institution ...retrospective analysis of patients presenting with 1-3 lymph node (LN) recurrences (N1 or M1a) on 18F-Choline PET/CT. Prior therapy included radical prostatectomy (RP) ± salvage radiotherapy (RT), in absence of any systemic therapy. Outcome parameters were biochemical response (BR), time to biochemical recurrence (TBR) and time interval between SBRT and androgen deprivation therapy start (TADT). Time to event endpoints was analysed using Kaplan-Meier method. Potential prognostic factors were examined using univariate proportional hazards regression for TADT and logistic regression for BR. The optimal cut-off point for LN size was calculated using the Contal and O'Quigley method.
25 patients fulfilling study criteria were treated with SBRT from January 2010 to January 2015 and retrospectively analysed. Median follow up was 18 months and median LN diameter 10.5 mm. SBRT was delivered to a median dose of 36 Gy in three fractions (range: 30-45 Gy). BR was reached in 52% of cases. Median TBR was 11.9 months and significantly longer in patients with larger LN (Hazard ratio HR = 0.87, P = 0.03). Using 14 mm as cut off for LN, median TBR was 10.8 months for patients with small LN (18 patients), and 21.2 months for patients with large LN (6 patients) (P unadjusted = 0.009; P adjusted = 0.099). ADT was started in 32% of patients after a median follow-up of 18 months.
For PCa patients with 1-3 LN recurrence after RP (± salvage RT), SBRT might result in a better biochemical control when delivered to larger sized (≥ 14 mm) LN metastases. This study is hypothesis generating and results should be tested in a larger prospective trial.
There is a trend towards hypofractionated stereotactic radiotherapy (RT) in prostate cancer to apply high single doses in a few fractions. Using the Cyberknife® robotic system multiple non-coplanar ...fields are usually given with a treatment time of one hour or more. We planned to evaluate organ motion in this setting injecting a hydrogel spacer to protect the anterior rectal wall during treatment.
A 66 years old man with low risk prostate cancer was planned for robotic hypofractionated stereotactic RT. After implantation of fiducial markers and a hydrogel spacer a total dose of 36.25 Gy in 5 fractions was given to the planning target volume (clinical target volume + 3 mm). After each beam the corresponding data reporting on the intra-fractional movement were pre-processed, the generated log-files extracted and the data analysed according to different directions: left -right (LR); anterior - posterior (AP); inferior -superior (IS). Clinical assessments were prospectively done before RT start, one week after the end of treatment as well as 1, 6 and 12 months afterwards. Symptoms were documented using Common Toxicity and Adverse Events Criteria 4.0.
Tolerability of marker and hydrogel implantation was excellent. A total of 284 non-coplanar fields were used per fraction. The total treatment time for all fields per fraction lasted more than 60 minutes. The detected and corrected movements over all 5 fractions were in a range of +/- 4 mm in all directions (LR: mean 0,238 - SD 0,798; AP: mean 0,450 - SD 1,690; and IS: mean 0,908 - SD 1,518). V36Gy for the rectum was 0.062 ccm. After RT, grade 1-2 intestinal toxicity and grade 1 genitourinarytoxicity occurred, but resolved completely after 10 days. On 1-, 6- and 12-months follow-up the patient was free of any symptoms with only slight decrease of erectile function (grade 1). There was a continuous PSA decline.
Prostate movement was relatively low (+/- 4 mm) even during fraction times of more than 60 minutes. The hydrogel spacer might serve as a kind of stabilisator for the prostate, but this should be analysed in a larger cohort of patients.
Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known ...regarding their respective applicability in clinical practice.
A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared.
Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm(3)), and decrease in the union volume (79.3 vs 84.2 cm(3)). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different.
The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.
Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP).
To report the outcomes of the SAKK 09/10 trial comparing conventional and ...dose-intensified SRT.
SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP.
Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy.
The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL).
Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82–1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL.
Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP.
The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient.
This clinical trial is registered on ClinicalTrials.gov as NCT01272050.
Dose-intensified salvage radiotherapy after radical prostatectomy did not show superior outcomes for freedom from biochemical progression when compared to conventional-dose treatment. However, the higher dose was associated with a higher rate of late gastrointestinal toxicity.
To evaluate the results of the radiation therapy (RT) quality assurance (QA) program of the phase 3 randomized SAKK 09/10 trial in patients with biochemically recurrent prostate cancer after ...prostatectomy.
Within the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) 09/10 trial testing 64-Gy versus 70-Gy salvage RT, a central collection of treatment plans was performed and thoroughly reviewed by a dedicated medical physicist and radiation oncologist. Adherence to the treatment protocol and specifically to the European Organization for the Research and Treatment of Cancer (EORTC) guidelines for target volume definition (classified as deviation observed yes vs no) and its potential correlation with acute and late toxicity (Common Terminology Criteria for Adverse Events version 4.0) and freedom from biochemical progression (FFBP) were investigated.
The treatment plans for 344 patients treated between February 2011 and April 2014 depicted important deviations from the EORTC guidelines and the recommendations per trial protocol. For example, in up to half of the cases, the delineated structures deviated from the protocol (eg, prostate bed in 48.8%, rectal wall RW in 41%). In addition, variations in clinical target volume (CTV) and planning target volume (PTV) occurred frequently (eg, CTV and PTV deviations in up to 42.4% and 25.9%, respectively). The detected deviations showed a significant association with a lower risk of grade ≥2 gastrointestinal acute toxicity when the CTV did not overlap the RW versus when the CTV overlapped the RW (odds ratio OR, 0.43; 95% confidence interval CI, 0.22-0.85; P = .014), and a higher rate of grade ≥2 late genitourinary (GU) toxicity when the CTV overlapped the RW (OR, 2.58; 95% CI, 1.17-5.72; P = .019). A marginally significant lower risk of grade ≥2 late GU toxicity was observed when the prostate bed did not overlap versus did overlap the RW (OR, 0.51; 95% CI, 0.25-1.03; P = .06). In addition, a marginally significant decrease in FFBP was observed in patients with PTV not including surgical clips as potential markers of the limits of the prostate bed (hazard ratio, 1.44; 95% CI, 0.96-2.17; P = .07).
Despite a thorough QA program, the central review of a phase 3 trial showed limited adherence to treatment protocol recommendations, which was associated with a higher risk of toxicity by means of acute or late gastrointestinal or GU toxicity and showed a trend toward worse FFBP. Data from this QA review might help to refine future QA programs and prostate bed delineation guidelines.
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