Treatment data and technical process challenges for practical big data efforts in radiation oncology.

The term Big Data has come to encompass a number of concepts and uses within medicine. This paper lays out the relevance and application of large collections of data in the radiation oncology community. We describe the potential importance and uses in clinical practice. The important concepts are then described and how they have been or could be implemented are discussed. Impediments to progress in the collection and use of sufficient quantities of data are also described. Finally, recommendations for how the community can move forward to achieve the potential of big data in radiation oncology are provided.

Inverse plan optimization accounting for random geometric uncertainties with a multiple instance geometry approximation (MIGA).

Radiotherapy treatment plans that are optimized to be highly conformal based on a static patient geometry can be degraded by setup errors and/or intratreatment motion, particularly for IMRT plans. To achieve improved plans in the face of geometrical uncertainties, direct simulation of multiple instances of the patient anatomy (to account for setup and/or motion uncertainties) is used within the inverse planning process. This multiple instance geometry approximation (MIGA) method uses two or more instances of the patient anatomy and optimizes a single beam arrangement for all instances concurrently. Each anatomical instance can represent expected extremes or a weighted distribution of geometries. The current implementation supports mapping between instances that include distortions, but this report is limited to the use of rigid body translations/ rotations. For inverse planning, the method uses beamlet dose calculations for each instance, with the resulting doses combined using a weighted sum of the results for the multiple instances. Beamlet intensities are then optimized using the inverse planning system based on the cost for the composite dose distribution. MIGA can simulate various types of geometrical uncertainties, including random setup error and intratreatment motion. A limited number of instances are necessary to simulate Gaussian-distributed errors. IMRT plans optimized using MIGA show significantly less degradation in the face of geometrical errors, and are robust to the expected (simulated) motions. Results for a complex head/neck plan involving multiple target volumes and numerous normal structures are significantly improved when the MIGA method of inverse planning is used. Inverse planning using MIGA can lead to significant improvements over the use of simple PTV volume expansions for inclusion of geometrical uncertainties into inverse planning, since it can account for the correlated motions of the entire anatomical representation. The optimized plan results reflect the differing patient geometry situations which can be important near the surface or heterogeneities. For certain clinical situations, the MIGA optimization approach can correct for a significant part of the degradation of the plan caused by the setup uncertainties.

Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.

PURPOSE: To develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd). PATIENTS AND METHODS: Twenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months. RESULTS: Whole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months. CONCLUSION: These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.

Optimization and clinical use of multisegment intensity-modulated radiation therapy for high-dose conformal therapy.

Intensity-modulated radiation therapy (IMRT) may be performed with many different treatment delivery techniques. This article summarizes the clinical use and optimization of multisegment IMRT plans that have been used to treat more than 350 patients with IMRT over the last 4.5 years. More than 475 separate clinical IMRT plans are reviewed, including treatments of brain, head and neck, thorax, breast and chest wall, abdomen, pelvis, prostate, and other sites. Clinical planning, plan optimization, and treatment delivery are summarized, including efforts to minimize the number of additional intensity-modulated segments needed for particular planning protocols. Interactive and automated optimization of segmental and full IMRT approaches are illustrated, and automation of the segmental IMRT planning process is discussed.

Integration of multimodality imaging data for radiotherapy treatment planning.

This paper describes computational techniques to permit the quantitative integration of magnetic resonance (MR), positron emission tomography (PET), and x-ray computed tomography (CT) imaging data sets. These methods are used to incorporate unique diagnostic information provided by PET and MR imaging into CT-based treatment planning for radiotherapy of intracranial tumors and vascular malformations. Integration of information from the different imaging modalities is treated as a two-step process. The first step is to determine the set of geometric parameters relating the coordinates of two imaging data sets. No universal method for determining these parameters is appropriate because of the diversity of contemporary imaging methods and data formats. Most situations can be handled by one of the four different techniques described. These four methods make use of specific geometric objects contained in the two data sets to determine the parameters. These objects are: (a) anatomical and/or fiducial points, (b) attached line markers, (c) anatomical surfaces, and (d) outlines of anatomical structures. The second step involves using the derived transformation to transfer outlines of treatment volumes and/or anatomical structures drawn on the images of one imaging study to the images of another study, usually the treatment planning CT. Solid modelling and image processing techniques have been adapted and developed further to accomplish this task. Clinical examples and phantom studies are presented which verify the different aspects of these techniques and demonstrate the accuracy with which they can be applied. Clinical use of these techniques for treatment planning has resulted in improvements in localization of treatment volumes and critical structures in the brain. These improvements have allowed greater sparing of normal tissues and more precise delivery of energy to the desired irradiation volume. It is believed that these improvements will have a positive impact on the outcome of radiation therapy.

Advanced interactive planning techniques for conformal therapy: high level beam descriptions and volumetric mapping techniques.

PURPOSE: To aid in design of conformal radiation therapy treatment plans involving many conformally shaped fields, this work investigates the use of two methodologies to enhance the ease of interactive treatment planning: high-level beam constructs and beam's-eye view volumetric mapping. METHODS AND MATERIALS: High-performance computer graphics running on various workstations using a graphical visualization system (AVS) have been used in this work. Software specific to this application has been written in standard FORTRAN and C languages. A new methodology is introduced by defining radiation therapy "fields" to be composed of multiple beam "segments." Fields can then be defined as higher-level entities such as arcs, cones, and other shapes. A "segmental cone" field, for example, is defined by a symmetry axis and a cone angle, and can be used to rapidly place a series of beam segments that converge at the target volume, while reducing the degree of overlap elsewhere. A new beam's-eye view (BEV) volumetric mapping technique is presented to aid in selecting the placement of conformal radiation fields. With this technique, the relative average dose within an organ of interest is calculated for a sampling of isocentric, conformally shaped beams and displayed either as a "globe," which can be combined with the display of anatomical surfaces, or as a two-dimensionally mapped projection. The dose maps from multiple organs can be generated, stacked, or composited with relative weightings to aid in the placement of fields that minimize overlap with critical structures. RESULTS: The use of these new methodologies is demonstrated for prostate and lung treatment sites and compared to conventional planning techniques. DISCUSSION: The use of many beams for conformal treatment delivery is difficult with current interactive planning. The use of high-level beam constructs provides a means to quickly specify, place, and configure multiple beam arrangements. The BEV volumetrics aids in the placing of fields, which minimize involvement with critical normal tissues. CONCLUSIONS: Early experience with the new methodologies suggest that the new methods help to enhance (or at least speed up) the ability of a treatment planner to create optimal radiation treatment field arrangements.

A computer-controlled conformal radiotherapy system. III: Graphical simulation and monitoring of treatment delivery.

PURPOSE: Safe and efficient delivery of radiotherapy using computer-controlled machines requires new procedures to design and verify the actual delivery of these treatments. Graphical simulation and monitoring techniques for treatment delivery have been developed for this purpose. METHODS AND MATERIALS: A graphics-based simulator of the treatment machine and a set of procedures for creating and manipulating treatment delivery scripts are used to simulate machine motions, detect collisions, and monitor machine positions during treatment. The treatment delivery simulator is composed of four components: a three-dimensional dynamic model of the treatment machine; a motion simulation and collision detection algorithm, user-interface widgets that mimic the treatment machine's control and readout devices; and an icon-based interface for creating and manipulating treatment delivery scripts. These components are used in a stand-alone fashion for interactive treatment delivery planning and integrated with a machine control system for treatment implementation and monitoring. RESULTS: A graphics-based treatment delivery simulator and a set of procedures for planning and monitoring computer-controlled treatment delivery have been developed and implemented as part of a comprehensive computer-controlled conformal radiotherapy system. To date, these techniques have been used to design and help monitor computer-controlled treatments on a radiotherapy machine for more than 200 patients. Examples using these techniques for treatment delivery planning and on-line monitoring of machine motions during therapy are described. CONCLUSION: A system that provides interactive graphics-based tools for defining the sequence of machine motions, simulating treatment delivery including collision detection, and presenting the therapists with continual visual feedback from the treatment machine has been successfully implemented for routine clinical use as part of an overall system for computer-controlled conformal radiotherapy treatment, and is considered a necessary part of the routine treatment methodology.

Expanding the use and effectiveness of dose-volume histograms for 3-D treatment planning. I: Integration of 3-D dose-display.

PURPOSE: A technique is presented for overcoming a major deficiency of histogram analysis in three-dimensional (3-D) radiotherapy treatment planning; the lack of spatial information. METHODS AND MATERIALS: In this technique, histogram data and anatomic images are displayed in a side-by-side fashion. The histogram curve is used as a guide to interactively probe the nature of the corresponding 3-D dose distribution. Regions of dose that contribute to a specific dose bin or range of bins are interactively highlighted on the anatomic display as a window-style cursor is positioned along the dose-axis of the histogram display. This dose range highlighting can be applied to two-dimensional (2-D) images and to 3-D views which contain anatomic surfaces, multimodality image data, and representations of radiation beams and beam modifiers. Additionally, as a range of histogram bins is specified, dose and volume statistics for the range are continually updated and displayed. RESULTS: The implementation of these techniques is presented and their use illustrated for a nonaxial three field treatment of a hepatic tumor. CONCLUSION: By integrating displays of 3-D doses and the corresponding histogram data, it is possible to recover the positional information inherently lost in the calculation of a histogram. Important questions such as the size and location of hot spots in normal tissues and cold spots within target volumes can be more easily uncovered, making the iterative improvement of treatment plans more efficient.

Fraction size and dose parameters related to the incidence of pericardial effusions.

PURPOSE: The influence of treatment parameters, such as (a) fraction size and (b) average and maximum dose (as derived from three-dimensional (3D) distributions), on the incidence of pericarditis was analyzed. To understand and predict the dose and volume effect on the pericardium, a normal tissue-complication probability model was tested with these complication data. METHODS AND MATERIALS: Patients (n = 57) entered in 3 consecutive University of Michigan protocols of combined modality for treatment of localized esophageal carcinoma, and having 3D treatment planning for radiation therapy were the subject of this study. Univariate and multivariate analyses were performed to determine the significance of the effect of fraction size and dose parameters on the development of any grade of pericarditis. Dose distributions were corrected for the biological effect of fraction size using the linear-quadratic method. Normal tissue complication probability (NTCP) was calculated with the Lyman model. RESULTS: Nonmalignant pericardial effusions occurred in 5 of the 57 patients; all effusions were in patients who received treatment with 3.5 Gy daily fractions. On multivariate analysis, no dose factor except fraction size predicted pericarditis, until the dose distributions were corrected for the effect of fraction size ("bio"-dose). Then, both "bio-average" and "bio-maximum" dose were significant predictive factors (p = 0.014). NTCPs for the patients with pericarditis range from 62% to 99% for the calculations with the "bio"-dose distributions vs. 0.5% to 27% for the uncorrected distributions. DISCUSSION: A normal tissue complication probability (NTCP) model predicts a trend towards a high incidence of radiation pericarditis for patients who have high complication probabilities. It is important to correct the dose distribution for the effects of fractionation, particularly when the fraction size deviates greatly from standard (2.0 Gy) fractionation.

Use of Veff and iso-NTCP in the implementation of dose escalation protocols.

PURPOSE: This report investigates the use of a normal tissue complication probability (NTCP) model, 3-D dose distributions, and a dose volume histogram reduction scheme in the design and implementation of dose escalation protocols for irradiation of sites that are primarily limited by the dose to a normal tissue which exhibits a strong volume effect (e.g., lung, liver). METHODS AND MATERIALS: Plots containing iso-NTCP contours are generated as a function of dose and partial volume using a parameterization of a NTCP description. Single step dose volume histograms are generated from 3-D dose distributions using the effective-volume (Veff) reduction scheme. In this scheme, the value of Veff for each dose volume histogram is independent of dose units (Gy, %). Thus, relative dose distributions (%) may be used to segregate patients by Veff into bins containing different ranges of Veff values before the assignment of prescription doses (Gy). The doses for each bin of Veff values can then be independently escalated between estimated complication levels (iso-NTCP contours). RESULTS AND CONCLUSION: Given that for the site under study, an investigator believes that the NTCP parameterization and the Veff methodology at least describe the general trend of clinical expectations, the concepts discussed allow the use of patient specific 3-D dose/volume information in the design and implementation of dose escalation studies. The result is a scheme with which useful prospective tolerance data may be systematically obtained for testing the different NTCP parameterizations and models.

Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy for primary hepatobiliary cancers.

PURPOSE: We have previously shown that conformal radiation therapy (RT) combined with hepatic artery (HA) fluorodeoxyuridine (FdUrd) had encouraging hepatic control and survival rates for patients with nondiffuse primary hepatobiliary malignancies. With longer follow-up, we were particularly interested if long-term hepatic control and disease-free survival could be achieved, and if late hepatic complications due to radiation therapy were observed. METHODS AND MATERIALS: Patients with unresectable primary hepatobiliary cancer were treated with concurrent HA FdUrd (0.2 mg/kg/day) and conformal RT (1.5-1.65 Gy per fraction, twice a day), directed only to the liver abnormalities. Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of radiation (48 or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. Patients were followed routinely for response, patterns of failure, long-term toxicity, and survival. The median potential follow-up was 54 months. RESULTS: A total of 22 patients (11 with hepatocellular carcinoma and 11 with cholangiocarcinoma) were treated. There were 10 objective responses in the 11 evaluable patients. The overall freedom from hepatic progression at more than 2 years was about 50%. The median survival was 16 months with an actuarial 4-year survival of about 20%. Gastrointestinal bleeding was the most common long-term toxicity. Late hepatic toxicity was not observed; in fact, hypertrophy of the untreated liver was seen. CONCLUSIONS: Combined conformal RT and HA FdUrd can produce long-term freedom from hepatic progression and survival in patients with unresectable, nondiffuse primary hepatobiliary malignancies. There were no long-term liver complications observed.

A computer-controlled conformal radiotherapy system. I: Overview.

PURPOSE: Equipment developed for use with computer-controlled conformal radiotherapy (CCRT) treatment techniques, including multileaf collimators and/or computer-control systems for treatment machines, are now available. The purpose of this work is to develop a system that will allow the safe, efficient, and accurate delivery of CCRT treatments as routine clinical treatments, and permit modifications of the system so that the delivery process can be optimized. METHODS AND MATERIALS: The needs and requirements for a system that can fully support modern computer-controlled treatment machines equipped with multileaf collimators and segmental or dynamic conformal therapy capabilities have been analyzed and evaluated. This analysis has been used to design and then implement a complete approach to the delivery of CCRT treatments. RESULTS: The computer-controlled conformal radiotherapy system (CCRS) described here consists of a process for the delivery of CCRT treatments, and a complex software system that implements the treatment process. The CCRS system described here includes systems for plan transfer, treatment delivery planning, sequencing of the actual treatment delivery process, graphical simulation and verification tools, as well as an electronic chart that is an integral part of the system. The CCRS system has been implemented for use with a number of different treatment machines. The system has been used clinically for more than 2 years to perform CCRT treatments for more than 200 patients. CONCLUSIONS: A comprehensive system for the implementation and delivery of computer-controlled conformal radiation therapy (CCRT) plans has been designed and implemented for routine clinical use with multisegment, computer-controlled, multileaf-collimated conformal therapy. The CCRS system has been successfully implemented to perform these complex treatments, and is considered quite important to the clinical use of modern computer-controlled treatment techniques.

A computer-controlled conformal radiotherapy system. II: Sequence processor.

PURPOSE: A sequence processor (SP) is described as part of a larger computer-controlled conformal radiotherapy system (CCRS). The SP provides the means to accept and then translate highly sophisticated radiation therapy treatment plans into vendor specific instructions to control treatment delivery on a computer-controlled treatment machine. METHODS AND MATERIALS: The sequence processor (SP) is a small workstation computer that interfaces to the control computer of computer-controlled treatment machines, and to other parts of the larger CCRS system. The system reported here has been interfaced to a computer-controlled racetrack microtron with two treatment gantries, and also to other linear accelerator treatment machines equipped with multileaf collimators. An extensive design process has been used in defining the role of the SP within the context of the larger CCRS project. Flexibility and integration with various components of the project, including databases, treatment planning system, graphical simulator, were key factors in the development. In conjunction with the planned set of treatment fields, a procedural scripting language is used to define the sequence of treatment events that are performed, including operator interactions, communications to other systems such as dosimetry and portal imaging devices, and database management. RESULTS: A flexible system has been developed to allow investigation into procedural steps required for simulating and delivering complex radiation treatments. The system has been used to automate portions of the acceptance testing for the control system of the microtron, and is used for routine daily quality assurance testing. The sequence processor system described here has been used to deliver all clinical treatments performed on the microtron system in 2 years of clinical treatment (more than 200 patients treated to a variety of treatment sites). CONCLUSIONS: The sequence processor system has enabled the delivery of complex treatment using computer-controlled treatment machines. The flexibility of the system allows integration with secondary devices and modification of procedural steps, making it possible to develop effective techniques for insuring safe and efficient computer-controlled conformal radiation therapy treatments.

A computer-controlled conformal radiotherapy system. IV: Electronic chart.

PURPOSE: The design and implementation of a system for electronically tracking relevant plan, prescription, and treatment data for computer-controlled conformal radiation therapy is described. METHODS AND MATERIALS: The electronic charting system is implemented on a computer cluster coupled by high-speed networks to computer-controlled therapy machines. A methodical approach to the specification and design of an integrated solution has been used in developing the system. The electronic chart system is designed to allow identification and access of patient-specific data including treatment-planning data, treatment prescription information, and charting of doses. An in-house developed database system is used to provide an integrated approach to the database requirements of the design. A hierarchy of databases is used for both centralization and distribution of the treatment data for specific treatment machines. RESULTS: The basic electronic database system has been implemented and has been in use since July 1993. The system has been used to download and manage treatment data on all patients treated on our first fully computer-controlled treatment machine. To date, electronic dose charting functions have not been fully implemented clinically, requiring the continued use of paper charting for dose tracking. CONCLUSIONS: The routine clinical application of complex computer-controlled conformal treatment procedures requires the management of large quantities of information for describing and tracking treatments. An integrated and comprehensive approach to this problem has led to a full electronic chart for conformal radiation therapy treatments.

Is uniform target dose possible in IMRT plans in the head and neck?

PURPOSE: Various published reports involving intensity-modulated radiotherapy (IMRT) plans developed using automated optimization (inverse planning) have demonstrated highly conformal plans. These reported conformal IMRT plans involve significant target dose inhomogeneity, including both overdosage and underdosage within the target volume. In this study, we demonstrate the development of optimized beamlet IMRT plans that satisfy rigorous dose homogeneity requirements for all target volumes (e.g., +/-5%), while also sparing the parotids and other normal structures. METHODS AND MATERIALS: The treatment plans of 15 patients with oropharyngeal cancer who were previously treated with forward-planned multisegmental IMRT were planned again using an automated optimization system developed in-house. The optimization system allows for variable sized beamlets computed using a three-dimensional convolution/superposition dose calculation and flexible cost functions derived from combinations of clinically relevant factors (costlets) that can include dose, dose-volume, and biologic model-based costlets. The current study compared optimized IMRT plans designed to treat the various planning target volumes to doses of 66, 60, and 54 Gy with varying target dose homogeneity while using a flexible optimization cost function to minimize the dose to the parotids, spinal cord, oral cavity, brainstem, submandibular nodes, and other structures. RESULTS: In all cases, target dose uniformity was achieved through steeply varying dose-based costs. Differences in clinical plan evaluation metrics were evaluated for individual cases (eight different target homogeneity costlets), and for the entire cohort of plans. Highly conformal plans were achieved, with significant sparing of both the contralateral and ipsilateral parotid glands. As the homogeneity of the target dose distributions was allowed to decrease, increased sparing of the parotids (and other normal tissues) may be achieved. However, it was shown that relatively few patients would benefit from the use of increased target inhomogeneity, because the range of improvement in the parotid dose is relatively limited. Hot spots in the target volumes are shown to be unnecessary and do not assist in normal tissue sparing. CONCLUSION: Sparing of both parotids in patients receiving bilateral neck radiation can be achieved without compromising strict target dose homogeneity criteria. The geometry of the normal tissue and target anatomy are shown to be the major factor necessary to predict the parotid sparing that will be possible for any particular case.

The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy.

PURPOSE: Whole-liver radiation, with or without chemotherapy, has been of modest benefit in the treatment of unresectable hepatic metastases from colorectal cancer. A Phase I/II study combining escalating doses of conformally planned radiation therapy (RT) with intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd) was performed. METHODS AND MATERIALS: Twenty-two patients with unresectable hepatic metastases from colorectal cancer, 14 of whom had progressed after previous chemotherapy (2 with prior IAH FdUrd), were treated with concurrent IAH FdUrd (0.2 mg/kg/day) and conformal hepatic radiation therapy (1.5-1.65 Gy/fraction twice a day). The total dose of radiation given to the tumor (48-72.6 Gy) depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for response, toxicity, hepatobiliary relapse, and survival. Median potential follow-up was 42 months. RESULTS: Eleven of 22 patients demonstrated an objective response, with the remainder showing stable disease. Actuarial freedom from hepatic progression was 25% at 1 years. The most common acute toxicity was mild to moderate nausea and transient liver function test abnormalities. There were three patients with gastrointestinal bleeding (none requiring surgical intervention) after the completion of treatment. Overall median survival was 20 months. The presence of extrahepatic disease was associated with decreased survival (p < 0.01). CONCLUSIONS: Combined conformal radiation therapy and IAH FdUrd can produce an objective response in 50% of patients with hepatic metastases from colorectal cancer. However, response was not durable, and hepatic progression was frequent. Improvements in hepatic tumor control for patients with metastatic colorectal cancer may require higher doses of conformal radiation and/or improved radiosensitization. In an effort to increase radiosensitization, we have recently initiated a clinical trial combining IAH bromode-oxyuridine, a thymidine analog radiosensitizer, with conformal high dose radiation therapy.

A phase I trial of hepatic arterial bromodeoxyuridine and conformal radiation therapy for patients with primary hepatobiliary cancers or colorectal liver metastases.

PURPOSE: We have previously found that conformal radiation therapy (RT) and hepatic arterial fluorodeoxyuridine was associated with durable responses and long-term survival for patients treated for nondiffuse primary hepatobiliary tumors and colorectal liver metastases. Further improvements in hepatic control may result from the addition of selective radiosensitization using bromodeoxyuridine (BrdU) infused through the hepatic artery (HA) concurrently with RT. This is a Phase I study of escalating doses of HA BrdU combined with our standard hepatic RT. METHODS AND MATERIALS: Patients with unresectable primary hepatobiliary cancer or colorectal liver metastases were treated with concurrent HA BrdU and conformal RT (1.5 Gy per fraction, twice a day). Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of RT (24, 48, or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. HA BrdU was escalated in standard Phase I fashion with at least three patients receiving each combination of RT dose and BrdU dose. The starting dose of HA BrdU was 10 mg/kg/day, with two potential escalations to a maximum of 25 mg/kg/day (the maximum tolerable dose of HA BrdU when given alone on this same schedule). Grade > or = 3 toxicity was considered dose limiting. Patients receiving 24 Gy had one cycle of HA BrdU, while those receiving either 48 or 66 Gy had two cycles. Patients were followed for toxicity, complications, and response (when evaluable). RESULTS: A total of 41 patients (18 with colorectal liver metastases, 16 with cholangiocarcinoma and 7 with hepatoma) were treated. Five patients were removed from the protocol (three had HA catheter complications, one developed atrial fibrillation, and one was removed due to recurrent Grade 4 toxicity), although all five are included for toxicity purposes. Dose-limiting toxicity was primarily thrombocytopenia and there was no obvious relationship with the RT dose. Only 2 of 17 cycles given at 25 mg/kg/day had Grade > or = 3 toxicity. Complications developed in four patients, including one patient with radiation-induced liver disease. Response rates were not improved compared to our previous experience. CONCLUSIONS: The appropriate dose of HA BrdU for Phase II evaluation is 25 mg/kg/day. Neither the hepatic parenchyma nor the gastrointestinal mucosa appeared to be sensitized by this method of BrdU administration. It is anticipated that these, or still newer methods of therapy, can improve treatment results in the near future.

Analysis of clinical complication data for radiation hepatitis using a parallel architecture model.

PURPOSE: The detailed knowledge of dose volume distributions available from the three-dimensional (3D) conformal radiation treatment of tumors in the liver (reported elsewhere) offers new opportunities to quantify the effect of volume on the probability of producing radiation hepatitis. We aim to test a new parallel architecture model of normal tissue complication probability (NTCP) with these data. METHODS AND MATERIALS: Complication data and dose volume histograms from a total of 93 patients with normal liver function, treated on a prospective protocol with 3D conformal radiation therapy and intraarterial hepatic fluorodeoxyuridine, were analyzed with a new parallel architecture model. Patient treatment fell into six categories differing in doses delivered and volumes irradiated. By modeling the radiosensitivity of liver subunits, we are able to use dose volume histograms to calculate the fraction of the liver damaged in each patient. A complication results if this fraction exceeds the patient's functional reserve. To determine the patient distribution of functional reserves and the subunit radiosensitivity, the maximum likelihood method was used to fit the observed complication data. RESULTS: The parallel model fit the complication data well, although uncertainties on the functional reserve distribution and subunit radiosensitivity are highly correlated. CONCLUSION: The observed radiation hepatitis complications show a threshold effect that can be described well with a parallel architecture model. However, additional independent studies are required to better determine the parameters defining the functional reserve distribution and subunit radiosensitivity.

The impact of treatment complexity and computer-control delivery technology on treatment delivery errors.

PURPOSE: To analyze treatment delivery errors for three-dimensional (3D) conformal therapy performed at various levels of treatment delivery automation and complexity, ranging from manual field setup to virtually complete computer-controlled treatment delivery using a computer-controlled conformal radiotherapy system (CCRS). METHODS AND MATERIALS: All treatment delivery errors which occurred in our department during a 15-month period were analyzed. Approximately 34,000 treatment sessions (114,000 individual treatment segments [ports]) on four treatment machines were studied. All treatment delivery errors logged by treatment therapists or quality assurance reviews (152 in all) were analyzed. Machines "M1" and "M2" were operated in a standard manual setup mode, with no record and verify system (R/V). MLC machines "M3" and "M4" treated patients under the control of the CCRS system, which (1) downloads the treatment delivery plan from the planning system; (2) performs some (or all) of the machine set up and treatment delivery for each field; (3) monitors treatment delivery; (4) records all treatment parameters; and (5) notes exceptions to the electronically-prescribed plan. Complete external computer control is not available on M3; therefore, it uses as many CCRS features as possible, while M4 operates completely under CCRS control and performs semi-automated and automated multi-segment intensity modulated treatments. Analysis of treatment complexity was based on numbers of fields, individual segments, nonaxial and noncoplanar plans, multisegment intensity modulation, and pseudoisocentric treatments studied for a 6-month period (505 patients) concurrent with the period in which the delivery errors were obtained. Treatment delivery time was obtained from the computerized scheduling system (for manual treatments) or from CCRS system logs. Treatment therapists rotate among the machines; therefore, this analysis does not depend on fixed therapist staff on particular machines. RESULTS: The overall reported error rate (all treatments, machines) was 0.13% per segment, or 0.44% per treatment session. The rate (per machine) depended on automation and plan complexity. The error rates per segment for machines M1 through M4 were 0.16%, 0.27%, 0.12%, 0.05%, respectively, while plan complexity increased from M1 up to machine M4. Machine M4 (the most complex plans and automation) had the lowest error rate. The error rate decreased with increasing automation in spite of increasing plan complexity, while for the manual machines, the error rate increased with complexity. Note that the real error rates on the two manual machines are likely to be higher than shown here (due to unnoticed and/or unreported errors), while (particularly on M4) virtually all random treatment delivery errors were noted by the CCRS system and related QA checks (including routine checks of machine and table readouts for each treatment). Treatment delivery times averaged from 14 min to 23 min per plan, and depended on the number of segments/plan, although this analysis is complicated by other factors. CONCLUSION: Use of a sophisticated computer-controlled delivery system for routine patient treatments with complex 3D conformal plans has led to a decrease in treatment delivery errors, while at the same time allowing delivery of increasingly complex and sophisticated conformal plans with little increase in treatment time. With renewed vigilance for the possibility of systematic problems, it is clear that use of complete and integrated computer-controlled delivery systems can provide improvements in treatment delivery, since more complex plans can be delivered with fewer errors, and without increasing treatment time.

The use of 3-D dose volume analysis to predict radiation hepatitis.

Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence. Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated. Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients. Nine of the 79 patients treated developed clinical radiation hepatitis. None of the patient related variables assessed were associated with radiation hepatitis. All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose greater than or equal to 37 Gy. Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature. The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment. An estimation of model parameters based on the clinical results indicated a larger magnitude for the "volume effect parameter" than the literature estimate (n = 0.69 +/- 0.05 vs 0.32; p less than 0.001). Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis. These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation. The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial.