A general method for the definition of margin recipes depending on the treatment technique applied in helical tomotherapy prostate plans.

PURPOSE: To obtain specific margin recipes that take into account the dosimetric characteristics of the treatment plans used in a single institution. METHODS: We obtained dose-population histograms (DPHs) of 20 helical tomotherapy treatment plans for prostate cancer by simulating the effects of different systematic errors (Σ) and random errors (σ) on these plans. We obtained dosimetric margins and margin reductions due to random errors (random margins) by fitting the theoretical results of coverages for Gaussian distributions with coverages of the planned D99% obtained from the DPHs. RESULTS: The dosimetric margins obtained for helical tomotherapy prostate treatments were 3.3 mm, 3 mm, and 1 mm in the lateral (Lat), anterior-posterior (AP), and superior-inferior (SI) directions. Random margins showed parabolic dependencies, yielding expressions of 0.16σ(2), 0.13σ(2), and 0.15σ(2) for the Lat, AP, and SI directions, respectively. When focusing on values up to σ = 5 mm, random margins could be fitted considering Gaussian penumbras with standard deviations (σp) equal to 4.5 mm Lat, 6 mm AP, and 5.5 mm SI. CONCLUSIONS: Despite complex dose distributions in helical tomotherapy treatment plans, we were able to simplify the behaviour of our plans against treatment errors to single values of dosimetric and random margins for each direction. These margins allowed us to develop specific margin recipes for the respective treatment technique. The method is general and could be used for any treatment technique provided that DPHs can be obtained.

Ethnic difference in risk of toxicity in prostate cancer patients treated with dynamic arc radiation therapy.

AIMS AND BACKGROUND: The objective of this study was to assess the influence of ethnicity on toxicity in patients treated with dynamic arc radiation therapy (ART) for prostate cancer (PC). METHODS: From June 2006 to May 2012, 162 cT1-T3 cN0 cM0 PC patients were treated with ART (primary diagnosis, n = 125; post-prostatectomy/brachytherapy biochemical recurrence, n = 26; adjuvant post-prostatectomy, n = 11) at 2 institutions. Forty-five patients were Latin Americans and 117 were Europeans. The dose prescribed to the prostate ranged between 68 Gy and 81 Gy. RESULTS: The median age was 69 years (range 43-87 years). The median follow-up was 18 months (range 2-74 months). Overall, only 3 patients died, none due to a cancer-related cause. Biochemical recurrence was seen in 7 patients. The rates of acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicities were 19.7% and 17%, respectively. Only 1 patient experienced acute grade 3 GI toxicity, whereas 11 patients (6.7%) experienced acute grade 3 GU toxicity. Multivariate analysis showed that undergoing whole pelvic lymph node irradiation was associated with a higher grade of acute GI toxicity (OR: 3.46; p = 0.003). In addition, older age was marginally associated with a higher grade of acute GI toxicity (OR: 2.10; p = 0.074). Finally, ethnicity was associated with acute GU toxicity: Europeans had lower-grade toxicity (OR: 0.27; p = 0.001). CONCLUSIONS: Our findings suggest an ethnic difference in GU toxicity for PC patients treated with ART. In addition, we found that ART is associated with a very low risk of severe toxicity and a low recurrence rate.

Retrospective evaluation of CTV to PTV margins using CyberKnife in patients with thoracic tumors.

The objectives of this study were to estimate global uncertainty for patients with thoracic tumors treated in our center using the CyberKnife VSI after placement of fiducial markers and to compare our findings with the standard CTV to PTV margins used to date. Datasets for 16 patients (54 fractions) treated with the CyberKnife and the Synchrony Respiratory Tracking System were analyzed retrospectively based on CT planning, tracking information, and movement data generated and saved in the logs files by the system. For each patient, we analyzed all the main uncertainty sources and assigned a value. We also calculated an expanded global uncertainty to ensure a robust estimation of global uncertainty and to enable us to determine the position of 95% of the CTV points with a 95% confidence level during treatment. Based on our estimation of global uncertainty and compared with our general mar- gin criterion (5 mm in all three directions: superior/inferior [SI], anterior/posterior [AP], and lateral [LAT]), 100% were adequately covered in the LAT direction, as were 94% and 94% in the SI and AP directions. We retrospectively analyzed the main sources of uncertainty in the CyberKnife process patient by patient. This individualized approach enabled us to estimate margins for patients with thoracic tumors treated in our unit and compare the results with our standard 5 mm margin. 

Image-guided radiation therapy based on helical tomotherapy in prostate cancer: minimizing toxicity.

BACKGROUND: We report the clinical results and prognostic factors of image-guided radiation therapy (RT) with helical tomotherapy (HT) for localized and recurrent prostate cancer (PC). PATIENTS AND METHODS: We evaluated 70 patients with PC (primary diagnosis, n = 48; adjuvant, n = 5; salvage, n = 17) treated with HT from May 2006 through January 2011. The dose prescribed to the prostate/surgical bed ranged between 60 and 78 Gy. Potential risk factors for genitourinary (GU) and gastrointestinal (GI) toxicity were assessed. RESULTS: The median age was 68 years (range 51-87 years). The median follow-up was 37 months (range 3-74 months). The rates of acute grade 2 GI and GU toxicities were 10 and 13%, respectively. Only 1 patient experienced acute grade 3 GU toxicity. The rates of late grade ≥ 2 GI and GU toxicities were 1% each. Multivariate analysis showed an association between rectum mean dose > median (39 Gy) and bladder median dose > median (46 Gy) with a higher grade of acute GI (p = 0.017) and GU (p = 0.019) toxicity, respectively. Additionally, older age was associated with late GU toxicity (p = 0.026). CONCLUSION: Toxicity with HT is low and is associated with higher median/mean doses in organs at risk as well as with older age. A prospective validation would be necessary to confirm these results.

Experience with the CyberKnife for intracranial stereotactic radiosurgery: analysis of dosimetry indices.

We evaluated coverage, dose homogeneity, dose conformity, and dose gradient in CyberKnife VSI treatment plans. Several dosimetric indices were calculated, and the results were compared with those of previous publications. The effect of target volume on the radiosurgical treatment indices selected was also investigated. The study population comprised the first 40 patients treated at our department from March 2011 to September 2012. Dosimetric indices were calculated and compared with published results for other frame-based and frameless intracranial stereotactic radiotherapy techniques. A comparison of the indices confirmed the ability of the CyberKnife VSI system to provide very high-quality dosing plans. The results were independent of target volume for coverage, homogeneity, and dose conformity. However, a dependence on target volume was observed for the dose-gradient indices analyzed. Based on the indices proposed, CyberKnife provides very good treatment plans and compares favorably with other techniques in most cases. However, greater consensus on the radiosurgery indices calculated would be desirable to facilitate comparison of the various techniques or the same techniques when applied by different users.

Hypofractionated helical tomotherapy using 2.5-2.6 Gy daily fractions for localized prostate cancer.

BACKGROUND: The purpose of this study is to evaluate the tolerability of hypofractionated helical tomotherapy (HT) in the treatment of localized prostate cancer. MATERIALS AND METHODS: We evaluated 48 patients with primary adenocarcinoma of the prostate (cT1-T3N0M0) who were treated with hypofractionated HT from August 2008 through July 2011. Hypofractionated regimens included: 68.04 Gy at 2.52 Gy/fraction, 70 Gy at 2.5 Gy/fraction, and 70.2 Gy at 2.6 Gy/fraction. Genitourinary (GU) and gastrointestinal (GI) toxicity was scored using the Radiation Therapy Oncology Group scoring system. RESULTS: Thirty-two patients were treated with 68.04 Gy, 5 patients with 70 Gy, and 11 with 70.2 Gy. The median age at diagnosis was 69 years (range 49-87) and the median follow-up 11 months (range 7-40). Grade 2 acute GI toxicity occurred in 9 patients (19 %). No grade 3 or higher acute GI toxicity was observed. Grade 2 and 3 acute GU toxicities occurred in 19 and 6 % of patients, respectively. The incidence of late grade 2 GI and GU toxicity was 4 and 2 %, respectively. No grade 3 or higher late toxicities were observed. Multivariate analysis showed that patients treated at 2.6 Gy/fraction or those who received a total radiation dose ≥70 Gy had higher rates of grade ≥2 acute GU toxicity (P = 0.004 and P = 0.048, respectively). CONCLUSION: Hypofractionated HT in the treatment of localized prostate cancer is well tolerated with no grade 3 or higher early or late GI and GU toxicities. Further research is needed to assess definitive late toxicity and tumor control.

Initial evaluation of intrafraction motion using frameless CyberKnife VSI system.

AIM: To analyze intrafraction movement in patients undergoing frameless robotic radiosurgery and evaluate the influence of image acquisition frequency on global accuracy. BACKGROUND: Stereotactic radiosurgery requires high spatial accuracy in dose delivery. In conventional radiosurgery, a rigid frame is used to guarantee a correct target alignment and no subsequent movement. Frameless radiosurgery with thermoplastic mask for immobilization cannot completely eliminate intrafraction patient movement. In such cases, it is necessary to evaluate its influence on global treatment accuracy. MATERIALS AND METHODS: We analyzed the intrafraction motion of the first 15 patients undergoing intracranial radiosurgery (39 fractions) with the CyberKnife VSI system at our institution. Patient position was measured at a 15-90-s interval and was used to estimate intrafraction patient movement. RESULTS: With our acquisition image protocol and immobilization device, the 99% displacement error was lower than 0.85 mm. The systematic movement components were lower than 0.05 mm and the random component was lower than 0.3 mm in the 3 translational axes. Clear linear time dependence was found in the random component. CONCLUSIONS: Selection of the X-ray image acquisition time is necessary to meet the accuracy required for radiosurgery procedures with the CyberKnife VSI system. We verified that our image acquisition protocol met the 1-mm criterion.

Measurement and correction of leaf open times in helical tomotherapy.

PURPOSE: The binary multileaf collimator (MLC) is one of the most important components in helical tomotherapy (HT), as it modulates the dose delivered to the patient. However, methods to ensure MLC quality in HT treatments are lacking. The authors obtained data on the performance of the MLC in treatments administered in their department in order to assess possible delivery errors due to the MLC. Correction methods based on their data are proposed. METHODS: Twenty sinograms from treatments delivered using both of the authors HT systems were measured and analyzed by recording the fluence collected by the imaging detector. Planned and actual sinograms were compared using distributions of leaf open time (LOT) errors, as well as differences in fluence reconstructed at each of the 51 projections into which the treatment planning system divides each rotation for optimization purposes. They proposed and applied a method based on individual leaf error correction and the increase in projection time to prevent latency effects when LOT is close to projection time. In order to analyze the dosimetric impact of the corrections, inphantom measurements were made for four corrected treatments. RESULTS: The LOTs measured were consistent with those planned. Most of the mean errors in LOT distributions were within 1 ms with standard deviations of over 4 ms. Reconstructed fluences showed good results, with over 90% of points passing the 3% criterion, except in treatments with a short mean LOT, where the percentage of passing points was as low as 66%. Individual leaf errors were as long as 4 ms in some cases. Corrected sinograms improved error distribution, with standard deviations of over 3 ms and increased percentages of points passing 3% in the fluence per angle analysis, especially in treatments with a short mean LOT and those that were more subject to latency effects. The minimum percentage of points within 3% increased to 86%. In-phantom measurements of the corrected treatments showed that, while treatments affected by latency effects were improved, those affected by individual leaf errors were not. CONCLUSIONS: Measurement of MLC performance in real treatments provides the authors with a valuable tool for ensuring the quality of HT delivery. The LOTs of MLC are very accurate in most cases. Sources of error were found and correction methods proposed and applied. The corrections decreased the amount of LOT errors. The dosimetric impact of these corrections should be evaluated more thoroughly using 3D dose distribution analysis.

Three or four fractions of 4-5 Gy per week in postoperative high-dose-rate brachytherapy for endometrial carcinoma.

PURPOSE: To evaluate the results of high-dose-rate brachytherapy (HDRBT) using a schedule of three or four fractions per week, when possible, in 89 patients on local control and toxicity in postoperative treatment of endometrial carcinoma. The effect of the overall HDRBT treatment time (OTT) on toxicity was also evaluated. PATIENTS AND METHODS: Fédération Internationale de Gynécologie Obstétrique Stage: 24 IB, 45 IC, 4 IIA, 6 IIB, 4 IIIA, 2 IIIB, and 4 IIIC. Radiotherapy: Group 1-67 of 89 patients received external beam irradiation (EBI; 44-50 Gy) plus HDRBT (3 fractions of 4-6 Gy); Group 2-22 of 89 patients received HDRBT alone (6 fractions of 4-5 Gy). OTT: Group 1-HDRBT was completed in a median of 5 days in 32 patients and in >5 days in 35; Group 2-HDRBT was completed in <15 days in 11 patients and in ≥16 days in 11. Toxicity was evaluated using Radiation Therapy Oncology Group scores and the bioequivalent dose (BED) study was performed in vaginal mucosa surface. Statistics included Student's t test, chi-square test, and receiving operator curves. RESULTS: With a mean follow-up of 31 months (range, 6-70), 1 of 89 patients had vaginal relapse. Early toxicity appeared in 8 of 89 (9%) patients and was resolved. Late toxicity appeared in 13/89 (14%): vaginal nine Grade 1, three Grade 2, one Grade 4; bladder two Grade 2; rectal three Grade 1, one Grade 2. No differences were found in relation to OTT in Groups 1 and 2. Mean BED was 88.48 Gy in Group 1 and 165.28 Gy in Group 2. Cases with Grade 2 late vaginal toxicity received >75 Gy after EBI and >165 Gy in Group 2. CONCLUSIONS: Three fractions of 4-5 Gy in 3-5 days after EBI or 6 fractions in <15 days in patients receiving HDRBT alone was a safe treatment in relation to toxicity and local control. Vaginal surface BED less than 75 Gy after EBI and less than 160 Gy in HDRBT alone may be safe to avoid G2 toxicity.

Comparison of positron emission tomography (PET) and computed tomography (CT) for better target volume definition in radiation therapy planning.

BACKGROUND: In cancer patients, positron emission tomography/ computed tomography (PET/CT) fused images present less variability in target contouring, respect to use only CT images, respectively. However, the gold standard has not yet been clearly established between radiation oncologists with regard to PET images and the methodology of contouring targets with confidence using PET/CT fused images. The aim of this study was to determine whether integrated PET/CT fused images provide advantages in virtual simulation compared with morphological contouring only with CT. MATERIAL AND METHODS: Thirty cancer patients were evaluated in an adapted PET/CT hybrid in radiotherapy (RT) setup position, with 20 of them being suitable for RT: 17 were suitable for curative intent, which was the group of interest in this study. All image series were sent to the RT work station (WS) where CT and PET series were automatically fused by Digital Imaging and Communications in Medicine (DICOM) in each case. PET series were threshold and were subjected to source-to-background contrast algorithms to fi nally redefine the original tumour description. Three different radiotherapy plans (RTP) for each patient were compared after targets were contoured: [1] planning over metabolic (PET) contoured targets, [2] planning over only morphologic (CT) targets, and [3] planning over targets obtained for treatment based on fused PET/CT images. RESULTS: PET/CT findings altered initial-stage planning in four patients (23.5%) because they had been undergoing chemotherapy. Gross target volume (GTV) and planning target volume (PTV) based only on PET showed more homogeneity to obtain mean doses (p = 0.025) with respect to those based on PET/CT, respectively. However, no percentage differences were observed in median PTV doses between the planning methods, although there was higher variability in PET/CT planning. Morphological (CT) and PET/ CT target volumes were more voluminous than metabolic (PET) volumes. On the other hand, 20% of metabolic (PET) PTV were out of those defined by PET/CT. Thoracic RT plans based on PET preserved better bilateral lung [percentage volume of lung irradiated with a dose of 20 Gy (V20); significance, R(2) = 0.559, p = 0.006]. CONCLUSIONS: For our physicians, PET/CT fused images allowed better contouring of primary tumours in 40% of head and neck cancers and 34% of thoracic cancers. PET/CT provides useful information for virtual simulation therapy. Image treatment and planning in an RT workstation is mandatory.

Use of an electron spoiler for radiation treatment of surface skin diseases.

OBJECTIVES: Low-energy electron beams are characterised by low surface doses with a pronounced dose build-up and penetration of several centimetres, but often a higher surface dose and a lower penetration range is desired. The purpose of this study was to investigate the use of an electron spoiler to modify these beams for treating surface skin diseases and evaluate the feasibility of this method. MATERIALS AND METHODS: An aluminium foil 4-mm thick covering the end of the electron applicator was used as a spoiler for a 6 MeV electron beam. The dosimetric characteristics of this beam were measured, and Monte Carlo simulations were performed. RESULTS: The spoiler reduced the practical range and increased surface and build-up doses, but it also significantly broadened the penumbra and increased peripheral doses. Nevertheless, the beam was clinically acceptable when skin collimation with lead was employed. Monte Carlo simulations agreed well with all the experimental measurements. CONCLUSIONS: The feasibility of using a low-energy electron beam with a spoiler for treating surface skin diseases was demonstrated. The method is hygienic and avoids some of the disadvantages associated with the bolus technique, but it is valid only for flat surfaces and perpendicular incidence. As a consequence, it can be an alternative to bolus and other reported methods in certain cases, especially when a particular sterility assurance level is required.

Spanish patterns of care for 3D radiotherapy in non-small-cell lung cancer.

PURPOSE: Curative radiotherapy for non-small-cell lung cancer is a difficult challenge, despite the use of conformal radiotherapy. Optimal three-dimensional delineation of treatment volumes is essential for improvement of local control and for limiting of tissue toxicity. MATERIAL AND METHODS: A planning course on clinical practice of lung cancer was held in Barcelona. A questionnaire was given concerning (1) patient positioning, (2) planning-computed tomography scan, (3) accounting for tumor mobility, (4) investigative-procedure respiration-gated radiotherapy and breath-holding maneuvers, (5) generation of target volumes, (6) treatment planning, and (7) treatment delivery. This questionnaire was made to determine the Spanish application of European recommendations. RESULTS: On the negative side, 1 hospital did not use three-dimensional tools, less than 50% used immobilization devices, and 55.6% used computed tomography slices of greater than 5 mm. On the positive side, 70.4% did not use standard margins for gross target volume derived from a computed tomography scan, 92.6% agreed with the inclusion of Naruke anatomic criteria of 1 cm or more in gross target volume planning, and 75% used V20 to estimate the risk of pneumonitis. CONCLUSIONS: This study is the first validation of European recommendations for treatment planning and execution of radiotherapy in lung cancer. The main conclusion is the need to improve the negative aspects determined.

Brachytherapy with 192Ir as treatment of carcinoma of the tarsal structure of the eyelid.

PURPOSE: Some eyelid tumors present a great challenge for surgical therapy because of the cosmetic and functional impairment. Interstitial radiation with (192)Ir is an optimal alternative treatment modality. The aim of this study was to evaluate the local tumor control and cosmetic results in patients with eyelid tumors treated by interstitial (192)Ir wires. METHODS AND MATERIALS: Twenty-four previously untreated carcinomas involving the eyelid tarsal structure in 23 patients were treated with (192)Ir wire implantation. The tumor location was in the lower eyelid in 22 cases and in the upper eyelid in 2. The mean tumor size was 1.33 cm. Of the 24 tumors, 79.2% were basal cell carcinoma, 16.7% were squamous cell carcinoma, and 4.2% were adenocarcinoma. The total radiation dose was 4000 cGy, delivered to 2-mm depth (mean dose rate, 73 cGy/h). RESULTS: The mean follow-up was 43 months. Local control was obtained in 22 (91.6%) of 24 tumors. Good functional results were achieved in all patients. CONCLUSION: (192)Ir interstitial brachytherapy in a braided silk filament appears to be an excellent method to treat carcinomas involving the eyelid tarsal structure for tumor control and functional and cosmetic results.

Ganglioside GD3 sensitizes human hepatoma cells to cancer therapy.

Ganglioside GD3 (GD3) has emerged as a modulator of cell death pathways due to its ability to interact with mitochondria and disable survival pathways. Because NF-kappaB activation contributes to cancer therapy resistance, this study was undertaken to test whether GD3 modulates the response of human hepatoblastoma HepG2 cells to radio- and chemotherapy. NF-kappaB was activated in HepG2 cells shortly after therapeutic doses of ionizing radiation or daunorubicin treatment that translated into up-regulation of kappaB-dependent genes. These effects were accompanied by minimal killing of HepG2 cells by either ionizing radiation or daunorubicin. However, GD3 pretreatment blocked the nuclear translocation of active kappaB members, without effect on Akt phosphorylation, induced by either treatment. The suppression of kappaB-dependent gene induction by GD3 was accompanied by enhanced apoptotic cell death caused by these therapies. Furthermore, the combination of GD3 plus ionizing radiation stimulated the formation of reactive species followed by the mitochondrial release of cytochrome c and Smac/Diablo and caspase 3 activation. Pretreatment with cyclosporin A before radiotherapy protected HepG2 cells from the therapeutic combination of GD3 plus ionizing radiation. These findings underscore a key role of mitochondria in the response of tumor cells to cancer therapy and highlight the potential relevance of GD3 to overcome resistance to cancer therapy by combining its dual action as a mitochondria-interacting and NF-kappaB-inactivating agent.