The Influence of the Pretreatment Immune State on Response to Radiation Therapy in High-Risk Prostate Cancer: A Validation Study From NRG/RTOG 0521.

PURPOSE: The immunoinflammatory state has been shown to be associated with poor outcomes after radiation therapy (RT). We conducted an a priori designed validation study using serum specimens from Radiation Therapy Oncology Group (RTOG) 0521. It was hypothesized the pretreatment inflammatory state would correlate with clinical outcomes. METHODS AND MATERIALS: Patients on RTOG 0521 had serum banked for biomarker validation. This study was designed to validate previous findings showing an association between elevations in C-reactive protein (CRP) and shorter biochemical disease free survival (bDFS). CRP levels were measured in pretreatment samples. An exploratory panel of related cytokines was also measured including: monocyte chemotactic protein-1, granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-23, and tumor necrosis factor. The primary endpoint examined was bDFS. Additional exploratory endpoints included overall survival, distant metastases, and toxicity events attributed to RT. RESULTS: Two hundred and two patients in RTOG/NRG 0521 had serum samples available. Median age was 66 years (48-83), and 90% of patients were White. There was not an association between CRP and bDFS (adjusted hazard ratio [HR], 1.07 per 1 log increase in CRP; 95% confidence interval, 0.83-1.38; P = .60). In the exploratory, unplanned analysis, pretreatment IL-10 was significantly associated with worse bDFS (adjusted HR, 1.61 per log increase; P = .0027) and distant metastases (HR, 1.55 per log increase; P = .028). The association of IL-10 with bDFS was maintained on a multiplicity adjustment. The exploratory analyses of pretreatment levels of interferon-γ, IL-1b, IL-2, IL-13, IL-23 were negatively associated with grade 2 or higher pollakiuria (adjusted odds ratio, 0.64, 0.65, 0.71, 0.72, and 0.74, respectively, all P < .05), and IL-6 was negatively associated with grade 2 or higher erectile dysfunction (odds ratio, 0.62; P = .027). CONCLUSIONS: Pretreatment CRP was not associated with a poorer bDFS after RT. In a hypothesis- generating analysis, higher baseline levels of IL-10 were associated with lower rates of bDFS. These findings require additional prospective evaluation.

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126.

PURPOSE: External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer. METHODS AND MATERIALS: The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time. RESULTS: In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P = .051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk. CONCLUSIONS: Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.

Quality assurance issues in conducting multi-institutional advanced technology clinical trials.

The National Cancer Institute-sponsored Advanced Technology Quality Assurance (QA) Consortium, which consisted of the Image-Guided Therapy QA Center, Radiation Therapy Oncology Group, Radiological Physics Center, Quality Assurance Review Center, and Resource Center for Emerging Technologies, has pioneered the development of an infrastructure and QA method for advanced technology clinical trials that requires volumetric digital data submission of a protocol patient's treatment plan and verification data. In particular, the Image-Guided Therapy QA Center has nearly 15 years experience in facilitating QA review for Radiation Therapy Oncology Group advanced technology clinical trials. This QA process includes (1) a data integrity review for completeness of protocol required elements, the format of data, and possible data corruption, and recalculation of dose-volume histograms; (2) a review of compliance with target volume and organ-at-risk contours by study chairs; and (3) a review of dose prescription and dose heterogeneity compliance by the Radiation Therapy Oncology Group Headquarters Dosimetry Group or the Radiological Physics Center dosimetrists (for brachytherapy protocols). This report reviews the lessons learned and the QA challenges presented by the use of advanced treatment modalities in clinical trials requiring volumetric digital data submission.

Quality assurance needs for modern image-based radiotherapy: recommendations from 2007 interorganizational symposium on "quality assurance of radiation therapy: challenges of advanced technology".

This report summarizes the consensus findings and recommendations emerging from 2007 Symposium, "Quality Assurance of Radiation Therapy: Challenges of Advanced Technology." The Symposium was held in Dallas February 20-22, 2007. The 3-day program, which was sponsored jointly by the American Society for Therapeutic Radiology and Oncology (ASTRO), American Association of Physicists in Medicine (AAPM), and National Cancer Institute (NCI), included >40 invited speakers from the radiation oncology and industrial engineering/human factor communities and attracted nearly 350 attendees, mostly medical physicists. A summary of the major findings follows. The current process of developing consensus recommendations for prescriptive quality assurance (QA) tests remains valid for many of the devices and software systems used in modern radiotherapy (RT), although for some technologies, QA guidance is incomplete or out of date. The current approach to QA does not seem feasible for image-based planning, image-guided therapies, or computer-controlled therapy. In these areas, additional scientific investigation and innovative approaches are needed to manage risk and mitigate errors, including a better balance between mitigating the risk of catastrophic error and maintaining treatment quality, complimenting the current device-centered QA perspective by a more process-centered approach, and broadening community participation in QA guidance formulation and implementation. Industrial engineers and human factor experts can make significant contributions toward advancing a broader, more process-oriented, risk-based formulation of RT QA. Healthcare administrators need to appropriately increase personnel and ancillary equipment resources, as well as capital resources, when new advanced technology RT modalities are implemented. The pace of formalizing clinical physics training must rapidly increase to provide an adequately trained physics workforce for advanced technology RT. The specific recommendations of the Symposium included the following. First, the AAPM, in cooperation with other advisory bodies, should undertake a systematic program to update conventional QA guidance using available risk-assessment methods. Second, the AAPM advanced technology RT Task Groups should better balance clinical process vs. device operation aspects--encouraging greater levels of multidisciplinary participation such as industrial engineering consultants and use-risk assessment and process-flow techniques. Third, ASTRO should form a multidisciplinary subcommittee, consisting of physician, physicist, vendor, and industrial engineering representatives, to better address modern RT quality management and QA needs. Finally, government and private entities committed to improved healthcare quality and safety should support research directed toward addressing QA problems in image-guided therapies.

Comparison of peripheral dose from image-guided radiation therapy (IGRT) using kV cone beam CT to intensity-modulated radiation therapy (IMRT).

PURPOSE: The growing use of IMRT with volumetric kilovoltage cone-beam computed tomography (kV-CBCT) for IGRT has increased concerns over the additional (typically unaccounted) radiation dose associated with the procedures. Published data quantify the in-field dose of IGRT and the peripheral dose from IMRT. This study adds to the data on dose outside the target area by measuring peripheral CBCT dose and comparing it with out-of-field IMRT dose. MATERIALS AND METHODS: Measurements of the CBCT peripheral dose were made in an anthropomorphic phantom with TLDs and were compared to peripheral dose measurements for prostate IMRT, determined with MOSFET detectors. RESULTS: Doses above 1cGy (per scan) were found outside the CBCT imaged volume, with 0.2cGy at 25 cm from the central axis. IMRT peripheral dose was 1cGy at 20 cm and 0.4cGy at 25 cm (per fraction). CONCLUSIONS: An appreciable dose can be found beyond the edge of the IGRT field; of similar order of magnitude as peripheral dose from IMRT (mGy), and approximately half the dose delivered to the same point from the IMRT treatment (0.2cGy c.f. 0.4cGy 25 cm from the isocenter). This shows that peripheral dose, as well as the in-field dose from CBCT, needs to be taken into account when considering long term care of radiation oncology patients.

Commissioning experience with cone-beam computed tomography for image-guided radiation therapy.

This paper reports on the commissioning of an Elekta cone-beam computed tomography (CT) system at one of the first U.S. sites to install a "regular," off-the-shelf Elekta Synergy (Elekta, Stockholm, Sweden) accelerator system. We present the quality assurance (QA) procedure as a guide for other users. The commissioning had six elements: (1) system safety, (2) geometric accuracy (agreement of megavoltage and kilovoltage beam isocenters), (3) image quality, (4) registration and correction accuracy, (5) dose to patient and dosimetric stability, and (6) QA procedures. The system passed the safety tests, and agreement of the isocenters was found to be within 1 mm. Using a precisely moved skull phantom, the reconstruction and alignment algorithm was found to be accurate within 1 mm and 1 degree in each dimension. Of 12 measurement points spanning a 9x9x15-cm volume in a Rando phantom (The Phantom Laboratory, Salem, NY), the average agreement in the x, y, and z coordinates was 0.10 mm, -0.12 mm, and 0.22 mm [standard deviations (SDs): 0.21 mm, 0.55 mm, 0.21 mm; largest deviations: 0.6 mm, 1.0 mm, 0.5 mm] respectively. The larger deviation for the y component can be partly attributed to the CT slice thickness of 1 mm in that direction. Dose to the patient depends on the machine settings and patient geometry. To monitor dose consistency, air kerma (output) and half-value layer (beam quality) are measured for a typical clinical setting. Air kerma was 6.3 cGy (120 kVp, 40 mA, 40 ms per frame, 360-degree scan, S20 field of view); half value layer was 7.1 mm aluminum (120 kV, 40 mA). We suggest performing items 1, 2, and 3 monthly, and 4 and 5 annually. In addition, we devised a daily QA procedure to verify agreement of the megavoltage and kilovoltage isocenters using a simple phantom containing three small steel balls. The frequency of all checks will be reevaluated based on data collected during about 1 year.

From new frontiers to new standards of practice: advances in radiotherapy planning and delivery.

Radiation therapy treatment planning and delivery capabilities have changed dramatically since the introduction of three-dimensional treatment planning in the 1980s and continue to change in response to the implementation of new technologies. CT simulation and three-dimensional radiation treatment planning systems have become the standard of practice in clinics around the world. Medical accelerator manufacturers have employed advanced computer technology to produce treatment planning/delivery systems capable of precise shaping of dose distributions via computer-controlled multileaf collimators, in which the beam fluence is varied optimally to achieve the plan prescription. This mode of therapy is referred to as intensity-modulated radiation therapy (IMRT), and is capable of generating extremely conformal dose distributions including concave isodose volumes that provide conformal target volume coverage and avoidance of specific sensitive normal structures. IMRT is rapidly being implemented in clinics throughout the USA. This increasing use of IMRT has focused attention on the need to better account for both intrafraction and interfraction spatial uncertainties, which has helped spur the development of treatment machines with integrated planar and volumetric advanced imaging capabilities. In addition, advances in both anatomical and functional imaging provide improved ability to define the tumor volumes. Advances in all these technologies are occurring at a record pace and again pushing the cutting-edge frontiers of radiation oncology from IMRT to what is now referred to as image-guided IMRT, or simply image-guided radiation therapy (IGRT). A brief overview is presented of these latest advancements in conformal treatment planning and treatment delivery.

Helical tomotherapy shielding calculation for an existing LINAC treatment room: sample calculation and cautions.

This paper reports a step-by-step shielding calculation recipe for a helical tomotherapy unit (TomoTherapy Inc., Madison, WI, USA), recently installed in an existing Varian 600C treatment room. Both primary and secondary radiations (leakage and scatter) are explicitly considered. A typical patient load is assumed. Use factor is calculated based on an analytical formula derived from the tomotherapy rotational beam delivery geometry. Leakage and scatter are included in the calculation based on corresponding measurement data as documented by TomoTherapy Inc. Our calculation result shows that, except for a small area by the therapists' console, most of the existing Varian 600C shielding is sufficient for the new tomotherapy unit. This work cautions other institutions facing the similar situation, where an HT unit is considered for an existing LINAC treatment room, more secondary shielding might be considered at some locations, due to the significantly increased secondary shielding requirement by HT.

Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma.

PURPOSE: To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non-small-cell lung cancer. METHODS AND MATERIALS: A total of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V(20) > or =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method. RESULTS: The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V(20). The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50-78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure. CONCLUSIONS: The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V(20) values of <25% (Group 1) and to 77.4 Gy for patients with V(20) values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients.

Toxicity after three-dimensional radiotherapy for prostate cancer on RTOG 9406 dose Level V.

PURPOSE: This is the first report of toxicity outcomes at dose Level V (78 Gy) on Radiation Therapy Oncology Group 9406 for Stages T1-T2 adenocarcinoma of the prostate. METHODS AND MATERIALS: A total of 225 patients were entered in this cooperative group, Phase I-II dose-escalation trial of three-dimensional conformal radiotherapy for localized carcinoma of the prostate treated to a dose of 78 Gy (Level V). Of these patients, 219 were analyzed for acute and 218 for late toxicity. A minimum of 2 Gy/fraction was prescribed to the planning target volume (PTV). Patients were stratified according to the risk of seminal vesicle invasion as determined by Gleason score and presenting prostate-specific antigen level. Group 1 patients had clinical Stages T1-T2 tumors with a seminal vesicle invasion risk of <15%. Group 2 patients had clinical Stages T1-T2 tumors with a seminal vesicle invasion risk of >/=15%. Patients in Group 1 were prescribed 78 Gy to a prostate PTV. Patients in Group 2 were prescribed 54 Gy to the prostate and seminal vesicles (PTV1) followed by a boost to the prostate only (PTV2) to 78 Gy. PTV margins of between 5 and 10 mm were required. The average time at risk for late Grade 3+ toxicity after therapy completion was 23.2 and 23.1 months for Groups 1 and 2, respectively. The frequency of Grade 3 or worse late effects was compared with a similar group of patients treated in Radiation Therapy Oncology Group (RTOG) studies 7506 and 7706, with length of follow-up adjustments made for the interval from therapy completion. A second comparison was made with 170 patients treated to dose Level III (79.2 Gy in 1.8 Gy/fraction) to see whether the fraction size affected toxicity. Unlike other dose levels, patients treated at dose Level III had treatment prescribed as a minimum to the gross tumor volume. This effectively lowered the volume of the rectum treated to the study dose. RESULTS: Acute toxicity at dose Level V (78 Gy) was remarkably low, with Grade 3 acute effects reported in only 4% of Group 1 and 2% of Group 2 patients. No Grade 4 or 5 acute toxicity was reported. There was no statistically significant difference in rates of acute toxicities in patients who were treated to 79.2 Gy at 1.8 Gy/fraction or 78 Gy at 2.0 Gy/fraction. Late toxicity continues to be low compared with RTOG historical controls. The observed rate of Grade 3 or worse late effects for Group 1 (6 cases) was significantly lower (p = 0.0042) than the 18.2 cases that would have been expected from the historical control. The observed rate for Group 2 (8 cases) was lower than the 15.5 cases expected, but this difference was not statistically significant (p = 0.06). A trend was noted that Group 2 patients treated on dose Level V had more late Grade 3 or worse toxicity than patients treated to a similar dose on Level III (7% vs. 1%, p = 0.06). A significantly (p < 0.0001) greater incidence of late Grade 2 or greater toxicity occurred in patients treated at dose Level V (30% and 33% for Groups 1 and 2, respectively) than at dose Level III (13% and 9% for Groups 1 and 2, respectively). The longer follow-up at dose Level III suggests these differences may increase with additional follow-up. CONCLUSION: Tolerance to three-dimensional conformal radiotherapy with 78 Gy in 2-Gy fractions remains better than expected compared with historical controls. The magnitude of any effect from fraction size and treatment volume requires additional follow-up.

Errors in radiation oncology: a study in pathways and dosimetric impact.

As complexity for treating patients increases, so does the risk of error. Some publications have suggested that record and verify (R&V) systems may contribute in propagating errors. Direct data transfer has the potential to eliminate most, but not all, errors. And although the dosimetric consequences may be obvious in some cases, a detailed study does not exist. In this effort, we examined potential errors in terms of scenarios, pathways of occurrence, and dosimetry. Our goal was to prioritize error prevention according to likelihood of event and dosimetric impact. For conventional photon treatments, we investigated errors of incorrect source-to-surface distance (SSD), energy, omitted wedge (physical, dynamic, or universal) or compensating filter, incorrect wedge or compensating filter orientation, improper rotational rate for arc therapy, and geometrical misses due to incorrect gantry, collimator or table angle, reversed field settings, and setup errors. For electron beam therapy, errors investigated included incorrect energy, incorrect SSD, along with geometric misses. For special procedures we examined errors for total body irradiation (TBI, incorrect field size, dose rate, treatment distance) and LINAC radiosurgery (incorrect collimation setting, incorrect rotational parameters). Likelihood of error was determined and subsequently rated according to our history of detecting such errors. Dosimetric evaluation was conducted by using dosimetric data, treatment plans, or measurements. We found geometric misses to have the highest error probability. They most often occurred due to improper setup via coordinate shift errors or incorrect field shaping. The dosimetric impact is unique for each case and depends on the proportion of fields in error and volume mistreated. These errors were short-lived due to rapid detection via port films. The most significant dosimetric error was related to a reversed wedge direction. This may occur due to incorrect collimator angle or wedge orientation. For parallel-opposed 60 degrees wedge fields, this error could be as high as 80% to a point off-axis. Other examples of dosimetric impact included the following: SSD, approximately 2%/cm for photons or electrons; photon energy (6 MV vs. 18 MV), on average 16% depending on depth, electron energy, approximately 0.5 cm of depth coverage per MeV (mega-electron volt). Of these examples, incorrect distances were most likely but rapidly detected by in vivo dosimetry. Errors were categorized by occurrence rate, methods and timing of detection, longevity, and dosimetric impact. Solutions were devised according to these criteria. To date, no one has studied the dosimetric impact of global errors in radiation oncology. Although there is heightened awareness that with increased use of ancillary devices and automation, there must be a parallel increase in quality check systems and processes, errors do and will continue to occur. This study has helped us identify and prioritize potential errors in our clinic according to frequency and dosimetric impact. For example, to reduce the use of an incorrect wedge direction, our clinic employs off-axis in vivo dosimetry. To avoid a treatment distance setup error, we use both vertical table settings and optical distance indicator (ODI) values to properly set up fields. As R&V systems become more automated, more accurate and efficient data transfer will occur. This will require further analysis. Finally, we have begun examining potential intensity-modulated radiation therapy (IMRT) errors according to the same criteria.

Current ICRU definitions of volumes: limitations and future directions.

Volume definitions used in radiation treatment planning of 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) play and important role in advancing these treatment modalities. IMRT is now recognized to be more sensitive to geometric uncertainties than 3DCRT and conventional radiation therapy because of its characteristic sharper dose gradients around target volumes and organs at risk. This article reviews the current state of the art in specifying volumes for 3DCRT and IMRT and discusses some of the limitations and potential pitfalls with the current International Commission on Radiation Units and Measurements (ICRU) Reports 50 and 62 recommendations, particularly in regard to issues of organ motion when irradiated by a time-dependent irradiation modality such as dynamic multileaf collimation IMRT or other methods that have a time component in beam delivery.

Dose-volume specification: new challenges with intensity-modulated radiation therapy.

It has long been recognized that the specification of volumes and doses is an important issue for radiation oncology. Although in any individual center, policies and procedures of treatment delivery may be well understood by staff, reporting of treatment techniques in the archival literature in an unambiguous manner has been found to be less than desirable in many instances. For clinical studies utilizing three-dimensional conformal radiation therapy (3D-CRT), and even more so, intensity-modulated radiation therapy (IMRT), the situation has become even more complex. 3D-CRT and IMRT are now recognized to be more sensitive to geometric uncertainties than conventional radiation therapy because of their ability to create sharper dose gradients around target volumes and organs at risk (OARs). This article reviews the current status of specifying target volumes and doses for 3D-CRT and IMRT, and discusses some of the pertinent issues regarding the use of recommendations in Reports 50 and 62 of the International Commission on Radiation Units and Measurements (ICRU) in this task. It is imperative that physician and physicist fully appreciate the need to account for clinical and spatial uncertainties in the planning and delivery of cancer patients' treatment, paying even more attention to these issues for those cases in which 3D-CRT and/or IMRT is used. A brief review of the reporting requirements for Radiation Therapy Oncology Group (RTOG) 3D-CRT and IMRT protocols is also presented.

Trade-off to low-grade toxicity with conformal radiation therapy for prostate cancer on Radiation Therapy Oncology Group 9406.

The aim of this study was to evaluate and compare the rates of grade 2 or worse late effects in patients treated for prostate cancer on Radiation Therapy Oncology Group (RTOG) 9406. The authors previously have reported the results of patients treated on the first 2 dose levels of this study with respect to grade 3 or greater late toxicity. This analysis examines the incidence of grade 2 toxicity in this study. From August 1994 to September 1999, 424 patients were entered on this dose escalation trial of 3-dimensional conformal radiation therapy (3D CRT) for localized adenocarcinoma of the prostate at doses of 68.4 Gy (level I) and 73.8 Gy (level II). All radiation prescriptions were a minimum dose to a planning target volume. Patients were stratified according to clinical stage and risk of seminal vesicle invasion based on Gleason score and presenting prostate-specific antigen. Average time at risk after completion of therapy ranged from 33.1 to 40.1 months for patients treated at dose level I and 15.6 to 34.2 months for patients at dose level II. The frequency of late effects > or = grade 2 was compared with a similar group of patients treated on RTOG studies 7506 and 7706 with adjustments made for the interval from completion of therapy. The RTOG toxicity scoring scales for late effects were used. The rate of grade 3 or greater late toxicity continues to be low compared with RTOG historical controls. No grade 4 or 5 late complications were reported in any of the 406 evaluable patients during the period of observation. Interestingly, the incidence of grade 2 late toxicity was increased relative to historical controls in all groups and dose levels. In group 1, level I and group 3, level II, the increase in grade 2 complications was statistically significant; 16 complications were observed in group 1, level I when 9.2 were expected (P =.026) and 22 were observed in group 3, level II when 7.6 were expected (P <.0001). When examining all late effects > or = grade 2, there were no significant differences in the rate of late effects in both groups and both dose levels with the exception of group 1, level II. This, in combination with the statistically significant decrease in late effects > or = grade 3, suggests that in most circumstances there has been a shift of grade 3 complications to grade 2. In group 1, dose level II there was a statistically significant reduction in > or = grade 2 late effects, suggesting there was no shift from grade 3 to grade 2 in these patients. In this circumstance there may have been a global reduction in all complications or a shift to late effects less severe than grade 2. In group 2, dose level II there is a trend (P =.085) toward this same result. It is important to continue to examine late effects closely in patients treated on RTOG 9406. The primary objective of dose escalation without an increase rate of > or = grade 3 complications has been achieved. However, the reduction in grade 3 complications may have resulted in a higher incidence of grade 2 late effects. Because grade 2 late effects may have a significant impact on a patient's quality of life, it is important to reduce these complications as much as possible. Improved conformal treatment delivery with intensity-modulated radiation therapy or the use of radioprotective agents could be considered. Clinical trials should use quality-of-life measures to determine that trade-offs between severity and rates of toxicity are acceptable to patients.

Elective nodal failures are uncommon in medically inoperable patients with Stage I non-small-cell lung carcinoma treated with limited radiotherapy fields.

PURPOSE: To review the outcome for 56 Stage I non-small-cell lung cancer treated definitively with three-dimensional conformal radiotherapy (3D-CRT) and to investigate the value of elective nodal irradiation in this patient population. METHODS AND MATERIALS: Between 1992 and 2001, 56 patients were treated with 3D-CRT for inoperable Stage I histologically confirmed non-small-cell lung cancer; 31 with T1N0 and 25 with T2N0 disease. All patients were treated with 3D-CRT to a median isocenter dose of 70 Gy (range 59.94-83.85) given in daily doses of 1.8 or 2 Gy. Prognostic factors were analyzed with respect to their impact on overall survival. Twenty-two patients received radiotherapy (RT) directed to elective regional lymphatics to doses of 45-50 Gy. The remaining 33 patients were treated to limited fields confined to the primary lung cancer with a margin. The patterns of failure were reviewed. RESULTS: The median follow-up was 20 months (range 6 months to 6 years). The actuarial local control rate was 88%, 69%, and 63%, at 1, 2, and 3 years, respectively. The actuarial cause-specific survival rate was 82%, 67%, and 51% at 1, 2, and 3 years, respectively. The actuarial overall survival rate was 73%, 51%, and 34% at 1, 2, and 3 years, respectively. The actuarial metastasis-free survival rate was 90%, 85%, and 81% at 1, 2, and 3 years, respectively. The RT dose was the only factor predictive of overall survival in our analysis. No statistically significant difference was noted in cause-specific or overall survival according to whether patients received elective nodal irradiation. Two of 33 patients treated with limited fields had regional nodal failure. CONCLUSION: Many patients with medically inoperable Stage I lung cancer die of intercurrent causes. The omission of the elective nodal regions from the RT portals did not compromise either the cause-specific or overall survival rate. Elective nodal failures were uncommon in the group treated with limited RT fields. A radiation dose 70 Gy was predictive of better survival in our population. We await the results of prospective trials evaluating high-dose RT in patients treated with RT alone for Stage I lung cancer.

Performance evaluation of an 85-cm-bore X-ray computed tomography scanner designed for radiation oncology and comparison with current diagnostic CT scanners.

INTRODUCTION: The demand for computed tomography (CT) virtual simulation is constantly increasing with the wider adoption of three-dimensional conformal and intensity-modulated radiation therapy. Virtual simulation CT studies are typically acquired on conventional diagnostic scanners equipped with an external patient positioning laser system and specialized planning and visualization software. Virtual simulation technology has matured to a point where conventional simulators may be replaced with CT scanners. However, diagnostic CT scanner gantry bores (typically 65-70 cm) can present an obstacle to the CT simulation process by limiting patient positions, compared to those that can be attained in a conventional simulator. For example, breast cancer patients cannot always be scanned in the treatment position without compromising reproducibility and appropriateness of setup. Extremely large patients or patients requiring special immobilization or large setup devices are often unable to enter the limited-bore gantry. A dedicated 85-cm-bore radiation oncology CT scanner has the potential to eliminate these problems. The scanner should provide diagnostic-quality images at diagnostic-comparable dose levels. The purpose of this study was to independently evaluate the performance of a novel 85-cm-bore CT X-ray scanner designed specifically for radiation oncology and compare it against diagnostic-type, 70-cm-bore scanners that may be used in the same setting. MATERIALS AND METHODS: We performed image quality and dosimetric measurements on an 85-cm-bore CT scanner (AcQSim CT, Marconi Medical Systems, Inc., Cleveland, OH) and a 70-cm-bore, diagnostic-type scanner (UltraZ CT, Marconi Medical Systems, Inc.). Image quality measurements were performed using a manufacturer-supplied phantom (Performance Phantom, Marconi Medical Systems, Inc.), following the manufacturer's suggested testing procedures, and an independent image quality phantom (CATPHAN 500, The Phantom Laboratory, New York, NY). The standard image quality parameters evaluated for the purpose of comparison were as follows: slice thickness accuracy, high-contrast resolution (limiting spatial resolution), low-contrast resolution, uniformity and noise, and CT number accuracy and linearity. Standard head and body protocols were employed throughout most of our measurements and were kept equal between the two scanners. The computed tomography dose index was measured for standard head and body imaging protocols using accepted methods and procedures. For comparison purposes, data for a diagnostic-type, 70-cm-bore scanner (GE HighSpeed CT/i) were extracted from the literature. The results obtained for the 85-cm-bore scanner are compared with the following: (1) manufacturer-provided autoperformance phantom test results (validating its use for routine quality assurance), (2) a similar set of measurements performed on a conventional 70-cm-bore, diagnostic-type CT scanner (UltraZ CT, Marconi Medical Systems, Inc.), and (3) current available data on other diagnostic-type CT scanners (GE HighSpeed CT/i). RESULTS: Head and body doses seem on average to be slightly (1-2 cGy) higher for the 85-cm-bore unit than for conventional 70-cm units. Measured slice thickness was within acceptable criteria, +/-0.5 mm. There does not seem to be any significant difference in high-contrast resolution. Both units render a limiting value of approximately 7-8 lp/cm for slice thickness 8-10 mm. Both units exhibit comparable CT number uniformity, accuracy, and linearity. Noise levels seem to be slightly increased (by approximately 0.05-0.2%) for the large-bore geometry. Low-contrast resolution for both units was comparable (4.5-5.5 mm @ 0.35%). All image quality parameters are well within diagnostic acceptable levels. CONCLUSION: The overall imaging performance and mechanical integrity of the 85-cm-bore scanner are comparable to those of conventional diagnostic scanners that may be employed in a radiation oncology setting.

Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: findings from a prospective, multi-institutional, phase I/II dose-escalation study.

PURPOSE: To assess the relationship between the dose to the bulb of the penis and the risk of impotence in men treated on Radiation Therapy Oncology Group (RTOG) 9406. METHODS AND MATERIALS: Men enrolled on a Phase I/II dose-escalation study, RTOG 9406, who were reported to be potent at entry and evaluable (n = 158) were selected for inclusion. Follow-up evaluations were scheduled every 3, 4, and 6 months for the first, second, and the third through fifth years, then annually. At each follow-up visit an assessment of potency status was made. Penile structures were defined by a single observer blinded to the potency status, using Web-based, on-line software. The dosimetry for penile structures was calculated at the Quality Assurance Center at Washington University and provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. RESULTS: Patients whose median penile dose was > or = 52.5 Gy had a greater risk of impotence compared with those receiving <52.5 Gy (p = 0.039). In a multivariate analysis neither age, the dose to the prostate, nor the use of hormonal therapy correlated with the risk of impotence. CONCLUSIONS: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence.

Toward automated quality assurance for intensity- modulated radiation therapy.

PURPOSE: To investigate whether high-quality, relatively inexpensive, document and transparency scanners used as densitometers are sufficiently quantitative for routine quality assurance (QA). METHODS AND MATERIALS: The scanner we investigated used a linear amplifier, digitizing gray-scale images to 12-bit resolution with a user-selected spatial resolution of 0.170 mm(2) pixels. To reduce Newton's rings artifacts, the standard glass platen was replaced by glass with an antireflective coating. Conversion of reading to transmission was conducted by permanently placing a calibrated photographic step tablet on the scanner platen. After conversion to light transmission, a zero-phase two-dimensional Wiener filter was used to reduce pixel-to-pixel signal variation. Light-scatter artifacts were removed by deconvolution of a measured light-spread kernel. The light-spread kernel artifacts were significant along the scanner's detector axis, but were insignificant along the scanning axis. RESULTS: Pixel-to-pixel noise was better than 2% for optical densities, ranging from 0.4 to 2.0 and 0 to 2.7 for the unfiltered and filtered images, respectively. The document scanning system response was compared against a confocal scanning laser densitometer. A series of IMRT dose distribution and dose calibration film sets were scanned using the two scanners, and the measured dose was compared. The maximum mean and standard deviation of the measured dose difference between the document scanner and confocal scanner was 1.48% and 1.06%, respectively. CONCLUSION: While the document scanners are not as flexible as dedicated film densitometers, these results indicate that, using the intensity and scatter corrections, the system provides accurate and precise measurements up to an optical density of 2.0, sufficient for routine IMRT film QA. For some film types, this requires the reduction in monitor units to limit the dose delivered to the film. The user must be cautious that the delivered IMRT dose is scaled appropriately. This inexpensive and accurate system is being integrated into an automated QA program.

Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma.

PURPOSE: Three-dimensional conformal radiation therapy (3D-CRT) has recently become widely available with applications for patients with non-small-cell lung cancer (NSCLC). These techniques represent a significant advance in the delivery of radiotherapy, including improved ability to delineate target contours, choose beam angles, and determine dose distributions more accurately than were previously available. The purpose of this study is to identify prognostic factors in a population of NSCLC patients treated with definitive 3D-CRT. METHODS AND MATERIALS: Between March 1991 and December 1998, 207 patients with inoperable NSCLC were treated with definitive 3D-CRT. Tumor targets were contoured in multiple sections from a treatment planning computed tomography (CT) scan. Three-dimensional treatment volumes and normal structures were reconstructed. Doses to the International Commission on Radiation Units and Measurements (ICRU) reference point ranged from 60 to 83.85 Gy with a median dose of 70 Gy. The median dose inhomogeneity was +/- 5% across planning target volume. Outcome was analyzed by prognostic factors for NSCLC including pretreatment patient and tumor-related factors (age, gender, race, histology, clinical stage, tumor [T] stage, and node [N] stage), parameters from our 3D-CRT system (gross tumor volume [GTV] in cm3), irradiation dose prescribed to isocenter, volume of normal lung exceeding 20 Gy (V20), and treatment with or without chemotherapy. The median follow-up time was 24 months (range, 7.5 months to 7.5 years). RESULTS: One and two-year overall survival rates for the entire group were 59% and 41%, respectively. Overall survival, cause-specific survival, and local tumor control were most highly correlated with the GTV in cm3. On multivariate analysis the independent variable most predictive of survival was the GTV. Traditional staging such as T, N, and overall clinical staging were not independent prognostic factors. Patients receiving ICRU reference doses > or =70 Gy had better local control and cause-specific survivals than those treated with lower doses (p = 0.05). Increased irradiation dose did not improve overall survival. CONCLUSIONS: GTV as determined by CT and 3D-CRT planning is highly prognostic for overall and cause-specific survival and local tumor control and may be important in stratification of patients in prospective therapy trials. T, N, and overall stage were not independent prognostic factors in this population of patients treated nonsurgically. The value of dose escalation beyond 70 Gy should be tested prospectively by clinical trial.

Toxicity after three-dimensional radiotherapy for prostate cancer with RTOG 9406 dose level IV.

PURPOSE: This is the first report of the toxicity outcomes using dose level IV (74 Gy) on Radiation Therapy Oncology Group (RTOG) study 9406 for Stage T1-T2 prostate adenocarcinoma. METHODS AND MATERIALS: A total of 262 patients were entered in this cooperative group, Phase I-II, dose-escalation trial of three-dimensional conformal radiotherapy for localized prostate carcinoma treated to a dose of 74 Gy (Level IV); 256 patients were analyzable for toxicity. A minimal dose of 2 Gy/fraction was prescribed to the planning target volume (PTV). Patients were stratified according to the risk of seminal vesicle invasion on the basis of the Gleason score and presenting prostate-specific antigen level. Group 1 patients had clinical Stage T1-T2 tumors with a seminal vesicle invasion risk of <15%. Group 2 patients had clinical Stage T1-T2 tumors with a seminal vesicle invasion risk of >/=15%. Patients in Group 1 were prescribed 74 Gy to a prostate PTV. Patients in Group 2 were prescribed 54 Gy to the prostate and seminal vesicles (PTV1) followed by a boost to the prostate only (PTV2) to 74 Gy. PTV margins between 5 and 10 mm were required. Elective pelvic radiotherapy was not used. The frequency of late effects of Grade 3 or greater was compared with that for a similar group of patients treated in RTOG studies 7506 and 7706, with length of follow-up adjustments made for the interval from therapy completion. A second comparison was made with 206 patients treated to dose level II (73.8 Gy in 1.8-Gy fractions) to see whether the fraction size affected toxicity. RESULTS: The average months at risk for late Grade 3+ toxicity after therapy completion were 28.9 and 23.9 months for Group 1 and 2, respectively. Acute toxicity at dose level IV (74 Gy) was remarkably low, with Grade 3 acute effects reported in only 1% of Group 1 and 3% of Group 2 patients. No Grade 4 or 5 acute toxicities were reported. Late toxicity continued to be low compared with RTOG historical controls. One patient in Group 1 and 4 patients in Group 2 experienced Grade 3 bladder toxicity. Two patients in Group 2 experienced Grade 3 bowel toxicity. No Grade 4 or 5 late effects were reported. The rate of late Grade 2 toxicity (any type) was 23% and 16% in Group 1 and 2, respectively. The observed rate of Grade 3 or greater late effects for Group 1 (1 case) was significantly lower (p <0.0001) than the 18.5 cases that would have been expected from the historical control data. The observed rate for Group 2 (6 cases) was also significantly lower (p = 0.0009) than the 21.3 cases expected. No statistically significant difference was noted in the rate of acute or late toxicity in patients who were treated to 73.8 Gy at 1.8 Gy/fraction or 74 Gy at 2.0 Gy/fraction. Patients treated with the larger 2.0-Gy fractions tended to have more Grade 3 or greater toxicity than patients treated with 1.8-Gy fractions (2% vs. 1%, p = 0.09). The results after the longer follow-up with dose level II suggest these differences may increase with additional follow-up. CONCLUSION: Tolerance to three-dimensional conformal radiotherapy with 74 Gy in 2-Gy fractions remains better than expected compared with historical controls. The magnitude of any effect from fraction size requires additional follow-up.