Abstract A great deal of quantitative information regarding the dose–volume relationships of pelvic organs at risk has been collected and analysed over the last 10 years. The need to improve our ...knowledge in the modelling of late and acute toxicity has become increasingly important, due to the rapidly increasing use of inverse-planned intensity-modulated radiotherapy (IMRT) and the consequent need of a quantitative assessment of dose–volume or biological-based cost functions. This comprehensive review concerns most organs at risk involved in planning optimisation for prostate and other types of pelvic cancer. The rectum is the most investigated organ: the largest studies on dose–volume modelling of rectal toxicity show quite consistent results, suggesting that sufficiently reliable dose–volume/EUD-based constraints can be safely applied in most clinical situations. Quantitative data on bladder, bowel, sexual organs and pelvic bone marrow are more lacking but are rapidly emerging; however, for these organs, further investigation on large groups of patients is necessary.
Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa). Patients ...and Methods This single-institution, randomized clinical trial, conducted from January 2003 to December 2007, enrolled 168 patients with high-risk PCa who were randomly assigned in a 1:1 ratio to conventional (80 Gy in 40 fractions in 8 weeks) or hypofractionated radiotherapy (62 Gy in 20 fractions in 5 weeks) to prostate and seminal vesicles. The primary outcome measure was late toxicity. Additional outcomes were freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCaSS), and overall survival (OS), evaluated on an intention-to-treat basis. Results A total of 85 patients were assigned to conventional and 83 to hypofractionated radiotherapy. At a median follow-up of 9 years (interquartile range, 7.5 to 10.1 years), no differences was observed in physician-assessed late gastro intestinal and genitourinary toxicity greater than or equal to grade 2 ( P = .68 and .57, respectively) were found between the two arms. The 10-year FFBF rate was 72% in the hypofractionation group and 65% in the conventional fractionation group ( P = .148). Ten-year OS rates were 75% in the hypofractionation group and 64% in the conventional group, respectively ( P = .22). The same features for 10-year PCaSS were 95% and 88%, respectively ( P = .066). Hypofractionation, pretreatment prostate-specific antigen level, Gleason score, and clinical tumor stage for FFBF, and hypofractionation and Gleason score for PCaSS were significant prognostic variables on the multivariate analysis. Conclusion Long-term findings showed that hypofractionated radiotherapy failed the intent of either reducing physician-assessed late toxicity or maintaining the same efficacy. A postrandomization analysis, however, revealed that hypofractionation was a significant prognostic factor for FFBF and PCaSS, when adjusted for clinical prognostic variables.
To propose a method of intensity-modulated radiotherapy (IMRT) planning that generates achievable dose-volume histogram (DVH) objectives using a database containing geometric and dosimetric ...information of previous patients.
The overlap volume histogram (OVH) is used to compare the spatial relationships between the organs at risk and targets of a new patient with those of previous patients in a database. From the OVH analysis, the DVH objectives of the new patient were generated from the database and used as the initial planning goals. In a retrospective OVH-assisted planning demonstration, 15 patients were randomly selected from a database containing clinical plans (CPs) of 91 previous head-and-neck patients treated by a three-level IMRT-simultaneous integrated boost technique. OVH-assisted plans (OPs) were planned in a leave-one-out manner by a planner who had no knowledge of CPs. Thus, DVH objectives of an OP were generated from a subdatabase containing the information of the other 90 patients. Those DVH objectives were then used as the initial planning goals in IMRT optimization. Planning efficiency was evaluated by the number of clicks of the "Start Optimization" button in the course of planning. Although the Pinnacle(3) treatment planning system allows planners to interactively adjust the DVH parameters during optimization, planners in our institution have never used this function in planning.
The average clicks required for completing the CP and OP was 27.6 and 1.9, respectively (p <.00001); three OPs were finished within a single click. Ten more patient's cord + 4 mm reached the sparing goal D(0.1cc) <44 Gy (p <.0001), where D(0.1cc) represents the dose corresponding to 0.1 cc. For planning target volume uniformity, conformity, and other organ at risk sparing, the OPs were at least comparable with the CPs. Additionally, the averages of D(0.1cc) to the cord + 4 mm decreased by 6.9 Gy (p <.0001); averages of D(0.1cc) to the brainstem decreased by 7.7 Gy (p <.005). The averages of V(30 Gy) to the contralateral parotid decreased by 8.7% (p <.0001), where V(30 Gy) represents the percentage volume corresponding to 30 Gy.
The method heralds the possibility of automated IMRT planning.
To assess the results of a multi-institutional study of intensity-modulated radiation therapy (IMRT) for early oropharyngeal cancer.
Patients with oropharyngeal carcinoma Stage T1-2, N0-1, M0 ...requiring treatment of the bilateral neck were eligible. Chemotherapy was not permitted. Prescribed planning target volumes (PTVs) doses to primary tumor and involved nodes was 66 Gy at 2.2 Gy/fraction over 6 weeks. Subclinical PTVs received simultaneously 54-60 Gy at 1.8-2.0 Gy/fraction. Participating institutions were preapproved for IMRT, and quality assurance review was performed by the Image-Guided Therapy Center.
69 patients were accrued from 14 institutions. At median follow-up for surviving patients (2.8 years), the 2-year estimated local-regional failure (LRF) rate was 9%. 2/4 patients (50%) with major underdose deviations had LRF compared with 3/49 (6%) without such deviations (p = 0.04). All cases of LRF, metastasis, or second primary cancer occurred among patients who were current/former smokers, and none among patients who never smoked. Maximal late toxicities Grade >or=2 were skin 12%, mucosa 24%, salivary 67%, esophagus 19%, osteoradionecrosis 6%. Longer follow-up revealed reduced late toxicity in all categories. Xerostomia Grade >or=2 was observed in 55% of patients at 6 months but reduced to 25% and 16% at 12 and 24 months, respectively. In contrast, salivary output did not recover over time.
Moderately accelerated hypofractionatd IMRT without chemotherapy for early oropharyngeal cancer is feasible, achieving high tumor control rates and reduced salivary toxicity compared with similar patients in previous Radiation Therapy Oncology Group studies. Major target underdose deviations were associated with higher LRF rate.
The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival ...compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials.
For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival.
Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio HR 0·94, 95% CI 0·90–0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3–4·9) and at 10 years of 1·2% (−0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74–0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (−0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05–1·42; p=0·0098), with absolute differences at 5 years of −5·8% (−11·9 to 0·3) and at 10 years of −5·1% (−13·0 to 2·8).
This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested.
Institut National du Cancer; and Ligue Nationale Contre le Cancer.
To prospectively determine whether overlap volume histogram (OVH)-driven, automated simultaneous integrated boosted (SIB)-intensity-modulated radiation therapy (IMRT) treatment planning for ...head-and-neck cancer can be implemented in clinics.
A prospective study was designed to compare fully automated plans (APs) created by an OVH-driven, automated planning application with clinical plans (CPs) created by dosimetrists in a 3-dose-level (70 Gy, 63 Gy, and 58.1 Gy), head-and-neck SIB-IMRT planning. Because primary organ sparing (cord, brain, brainstem, mandible, and optic nerve/chiasm) always received the highest priority in clinical planning, the study aimed to show the noninferiority of APs with respect to PTV coverage and secondary organ sparing (parotid, brachial plexus, esophagus, larynx, inner ear, and oral mucosa). The sample size was determined a priori by a superiority hypothesis test that had 85% power to detect a 4% dose decrease in secondary organ sparing with a 2-sided alpha level of 0.05. A generalized estimating equation (GEE) regression model was used for statistical comparison.
Forty consecutive patients were accrued from July to December 2010. GEE analysis indicated that in APs, overall average dose to the secondary organs was reduced by 1.16 (95% CI = 0.09-2.33) with P=.04, overall average PTV coverage was increased by 0.26% (95% CI = 0.06-0.47) with P=.02 and overall average dose to the primary organs was reduced by 1.14 Gy (95% CI = 0.45-1.8) with P=.004. A physician determined that all APs could be delivered to patients, and APs were clinically superior in 27 of 40 cases.
The application can be implemented in clinics as a fast, reliable, and consistent way of generating plans that need only minor adjustments to meet specific clinical needs.
The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent ...organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference.
A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement.
Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed.
Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk.
Abstract
Purpose
The purpose of this study is to evaluate inter- and intra-fraction organ motion as well as to quantify clinical target volume (CTV) to planning target volume (PTV) margins to be ...adopted in the stereotactic treatment of early stage glottic cancer.
Methods and materials
Stereotactic body radiotherapy (SBRT) to 36 Gy in 3 fractions was administered to 23 patients with early glottic cancer T1N0M0. Patients were irradiated with a volumetric intensity modulated arc technique delivered with 6 MV FFF energy. Each patient underwent a pre-treatment cone beam computed tomography (CBCT) to correct the setup based on the thyroid cartilage position. Imaging was repeated if displacement exceeded 2 mm in any direction. CBCT imaging was also performed after each treatment arc as well as at the end of the delivery. Swallowing was allowed only during the beam-off time between arcs. CBCT images were reviewed to evaluate inter- and intra-fraction organ motion. The relationships between selected treatment characteristics, both beam-on and delivery times as well as organ motion were investigated.
Results
For the population systematic (Ʃ) and random (σ) inter-fraction errors were 0.9, 1.3 and 0.6 mm and 1.1, 1.3 and 0.7 mm in the left-right (X), cranio-caudal (Y) and antero-posterior (Z) directions, respectively. From the analysis of CBCT images acquired after treatment, systematic (Ʃ) and random (σ) intra-fraction errors resulted 0.7, 1.6 and 0.7 mm and 1.0, 1.5 and 0.6 mm in the X, Y and Z directions, respectively. Margins calculated from the intra-fraction errors were 2.4, 5.1 and 2.2 mm in the X, Y and Z directions respectively. A statistically significant difference was found for the displacement in the Z direction between patients irradiated with > 2 arcs versus ≤ 2 arcs, (MW test,
p
= 0.038). When analyzing mean data from CBCT images for the whole treatment, a significant correlation was found between the time of delivery and the three dimensional displacement vector (r = 0.489,
p
= 0.055), the displacement in the Y direction (r = 0.553,
p
= 0.026) and the subsequent margins to be adopted (r = 0.626,
p
= 0.009). Finally, displacements and the subsequent margins to be adopted in Y direction were significantly greater for treatments with more than 2 arcs (MW test
p
= 0.037 and
p
= 0.019, respectively).
Conclusions
In the setting of controlled swallowing during treatment delivery, intra-fraction motion still needs to be taken into account when planning with estimated CTV to PTV margins of 3, 5 and 3 mm in the X, Y and Z directions, respectively. Selected treatments may require additional margins.
To determine whether frameless thermoplastic mask-based immobilization is adequate for image-guided cranial radiosurgery.
Cone-beam CT localization data from patients with intracranial tumors were ...studied using daily pre- and posttreatment scans. The systems studied were (1) Type-S IMRT (head only) mask (Civco) with head cushion; (2) Uni-Frame mask (Civco) with head cushion, coupled with a BlueBag body immobilizer (Medical Intelligence); (3) Type-S head and shoulder mask with head and shoulder cushion (Civco); (4) same as previous, coupled with a mouthpiece. The comparative metrics were translational shift magnitude and average rotation angle; systematic inter-, random inter-, and random intrafraction positioning error was computed. For strategies 1-4, respectively, the analysis for interfraction variability included data from 20, 9, 81, and 11 patients, whereas that for intrafraction variability included a subset of 7, 9, 16, and 8 patients. The results were compared for statistical significance using an analysis of variance test.
Immobilization system 4 provided the best overall accuracy and stability. The mean interfraction translational shifts (± SD) were 2.3 (± 1.4), 2.2 (± 1.1), 2.7 (± 1.5), and 2.1 (± 1.0) mm whereas intrafraction motion was 1.1 (± 1.2), 1.1 (± 1.1), 0.7 (± 0.9), and 0.7 (± 0.8) mm for devices 1-4, respectively. No significant correlation between intrafraction motion and treatment time was evident, although intrafraction motion was not purely random.
We find that all frameless thermoplastic mask systems studied are viable solutions for image-guided intracranial radiosurgery. With daily pretreatment corrections, symmetric PTV margins of 1 mm would likely be adequate if ideal radiation planning and targeting systems were available.
Abstract Background and purpose During radiotherapy (RT) for head-and-neck cancer, parotid glands undergo significant anatomic, functional and structural changes which could characterize pre-clinical ...signs of an increased risk of xerostomia. Texture analysis is proposed to assess structural changes of parotids induced by RT, and to investigate whether early variations of textural parameters (such as mean intensity and fractal dimension) can predict parotid shrinkage at the end of treatment. Material and methods Textural parameters and volumes of 42 parotids from 21 patients treated with intensity-modulated RT for nasopharyngeal cancer were extracted from CT images. To individuate which parameters changed during RT, a Wilcoxon signed-rank test between textural indices (first and second RT week; first and last RT week) was performed. Discriminant analysis was applied to variations of these parameters in the first two weeks of RT to assess their power in predicting parotid shrinkage at the end of RT. Results A significant decrease in mean intensity (1.7 HU and 3.8 HU after the second and last weeks, respectively) and fractal dimension (0.016 and 0.021) was found. Discriminant analysis, based on volume and fractal dimension, was able to predict the final parotid shrinkage (accuracy of 71.4%). Conclusion Textural features could be used in combination with volume to characterize structural modifications on parotid glands and to predict parotid shrinkage at the end of RT.
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