Olivier Gayou

Stereotactic radiosurgery boost to the resection bed for oligometastatic brain disease: challenging the tradition of adjuvant whole-brain radiotherapy.

OBJECTnWhole-brain radiation therapy (WBRT) has been the traditional approach to minimize the risk of intracranial recurrence following resection of brain metastases, despite its potential for late neurotoxicity. In 2007, the authors demonstrated an equivalent local recurrence rate to WBRT by using stereotactic radiosurgery (SRS) to the operative bed, sparing 72% of their patients WBRT. They now update their initial experience with additional patients and more mature follow-up.nnnMETHODSnThe authors performed a retrospective review of all cases involving patients with limited intracranial metastatic disease (< or = 4 lesions) treated at their institution with SRS to the operative bed following resection. No patient had prior cranial radiation and WBRT was used only for salvage.nnnRESULTSnFrom November 2000 to June 2009, 52 patients with a median age of 61 years met inclusion criteria. A single metastasis was resected in each patient. Thirty-four of the patients each had 1 lesion, 13 had 2 lesions, 3 had 3 lesions, and 2 had 4 lesions. A median dose of 1500 cGy (range 800-1800 cGy) was delivered to the resection bed targeting a median volume of 3.85 cm(3) (range 0.08-22 cm(3)). With a median follow-up of 13 months, the median survival was 15.0 months. Four patients (7.7%) had a local recurrence within the surgical site. Twenty-three patients (44%) ultimately developed distant brain recurrences at a median of 16 months postresection, and 16 (30.7%) received salvage WBRT (8 for diffuse disease [> 3 lesions], 4 for local recurrence, and 4 for diffuse progression following salvage SRS). The median time to WBRT administration postresection was 8.7 months (range 2-43 months). On univariate analysis, patient factors of a solitary tumor (19.0 vs 12 months, p = 0.02), a recursive partitioning analysis (RPA) Class I (21 vs 13 months, p = 0.03), and no extracranial disease on presentation (22 vs 13 months, p = 0.01) were significantly associated with longer survival. Cox multivariate analysis showed a significant association with longer survival for the patient factors of no extracranial disease on presentation (p = 0.01) and solitary intracranial metastasis (p = 0.02). Among patients with no extracranial disease, a solitary intracranial metastasis conferred significant additional survival advantage (43 vs 10.5 months, p = 0.05, log-rank test). No factor (age, RPA class, tumor size or histological type, disease burden, extent of resection, or SRS dose or volume) was related to the need for salvage WBRT.nnnCONCLUSIONSnAdjuvant SRS to the metastatic intracranial operative bed results in a local recurrence rate equivalent to adjuvant WBRT. In combination with SRS for unresected lesions and routine imaging surveillance, this approach achieves robust overall survival (median 15 months) while sparing 70% of the patients WBRT and its potential acute and chronic toxicity.

Patient dose and image quality from mega-voltage cone beam computed tomography imaging

The evolution of ever more conformal radiation delivery techniques makes the subject of accurate localization of increasing importance in radiotherapy. Several systems can be utilized including kilo-voltage and mega-voltage cone-beam computed tomography (MV-CBCT), CT on rail or helical tomography. One of the attractive aspects of mega-voltage cone-beam CT is that it uses the therapy beam along with an electronic portal imaging device to image the patient prior to the delivery of treatment. However, the use of a photon beam energy in the mega-voltage range for volumetric imaging degrades the image quality and increases the patient radiation dose. To optimize image quality and patient dose in MV-CBCT imaging procedures, a series of dose measurements in cylindrical and anthropomorphic phantoms using an ionization chamber, radiographic films, and thermoluminescent dosimeters was performed. Furthermore, the dependence of the contrast to noise ratio and spatial resolution of the image upon the dose delivered for a 20-cm-diam cylindrical phantom was evaluated. Depending on the anatomical site and patient thickness, we found that the minimum dose deposited in the irradiated volume was 5-9 cGy and the maximum dose was between 9 and 17 cGy for our clinical MV-CBCT imaging protocols. Results also demonstrated that for high contrast areas such as bony anatomy, low doses are sufficient for image registration and visualization of the three-dimensional boundaries between soft tissue and bony structures. However, as the difference in tissue density decreased, the dose required to identify soft tissue boundaries increased. Finally, the dose delivered by MV-CBCT was simulated using a treatment planning system (TPS), thereby allowing the incorporation of MV-CBCT dose in the treatment planning process. The TPS-calculated doses agreed well with measurements for a wide range of imaging protocols.

Commissioning and clinical implementation of a mega‐voltage cone beam CT system for treatment localization

The improvement in conformal radiotherapy techniques with steep dose gradients has allowed for the delivery of higher doses to a tumor volume while maintaining the sparing of surrounding normal tissue. In this situation, verification of patient setup and evaluation of internal organ motion just prior to radiation delivery is a crucial step. To this end, several volumetric image-guided techniques have been developed for patient localization, such as the Siemens MVision mega-voltage cone beam CT (MV-CBCT) system. In this work, the commissioning and clinical implementation of the MVision system is presented. The geometry and gain calibration procedures for the system are described, and guidelines for quality assurance procedures are provided. Different MV-CBCT clinical protocols, ranging from daily to weekly image-guidance, which includes image acquisition, reconstruction, registration with planning CT, and treatment couch offsets corrections, were commissioned. The image quality characteristics of the MVision system were measured and assessed qualitatively and quantitatively, including the image noise and uniformity, low-contrast resolution, and spatial resolution. Furthermore, the image reconstruction and registration software was evaluated. Data show that a 2 cm large object with 1% electron density contrast can be detected with the MVision system with 10 cGy at isocenter and that the registration software is accurate within 2 mm in the anterior-posterior, left-right, and superior-inferior directions.

IMRT planning and delivery incorporating daily dose from mega-voltage cone-beam computed tomography imaging.

The technology of online mega-voltage cone-beam (CB) computed tomography (MV-CBCT) imaging is currently used in many institutions to generate a 3D anatomical dataset of a patient in treatment position. It utilizes an accelerator therapy beam, delivered with 200 degrees gantry rotation, and captured by an electronic portal imager to account for organ motion and setup variations. Although the patient dose exposure from a single volumetric MV-CBCT imaging procedure is comparable to that from standard double-exposure orthogonal portal images, daily image localization procedures can result in a significant dose increase to healthy tissue. A technique to incorporate the daily dose, from a MV-CBCT imaging procedure, in the IMRT treatment planning optimization process was developed. A composite IMRT plan incorporating the total dose from the CB was optimized with the objective of ensuring uniform target coverage while sparing the surrounding normal tissue. One head and neck cancer patient and four prostate cancer patients were planned and treated using this technique. Dosimetric results from the prostate IMRT plans optimized with or without CB showed similar target coverage and comparable sparing of bladder and rectum volumes. Average mean doses were higher by 1.6 +/- 1.0 Gy for the bladder and comparable for the rectum (-0.3 +/- 1.4 Gy). In addition, an average mean dose increase of 1.9 +/- 0.8 Gy in the femoral heads and 1.7 +/- 0.6 Gy in irradiated tissue was observed. However, the V65 and V70 values for bladder and rectum were lower by 2.3 +/- 1.5% and 2.4 +/- 2.1% indicating better volume sparing at high doses with the optimized plans incorporating CB. For the head and neck case, identical target coverage was achieved, while a comparable sparing of the brain stem, optic chiasm, and optic nerves was observed. The technique of optimized planning incorporating doses from daily online MV-CBCT procedures provides an alternative method for imaging IMRT patients. It allows for daily treatment modifications where other volumetric tomographic imaging techniques may not be feasible and/or available and where accurate patient localization with a high degree of precision is required.

Dosimetric and technical aspects of intraoperative I-125 brachytherapy for stage I non-small cell lung cancer

Initial treatment outcome data from our institution for stage I non-small cell lung cancer (NSCLC) patients have shown that sublobar resection in combination with iodine-125 (I-125) brachytherapy is associated with recurrence rates of 2.0%, compared to 18.6% with sublobar resection alone. In this work, the technical and dosimetric aspects required to execute this procedure from the radiation oncology perspective as well as an analysis of the dose distributions of patients treated with this technique are presented. In this treatment technique, I-125 seeds in vicryl suture are embedded into vicryl mesh and surgically inserted providing a 2.0 cm margin on each side of the resection staple line. A nomogram is developed to determine the suture spacing in the vicryl mesh, as a function of seed activity in order to deliver 120 Gy at a distance of 0.5 cm above and below the seed array. Post-operative dosimetry consists of a CT-based planning and dose volume analysis. Dose distributions, dose volume histograms and mean dose data for lung are analysed in a group of patients. Dosimetric results show significant lung sparing with only a small volume of lung irradiated for all patients with mean lung dose values ranging from 1.5 Gy to 5.4 Gy. Lung brachytherapy with I-125 at the time of sublobar resection is a highly conformal option of dose delivery for stage I NSCLC patients with compromised physiologic reserve. Patient-related toxicity clinically measured by loss of pulmonary function and radiation-induced pneumonitis have not been linked to this procedure.

Comparison of mega‐voltage cone‐beam computed tomography prostate localization with online ultrasound and fiducial markers methods

The online image-guided localization data from 696 ultrasound (US), 598 mega-voltage cone-beam computed tomography (MV-CBCT), and 393 seed markers (SMs) couch alignments for patients undergoing intensity modulation radiotherapy of the prostate were analyzed. Daily US, MV-CBCT and SM images were acquired for 19, 17 and 12 patients, respectively, after each patient was immobilized in a vacuum cradle and setup to skin markers as the center of mass. The couch shifts applied in the lateral (left-right/LR), vertical (anterior-posterior/AP), and longitudinal (superior-inferior/SI) directions, along with the magnitude of the three-dimensional (3D) shift vector, were analyzed and compared for all three methods. The percentage of shifts larger than 5 mm in all directions was also compared. Clinical target volume-planning target volume (CTV-to-PTV) expansion margins were estimated based on the localization data with US, CB, and SM image guidance. Results show the US data have greater variability. Systematic and random shifts were -1.2 +/- 6.8 mm (LR), -2.8 +/- 5.1 mm (SI) and -1.0 +/- 5.9 mm (AP) for US, 1.0 +/- 3.9 mm (LR), -1.3 +/- 2.5 mm (SI) and -0.3 +/- 3.9 mm (AP) for CB, and -1.0 +/- 3.4 mm (LR), 0.0 +/- 3.4 mm (SI) and 0.5 +/- 4.1 mm (AP) for SM. The mean 3D shift distance was larger using US (8.8 +/- 6.2 mm) compared to CB and SM (5.3 +/- 3.4 mm and 5.2 +/- 3.7 mm, respectively). The percentage of US shifts larger than 5 mm were 34%, 31%, and 38% in the LR, SI, and AP directions, respectively, compared to 18%, 6%, and 16% for CB and 14%, 10%, and 20% for SM. MV-CBCT and SM localization data suggest a different distribution of prostate center-of-mass shifts with smaller variability, compared to US. The online MV-CBCT and SM image-guidance data show that for treatments that do not include daily prostate localization, one can use a CTV-to-PTV margin that is 4 mm smaller than the one suggested by US data, hence allowing more rectum and bladder sparing and potentially improving the therapeutic ratio.

MATURE FOLLOW-UP FOR HIGH-RISK STAGE I NON-SMALL-CELL LUNG CARCINOMA TREATED WITH SUBLOBAR RESECTION AND INTRAOPERATIVE IODINE-125 BRACHYTHERAPY

PURPOSEnTo update the Allegheny General Hospital experience of high-risk Stage I non-small-cell lung cancer patients treated with sublobar resection and intraoperative (125)I Vicryl mesh brachytherapy.nnnMETHODS AND MATERIALSnBetween January 5, 1996 and February 19, 2008, 145 patients with Stage I non-small-cell lung cancer who were not lobectomy candidates because of cardiopulmonary compromise underwent sublobar resection and placement of (125)I seeds along the resection line. The (125)I seeds embedded in Vicryl suture were attached with surgical clips to a sheet of Vicryl mesh, inserted over the target area, and prescribed to a 0.5-cm planar margin.nnnRESULTSnThe mean target area, total activity, number of seeds implanted, and prescribed total dose was 33.3 cm(2) (range, 18.0-100.8), 20.2 mCi (range, 11.1-29.7), 46 (range, 30-100), and 117 Gy (range, 80-180), respectively. The median length of the surgical stay was 6 days (range, 1-111), with a perioperative mortality rate of 3.4%. At a median follow-up of 38.3 months (range, 1-133), 6 patients had developed local recurrence (4.1%), 9 had developed regional failure (6.2%), and 25 had distant failure (17.2%). On multivariate analysis, no patient- or tumor-specific factors or surgical or dosimetric factors were predictive of local recurrence. The overall median survival was 30.5 months with a 3- and 5-year overall survival rate of 65% and 35%, respectively.nnnCONCLUSIONn(125)I brachytherapy for high-risk, Stage I non-small-cell lung cancer after sublobar resection is well tolerated and associated with a low local failure rate.

EUCLID: an outcome analysis tool for high-dimensional clinical studies

Treatment management decisions in three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) are usually made based on the dose distributions in the target and surrounding normal tissue. These decisions may include, for example, the choice of one treatment over another and the level of tumour dose escalation. Furthermore, biological predictors such as tumour control probability (TCP) and normal tissue complication probability (NTCP), whose parameters available in the literature are only population-based estimates, are often used to assess and compare plans. However, a number of other clinical, biological and physiological factors also affect the outcome of radiotherapy treatment and are often not considered in the treatment planning and evaluation process. A statistical outcome analysis tool, EUCLID, for direct use by radiation oncologists and medical physicists was developed. The tool builds a mathematical model to predict an outcome probability based on a large number of clinical, biological, physiological and dosimetric factors. EUCLID can first analyse a large set of patients, such as from a clinical trial, to derive regression correlation coefficients between these factors and a given outcome. It can then apply such a model to an individual patient at the time of treatment to derive the probability of that outcome, allowing the physician to individualize the treatment based on medical evidence that encompasses a wide range of factors. The softwares flexibility allows the clinicians to explore several avenues to select the best predictors of a given outcome. Its link to record-and-verify systems and data spreadsheets allows for a rapid and practical data collection and manipulation. A wide range of statistical information about the study population, including demographics and correlations between different factors, is available. A large number of one- and two-dimensional plots, histograms and survival curves allow for an easy visual analysis of the population. Several visual and analytical methods are available to quantify the predictive power of the multivariate regression model. The EUCLID tool can be readily integrated with treatment planning and record-and-verify systems.

A genetic algorithm for variable selection in logistic regression analysis of radiotherapy treatment outcomes

A given outcome of radiotherapy treatment can be modeled by analyzing its correlation with a combination of dosimetric, physiological, biological, and clinical factors, through a logistic regression fit of a large patient population. The quality of the fit is measured by the combination of the predictive power of this particular set of factors and the statistical significance of the individual factors in the model. We developed a genetic algorithm (GA), in which a small sample of all the possible combinations of variables are fitted to the patient data. New models are derived from the best models, through crossover and mutation operations, and are in turn fitted. The process is repeated until the sample converges to the combination of factors that best predicts the outcome. The GA was tested on a data set that investigated the incidence of lung injury in NSCLC patients treated with 3DCRT. The GA identified a model with two variables as the best predictor of radiation pneumonitis: the V30 (p=0.048) and the ongoing use of tobacco at the time of referral (p=0.074). This two-variable model was confirmed as the best model by analyzing all possible combinations of factors. In conclusion, genetic algorithms provide a reliable and fast way to select significant factors in logistic regression analysis of large clinical studies.

Monitoring tumor motion with on-line mega-voltage cone-beam computed tomography imaging in a cine mode

Accurate daily patient localization is becoming increasingly important in external-beam radiotherapy (RT). Mega-voltage cone-beam computed tomography (MV-CBCT) utilizing a therapy beam and an on-board electronic portal imager can be used to localize tumor volumes and verify the patients position prior to treatment. MV-CBCT produces a static volumetric image and therefore can only account for inter-fractional changes. In this work, the feasibility of using the MV-CBCT raw data as a fluoroscopic series of portal images to monitor tumor changes due to e.g. respiratory motion was investigated. A method was developed to read and convert the CB raw data into a cine. To improve the contrast-to-noise ratio on the MV-CB projection data, image post-processing with filtering techniques was investigated. Volumes of interest from the planning CT were projected onto the MV-cine. Because of the small exposure and the varying thickness of the patient depending on the projection angle, soft-tissue contrast was limited. Tumor visibility as a function of tumor size and projection angle was studied. The method was well suited in the upper chest, where motion of the tumor as well as of the diaphragm could be clearly seen. In the cases of patients with non-small cell lung cancer with medium or large tumor masses, we verified that the tumor mass was always located within the PTV despite respiratory motion. However for small tumors the method is less applicable, because the visibility of those targets becomes marginal. Evaluation of motion in non-superior-inferior directions might also be limited for small tumor masses. Viewing MV-CBCT data in a cine mode adds to the utility of MV-CBCT for verification of tumor motion and for deriving individualized treatment margins.