Future vision for the quality assurance of oncology clinical trials.

The National Cancer Institute clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based process improvements for clinical oncology patient care. The cooperative groups are undergoing a transformation process as we further integrate molecular biology into personalized patient care and move to incorporate international partners in clinical trials. To support this vision, data acquisition and data management informatics tools must become both nimble and robust to support transformational research at an enterprise level. Information, including imaging, pathology, molecular biology, radiation oncology, surgery, systemic therapy, and patient outcome data needs to be integrated into the clinical trial charter using adaptive clinical trial mechanisms for design of the trial. This information needs to be made available to investigators using digital processes for real-time data analysis. Future clinical trials will need to be designed and completed in a timely manner facilitated by nimble informatics processes for data management. This paper discusses both past experience and future vision for clinical trials as we move to develop data management and quality assurance processes to meet the needs of the modern trial.

Credentialing for participation in clinical trials.

The National Cancer Institute (NCI) clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based clinical trial processes for improvements in patient care. The cooperative groups are undergoing a transformation process to launch, conduct, and publish clinical trials more rapidly. Institutional participation in clinical trials can be made more efficient and include the expansion of relationships with international partners. This paper reviews the current processes that are in use in radiation therapy trials and the importance of maintaining effective credentialing strategies to assure the quality of the outcomes of clinical trials. The paper offers strategies to streamline and harmonize credentialing tools and processes moving forward as the NCI undergoes transformative change in the conduct of clinical trials.

Results of a multi-institutional benchmark test for cranial CT/MR image registration.

PURPOSE: Variability in computed tomography/magnetic resonance imaging (CT/MR) cranial image registration was assessed using a benchmark case developed by the Quality Assurance Review Center to credential institutions for participation in Children's Oncology Group Protocol ACNS0221 for treatment of pediatric low-grade glioma. METHODS AND MATERIALS: Two DICOM image sets, an MR and a CT of the same patient, were provided to each institution. A small target in the posterior occipital lobe was readily visible on two slices of the MR scan and not visible on the CT scan. Each institution registered the two scans using whatever software system and method it ordinarily uses for such a case. The target volume was then contoured on the two MR slices, and the coordinates of the center of the corresponding target in the CT coordinate system were reported. The average of all submissions was used to determine the true center of the target. RESULTS: Results are reported from 51 submissions representing 45 institutions and 11 software systems. The average error in the position of the center of the target was 1.8 mm (1 standard deviation = 2.2 mm). The least variation in position was in the lateral direction. Manual registration gave significantly better results than did automatic registration (p = 0.02). CONCLUSION: When MR and CT scans of the head are registered with currently available software, there is inherent uncertainty of approximately 2 mm (1 standard deviation), which should be considered when defining planning target volumes and PRVs for organs at risk on registered image sets.

Processes for quality improvements in radiation oncology clinical trials.

Quality assurance in radiotherapy (RT) has been an integral aspect of cooperative group clinical trials since 1970. In early clinical trials, data acquisition was nonuniform and inconsistent and computational models for radiation dose calculation varied significantly. Process improvements developed for data acquisition, credentialing, and data management have provided the necessary infrastructure for uniform data. With continued improvement in the technology and delivery of RT, evaluation processes for target definition, RT planning, and execution undergo constant review. As we move to multimodality image-based definitions of target volumes for protocols, future clinical trials will require near real-time image analysis and feedback to field investigators. The ability of quality assurance centers to meet these real-time challenges with robust electronic interaction platforms for imaging acquisition, review, archiving, and quantitative review of volumetric RT plans will be the primary challenge for future successful clinical trials.

Hybrid IMRT for treatment of cancers of the lung and esophagus.

PURPOSE: To report on a hybrid intensity-modulated radiation therapy (IMRT; static plus IMRT beams treated concurrently) technique for lung and esophageal patients to reduce the volume of lung treated to low doses while delivering a conformal dose distribution. METHODS: Treatment plans were analyzed for 18 patients (12 lung and 6 esophageal). Patients were treated with a hybrid technique that concurrently combines static (approximately two-thirds dose) and IMRT (approximately one-third dose) beams. These plans were compared with conventional three-dimensional (3D; non-IMRT) plans and all IMRT plans using custom four- and five-field arrangements and nine equally spaced coplanar beams. Plans were optimized to reduce V13 and V5 values. Dose-volume histograms were calculated for the planning target volume, heart, and the ipsilateral, contralateral, and total lung. Lung volumes V5, V13, V20, V30; mean lung dose (MLD); and the generalized equivalent uniform dose (gEUD) were calculated for each plan. RESULTS: Hybrid plans treated significantly smaller total and contralateral lung volumes with low doses than nine-field IMRT plans. Largest reductions were for contralateral lung V5, V13, and V20 values for lung (-11%, -15%, -7%) and esophageal (-16%, -20%, -7%) patients. Smaller reductions were found also for 3D and four- and five-field IMRT plans. MLD and gEUDs were similar for all plan types. The 3D plans treated much larger extra planning target volumes to prescribed dose levels. CONCLUSIONS: Hybrid IMRT demonstrated advantages for reduction of low-dose lung volumes in the thorax for reducing low dose to lung while also reducing the potential magnitude of dose deviations due to intrafraction motion and small field calculation accuracy.

Radiation therapy toxicity to the skin.

Radiation therapy has been integral to cancer patient care. The skin is an intentional and unintentional target of therapy, and is sensitive to the volume of normal tissue in the radiation therapy treatment field, daily treatment dose (fractionation), and total treatment dose. We must understand the relationship of these factors to patient outcome as we move toward hypofractionation treatment strategies (radiosurgery). Chemotherapy agents and prescription medications may influence therapy-associated sequelae. Understanding this may prevent significant injury and discomfort. This article reviews established platforms of radiation therapy and sequelae associated with skin therapy. Interactions with other agents and possible predisposition to sequelae are reviewed. Skin cancer resulting from treatment and disease processes associated with possible limited outcome are also reviewed.

Radiotherapy in pediatric medulloblastoma: quality assessment of Pediatric Oncology Group Trial 9031.

PURPOSE: To evaluate the potential influence of radiotherapy quality on survival in high-risk pediatric medulloblastoma patients. METHODS AND MATERIALS: Trial 9031 of the Pediatric Oncology Group (POG) aimed to study the relative benefit of cisplatin and etoposide randomization of high-risk patients with medulloblastoma to preradiotherapy vs. postradiotherapy treatment. Two-hundred and ten patients were treated according to protocol guidelines and were eligible for the present analysis. Treatment volume (whole brain, spine, posterior fossa, and primary tumor bed) and dose prescription deviations were assessed for each patient. An analysis of first site of failure was undertaken. Event-free and overall survival rates were calculated. A log-rank test was used to determine the significance of potential survival differences between patients with and without major deviations in the radiotherapy procedure. RESULTS: Of 160 patients who were fully evaluable for all treatment quality parameters, 91 (57%) had 1 or more major deviations in their treatment schedule. Major deviations by treatment site were brain (26%), spinal (7%), posterior fossa (40%), and primary tumor bed (17%). Major treatment volume or total dose deviations did not significantly influence overall and event-free survival. CONCLUSIONS: Despite major treatment deviations in more than half of fully evaluable patients, underdosage or treatment volume misses were not associated with a worse event-free or overall survival.

Hybrid IMRT plans--concurrently treating conventional and IMRT beams for improved breast irradiation and reduced planning time.

PURPOSE: To evaluate a hybrid intensity modulated radiation therapy (IMRT) technique as a class solution for treatment of the intact breast. METHODS AND MATERIALS: The following five plan techniques were compared for 10 breast patients using dose-volume histogram analysis: conventional wedged-field tangents (Tangents), forward-planned field-within-a-field tangents (FIF), IMRT-only tangents (IMRT tangents), conventional open plus IMRT tangents (4-field hybrid), and conventional open plus IMRT tangents with 2 anterior oblique IMRT beams (6-field hybrid). RESULTS: The 4-field hybrid and FIF achieved dose distributions better than Tangents and IMRT tangents. The volume of tissue outside the planning target volume receiving > or =110% of prescribed dose was largest for IMRT tangents (average 158 cc) and least for 6-field hybrid (average 1 cc); the FIF and 4-field hybrid were comparable (average 15 cc). Heart volume > or =30 Gy averaged 13 cc for all techniques, except Tangents, for which it was 32 cc. Average total lung volume > or =20 Gy was 7% for all. Contralateral breast doses were < 3% for all. Planning time for hybrid techniques was significantly less than for conventional FIF technique. CONCLUSIONS: The 4-field hybrid technique is a viable class solution. The 6-field hybrid technique creates the most conformal dose distribution at the expense of more normal tissue receiving low dose.

Forward-planned, multiple-segment, tangential fields with concomitant boost in the treatment of breast cancer.

We report on the utility of forward-planned, 3-dimensional (3D), multiple-segment tangential fields for radiation treatment of patients with breast cancer. The technique accurately targets breast tissue and the tumor bed and reduces dose inhomogeneity in the target. By decreasing excess dose to the skin and lung, a concomitant boost to the tumor bed can be delivered during the initial treatment, thereby decreasing the overall treatment time by one week. More than 120 breast cancer patients have been treated with this breast conservation technique in our clinic. For each patient, a 3D treatment plan based upon breast and tumor bed volumes delineated on computed tomography (CT) was developed. Segmented tangent fields were iteratively created to reduce "hot spots" produced by traditional tangents. The tumor bed received a concomitant boost with additional conformal photon beams. The final tumor bed boost was delivered either with conformal photon beams or conventional electron beams. All patients received 45 Gy to the breast target, plus an additional 5 Gy to the surgical excision site, bringing the total dose to 50 Gy to the boost target volume in 25 fractions. The final boost to the excision site brought the total target dose to 60 Gy. With minimum follow-up of 4 months and median follow-up of 11 months, all patients have excellent cosmetic results. There has been minimal breast edema and minimal skin changes. There have been no local relapses to date. Forward planning of multi-segment fields is facilitated with 3D planning and multileaf collimation. The treatment technique offers improvement in target dose homogeneity and the ability to confidently concomitantly boost the excision site. The technique also offers the advantage for physics and therapy staff to develop familiarity with multiple segment fields, as a precursor to intensity-modulated radiation therapy (IMRT) techniques.

A systematic benchmark method for analysis and comparison of IMRT treatment planning algorithms.

Tools and procedures for evaluating and comparing different intensity-modulated radiation therapy (IMRT) systems are presented. IMRT is increasingly in demand and there are numerous systems available commercially. These programs introduce significantly different software to dosimetrists and physicists than conventional planning systems, and the options often seem initially overwhelmingly complex to the user. By creating geometric target volumes and critical normal tissues, the characteristics of the algorithms may be investigated, and the influence of the different parameters explored. Overall optimization strategies of the algorithm may be characterized by treating a square target volume (TV) with 2 perpendicular beams, with and without heterogeneities. A half-donut (hemi-annulus) TV with a "donut hole" (central cylinder) critical normal tissue (CNT) on a CT of a simulated quality assurance phantom is suggested as a good geometry to explore the IMRT algorithm parameters. Using this geometry, the order of varying parameters is suggested. First is to determine the effects of the number of stratifications of optimized intensity fluence on the resulting dose distribution, and selecting a fixed number of stratifications for further studies. To characterize the dose distributions, a dose-homogeneity index (DHI) is defined as the ratio of the dose received by 90% of the volume to the minimum dose received by the "hottest" 10% of the volume. The next step is to explore the effects of priority and penalty on both the TV and the CNT. Then, choosing and fixing these parameters, the effects of varying the number of beams can be looked at. As well as evaluating the dose distributions (and DHI), the number of subfields and the number of monitor units required for different numbers of stratifications and beams can be evaluated.

Current calibration, treatment, and treatment planning techniques among institutions participating in the Children's Oncology Group.

PURPOSE: To report current technology implementation, radiation therapy physics and treatment planning practices, and results of treatment planning exercises among 261 institutions belonging to the Children's Oncology Group (COG). METHODS AND MATERIALS: The Radiation Therapy Committee of the newly formed COG mandated that each institution demonstrate basic physics and treatment planning abilities by satisfactorily completing a questionnaire and four treatment planning exercises designed by the Quality Assurance Review Center. The planning cases are (1) a maxillary sinus target volume (for two-dimensional planning), (2) a Hodgkin's disease mantle field (for irregular-field and off-axis dose calculations), (3) a central axis blocked case, and (4) a craniospinal irradiation case. The questionnaire and treatment plans were submitted (as of 1/30/02) by 243 institutions and completed satisfactorily by 233. Data from this questionnaire and analyses of the treatment plans with monitor unit calculations are presented. RESULTS: Of the 243 clinics responding, 54% use multileaf collimators routinely, 94% use asymmetric jaws routinely, and 13% use dynamic wedges. Nearly all institutions calibrate their linear accelerators following American Association of Physicists in Medicine protocols, currently 16% with TG-51 and 81% with TG-21 protocol. Treatment planning systems are relied on very heavily for all calculations, including monitor units. Techniques and results of each of the treatment planning exercises are presented. CONCLUSIONS: Together, these data provide a unique compilation of current (2001) radiation therapy practices in institutions treating pediatric patients. Overall, the COG facilities have the equipment and the personnel to perform high-quality radiation therapy. With ongoing quality assurance review, radiation therapy compliance with COG protocols should be high.

Commissioning of mini-multi-leaf-collimator (MMLC) for stereotactic radiosurgery and radiotherapy.

Commissioning of a Radionics miniature multi-leaf collimator (MMLC) for stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) is reported. With single isocenter and multi static fields, the MMLC can provide better conformity of dose distributions to the target and/or irregularly shaped target volumes than standard arc (circular) field beams with multiple isocenters. Advantages offered by the MMLC over traditional LINAC based SRS and SRT includes greatly improved dose homogeneity to the target, reduced patient positioning time and reduced treatment time. In this work, the MMLC is attached to a Varian 2300 C/D with Varian 80-leaf multi-leaf collimator. The MMLC has 62 leaves, each measured to a width of 3.53 mm at isocenter, with fields range from 1x1 cm to less than 10 × 12 cm. Beam parameters required by the Radionics treatment planning system (XPlan version 2) for evaluating the dose include tissue maximum ratio (TMR), scatter factors (SF), off-axis ratios (OAR), output factors, penumbra function (P) and transmission factors (TF) are performed in this work. Beam data are acquired with a small stereotactic diode, standard ion chambers and radiographic films. Measured profiles of dose distribution are compared to those calculated by the software and absolute dosimetry is performed.