John A. Antolak

PROSTATE CANCER RADIATION DOSE RESPONSE: RESULTS OF THE M. D. ANDERSON PHASE III RANDOMIZED TRIAL

PURPOSE A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer. METHODS AND MATERIALS A total of 305 Stage T1-T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis. RESULTS There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA <or=10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy. CONCLUSION An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives >or=70 Gy to <25% should be used.

Preliminary Results of a Randomized Radiotherapy Dose-Escalation Study Comparing 70 Gy With 78 Gy for Prostate Cancer

PURPOSE To determine the effect of radiotherapy dose on prostate cancer patient outcome and biopsy positivity in a phase III trial. PATIENTS AND METHODS A total of 305 stage T1 through T3 patients were randomized to receive 70 Gy or 78 Gy of external-beam radiotherapy between 1993 and 1998. Of these, 301 were assessable; stratification was based on pretreatment prostate-specific antigen level (PSA). Dose was prescribed to the isocenter at 2 Gy per fraction. All patients underwent planning pelvic computed tomography scan to confirm prostate position. Treatment failure was defined as an increasing PSA on three consecutive follow-up visits or the initiation of salvage treatment. Median follow-up was 40 months. RESULTS One hundred fifty patients were randomized to the 70-Gy arm and 151 to the 78-Gy arm. The difference in freedom from biochemical and/or disease failure (FFF) rates of 69% and 79% for the 70-Gy and 78-Gy groups, respectively, at 5 years was marginally significant (log-rank P: =.058). Multiple-covariate Cox proportional hazards regression showed that the study randomization was an independent correlate of FFF, along with pretreatment PSA, Gleason score, and stage. The patients who benefited most from the 8-Gy dose escalation were those with a pretreatment PSA of more than 10 ng/mL; 5-year FFF rates were 48% and 75% (P: =.011) for the 70-Gy and 78-Gy arms, respectively. There was no difference between the arms ( approximately 80% 5-year FFF) when the pretreatment PSA was < or = 10 ng/mL. CONCLUSION A modest dose increase of 8 Gy using conformal radiotherapy resulted in a substantial improvement in prostate cancer FFF rates for patients with a pretreatment PSA of more than 10 ng/mL. These findings document that local persistence of prostate cancer in intermediate- to high-risk patients is a major problem when doses of 70 Gy or less are used.

Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial

OBJECTIVE To compare early and late side effects in prostate cancer patients with Stage T1b-T3 disease randomized to receive 70 Gy or 78 Gy. METHODS There were 189 patients randomized with a minimum follow-up of 2 years, that were available for this analysis. All patients were initially treated with a 4-field box to an isocenter dose of 46 Gy at 2 Gy per fraction. In the 70-Gy arm, treatment was continued to a reduced volume using a 4-field box technique. In the 78-Gy arm, treatment was continued to a reduced volume using a conformal 6-field arrangement. Side effects were graded on a 1-4 scale, adapted from Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. RESULTS No significant differences in acute rectal or bladder toxicity were seen between the two treatment techniques (p > 0.6 for all comparisons). The 5-year Kaplan-Meier risks of Grade 2 or higher late bladder toxicity were 20% and 9% for 70-Gy and 78-Gy groups, respectively (log rank, p = 0.8). The 5-year risks of Grade 2 or higher late rectal toxicity were 14% and 21% for 70 Gy and 78 Gy, respectively (p = 0.4). Dose-volume histogram analysis of the 78-Gy patients showed a significant correlation between the percentage of rectum irradiated to 70 Gy or greater and the likelihood of developing late rectal complications. Patients with more than 25% of the rectum receiving 70 Gy or greater had a 5-year risk of Grade 2 or higher complications of 37% compared to 13% for patients with 25% or less (p = 0.05). All three Grade 3 complications occurred when greater than 30% of the rectum received 70 Gy or more. CONCLUSION The overall rate of complications was similar in both treatment arms. However, there is evidence for a significant increase in late rectal complications when more than 25% of the rectum received 70 Gy or greater. This parameter may serve as a benchmark for the design of future three-dimensional conformal trials.

Prostate target volume variations during a course of radiotherapy

PURPOSE The purpose of this study was to measure the mobility of the clinical target volume (CTV) in prostate radiotherapy with respect to the pelvic anatomy during a course of therapy. These data are needed to properly design the planning target volume (PTV). METHODS AND MATERIALS Seventeen patients were studied. Each patient underwent computed tomography (CT) scanning for treatment planning purposes. Subsequently, three CT scans were obtained at approximately 2-week intervals during treatment. The prostate, seminal vesicles, bladder, and rectum were outlined on each CT study. The second through the fourth CT studies were aligned with the first study using a rigid body transformation based on the bony anatomy. The transformation was used to compute the center of mass position and bounding box of each organ in the subsequent studies relative to the first study. Differences in the bounding box limits and center of mass positions between the first and subsequent studies were tabulated and correlated with bladder and rectal volume and positional parameters. RESULTS The mobility of the CTV was characterized by standard deviations of 0.09 cm (left-right), 0.36 cm (cranial-caudal), and 0.41cm (anterior-posterior). Prostate mobility was not significantly correlated with bladder volume. However, the mobility of both the prostate and seminal vesicles was very significantly correlated with rectal volume. Bladder and rectal volumes decreased between the pretreatment CT scan and the first on-treatment CT scan, but were constant for all on-treatment CT scans. CONCLUSION Margins between the CTV and PTV based on the simple geometric requirement that a point on the edge of the CTV is enclosed by the PTV 95% of the time are 0.7 cm in the lateral and cranial-caudal directions, and 1.1 cm in the anterior-posterior direction. However, minimum dose to the CTV and avoidance of organs at risk are more important considerations when drawing beam apertures. More consistent methods for reproducing prostate position (e.g., empty rectum) and more sophisticated beam aperture optimization are needed to guarantee consistent coverage of the CTV while avoiding organs at risk.

Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: Analysis of a prostate cancer randomized radiation dose escalation trial

PURPOSE A positive biopsy after external beam radiotherapy in patients free of any evidence of treatment failure is not synonymous with eventual recurrence. Although biopsy positivity is a predictor of outcome, the utility of biopsy status as a surrogate end point, the effect of radiation dose on biopsy status, and the interrelationships of these associations to prostate-specific antigen (PSA) nadir level are not well-defined. These issues were investigated in a cohort of men with Stage T1-T3 prostate cancer who were randomized to receive between 70 Gy and 78 Gy and were prospectively biopsied at about 2 years after the completion of radiotherapy (RT). METHODS AND MATERIALS Of the 301 assessable patients in the trial, 168 underwent planned sextant or greater prostate post-RT biopsies in the absence of biochemical or clinical failure; this group constituted the study cohort. Of the 168 patients, 87 were in the 70-Gy arm and 81 in the 78-Gy arm. Biopsies were classified into four groups: negative (no tumor), atypical/suspicious cells (not diagnostic of carcinoma), carcinoma with treatment effect (CaTxEffect), and carcinoma without treatment effect (CaNoTxEffect). Any diagnosis of carcinoma in the specimen was classified as biopsy positive. Freedom from failure (FFF) included biochemical failure and/or clinical failure. Kaplan-Meier curves were calculated from the completion of RT. For those alive in the study cohort, the median follow-up was 65 months. RESULTS The rate of biopsy without tumor was 42%; with atypical cells, it was 28%, with CaTxEffect 21%, and with CaNoTxEffect 9%. The overall biopsy positivity rate (CaTxEffect + CaNoTxEffect) was 30%; 28% in the 70-Gy group and 32% in the 78-Gy group (p = 0.52). The distribution of PSA nadir levels was 73% <or=0.5, 20% >0.5-1.0, 5% >1.0-2.0, and 1% >2.0 ng/mL. Significantly more patients randomized to 78 Gy had a PSA nadir of <or=0.5 ng/mL (80% vs. 67%; p = 0.02). No relationship was found between PSA nadir level and prostate biopsy status. The 5-year FFF rate for those classified as biopsy negative was 84% and for those biopsy positive was 60% (p = 0.0002). Radiation dose did not significantly alter FFF rates by prostate biopsy status. Nadir PSA level correlated with FFF, although this was dependent on the inclusion of the 2 patients with a PSA nadir >2.0 ng/mL. CONCLUSION For patients free of treatment failure at the time of prostate biopsy 2 years after RT, the prognosis of no tumor cells was the same as that of atypical/suspicious cells and CaTxEffect was the same as CaNoTxEffect. The biopsy positivity rate was not altered by dose, suggesting that most of the outcome differences between the 70-Gy and 78-Gy groups were due to events occurring before prostate biopsy at 2 years and/or were not entirely dependent on biopsy status. Biopsy status is a strong prognostic factor, but, as an early end point, it may be misleading. PSA nadir appears to have little clinical value in patients treated to doses of >/=70 Gy who are failure free 2 years after RT.

Patient-specific point dose measurement for IMRT monitor unit verification

PURPOSE To review intensity-modulated radiation therapy (IMRT) monitor unit verification in a phantom for 751 clinical cases. METHODS AND MATERIALS A custom water-filled phantom was used to measure the integral dose with an ion chamber for patient-specific quality assurance. The Corvus IMRT planning system was used for all cases reviewed. The 751 clinical cases were classified into 9 treatment sites: central nervous system (27 cases), gastrointestinal (24 cases), genitourinary (447 cases), gynecologic (18 cases), head and neck (200 cases), hematology (12 cases), pediatric (3 cases), sarcoma (8 cases), and thoracic (12 cases). Between December 1998 and January 2002, 1591 measurements were made for these 751 IMRT quality assurance plans. RESULTS The mean difference (MD) in percent between the measurements and the calculations was +0.37% (with the measurement being slightly higher). The standard deviation (SD) was 1.7%, and the range of error was from -4.5% to 9.5%. The MD and SD were +0.49% and 1.4% for MIMiC treatments delivered in 2-cm mode (261 cases) and -0.33% and 2.7% for those delivered in 1-cm mode (36 cases). Most treatments (420) were delivered using the step-and-shoot multileaf collimator with a 6-MV photon beam; the MD and SD were +0.31% and 1.8%, respectively. Among the 9 treatment sites, the prostate IMRT (in genitourinary site) was most consistent with the smallest SD (1.5%). There were 23 cases (3.1% of all cases) in which the measurement difference was greater than 3.5%; of those, 6 cases used the MIMiC in 1-cm mode, and 14 of the cases were from the head-and-neck treatment site. CONCLUSION IMRT monitor unit calculations from the Corvus planning system agreed within 3.5% with the point-dose ion chamber measurement in 97% of 751 cases representing 9 different treatment sites. A good consistency was observed across sites.

The impact of temporal inaccuracies on 4DCT image quality

Accurate delineation of target volumes is one of the critical components contributing to the success of image-guided radiotherapy treatments and several imaging modalities are employed to increase the accuracy in target identification. Four-dimensional (4D) techniques are incorporated into existing radiation imaging techniques like computed tomography (CT) to account for the mobility of the target volumes. However, these methods in some cases introduce further inaccuracies in the target delineation when further quality assurance measures are not implemented. A source of commonly observed inaccuracy is the misidentification of the respiration cycles and resulting respiration phase assignments used in the construction of the 4D patient model. The aim of this work is to emphasize the importance of optimal respiration phase assignment during the 4DCT image acquisition process and to perform a quantitative assessment of the effect of inaccurate phase assignments on the overall image quality. The accuracy of the phase assignment was assessed by comparison with an independent calculation of the respiration phases. Misplaced phase assignments manifest themselves as deformations and artifacts in reconstructed images. These effects are quantified as volumetric discrepancies in the localization of target objects represented by spherical phantoms. Measurements are performed using a fully programmable motion phantom designed and built at Mayo Clinic (Rochester, MN). Implementation of a case based independent check and correction procedure is also demonstrated with emphasis on the use of this procedure in the clinical environment. Review of clinical 4D scans performed in this institution showed discrepancies in the phase assignments in about 40% of the cases when compared to our independent calculations. It is concluded that for improved image reconstruction, an independent check of the sorting procedure should be performed for each clinical 4DCT case.

Recommendations for clinical electron beam dosimetry: Supplement to the recommendations of Task Group 25

The goal of Task Group 25 (TG-25) of the Radiation Therapy Committee of the American Association of.Physicists in Medicine (AAPM) was to provide a methodology and set of procedures for a medical physicist performing clinical electron beam dosimetry in the nominal energy range of 5-25 MeV. Specifically, the task group recommended procedures for acquiring basic information required for acceptance testing and treatment planning of new accelerators with therapeutic electron beams. Since the publication of the TG-25 report, significant advances have taken place in the field of electron beam dosimetry, the most significant being that primary standards laboratories around the world have shifted from calibration standards based on exposure or air kerma to standards based on absorbed dose to water. The AAPM has published a new calibration protocol, TG-51, for the calibration of high-energy photon and electron beams. The formalism and dosimetry procedures recommended in this protocol are based on the absorbed dose to water calibration coefficient of an ionization chamber at 60Co energy, N60Co(D,w), together with the theoretical beam quality conversion coefficient k(Q) for the determination of absorbed dose to water in high-energy photon and electron beams. Task Group 70 was charged to reassess and update the recommendations in TG-25 to bring them into alignment with report TG-51 and to recommend new methodologies and procedures that would allow the practicing medical physicist to initiate and continue a high quality program in clinical electron beam dosimetry. This TG-70 report is a supplement to the TG-25 report and enhances the TG-25 report by including new topics and topics that were not covered in depth in the TG-25 report. These topics include procedures for obtaining data to commission a treatment planning computer, determining dose in irregularly shaped electron fields, and commissioning of sophisticated special procedures using high-energy electron beams. The use of radiochromic film for electrons is addressed, and radiographic film that is no longer available has been replaced by film that is available. Realistic stopping-power data are incorporated when appropriate along with enhanced tables of electron fluence data. A larger list of clinical applications of electron beams is included in the full TG-70 report available at http://www.aapm.org/pubs/reports. Descriptions of the techniques in the clinical sections are not exhaustive but do describe key elements of the procedures and how to initiate these programs in the clinic. There have been no major changes since the TG-25 report relating to flatness and symmetry, surface dose, use of thermoluminescent dosimeters or diodes, virtual source position designation, air gap corrections, oblique incidence, or corrections for inhomogeneities. Thus these topics are not addressed in the TG-70 report.

PLANNING TARGET VOLUMES FOR RADIOTHERAPY: HOW MUCH MARGIN IS NEEDED?

PURPOSE The radiotherapy planning target volume (PTV) encloses the clinical target volume (CTV) with anisotropic margins to account for possible uncertainties in beam alignment, patient positioning, organ motion, and organ deformation. Ideally, the CTV-PTV margin should be determined solely by the magnitudes of the uncertainties involved. In practice, the clinician usually also considers doses to abutting healthy tissues when deciding on the size of the CTV-PTV margin. This study calculates the ideal size of the CTV-PTV margin when only physical position uncertainties are considered. METHODS AND MATERIALS The position of the CTV for any treatment is assumed to be described by independent Gaussian distributions in each of the three Cartesian directions. Three strategies for choosing a CTV-PTV margin are analyzed. The CTV-PTV margin can be based on: 1. the probability that the CTV is completely enclosed by the PTV; 2. the probability that the projection of the CTV in the beams eye view (BEV) is completely enclosed by the projection of the PTV in the BEV; and 3. the probability that a point on the edge of the CTV is within the PTV. Cumulative probability distributions are derived for each of the above strategies. RESULTS Expansion of the CTV by 1 standard deviation (SD) in each direction results in the CTV being entirely enclosed within the PTV 24% of the time; the BEV projection of the CTV is enclosed within the BEV projection of the PTV 39% of the time; and a point on the edge of the CTV is within the PTV 84% of the time. To have the CTV enclosed entirely within the PTV 95% of the time requires a margin of 2.8 SD. For the BEV projection of the CTV to be within the BEV projection of the PTV 95% of the time requires a margin of 2.45 SD. To have any point on the surface of the CTV be within the PTV 95% of the time requires a margin of 1.65 SD. CONCLUSION In the first two strategies for selecting a margin, the probability of finding the CTV within the PTV is unrelated to dose variations in the CTV. In the third strategy, the specified confidence limit is correlated with the minimum target dose. We recommend that the PTV be calculated from the CTV using a margin of 1.65 SD in each direction. This gives a minimum CTV dose that is greater than 95% of the minimum PTV dose. Additional sparing of adjoining healthy structures should be accomplished by modifying beam portals, rather than adjusting the PTV. Then, the dose distributions more accurately reflect the clinical compromise between treating the tumor and sparing the patient.

Dosimetry of a prototype retractable eMLC for fixed-beam electron therapy

An electron multileaf collimator (eMLC) has been designed that is unique in that it retracts to 37 cm from the isocenter [63-cm source-to-collimator distance (SCD)] and can be deployed to distances of 20 and 10 cm from the isocenter (80 and 90 cm SCD, respectively). It is expected to be capable of arc therapy at 63 cm SCD; isocentric, fixed-beam therapy at 80 cm SCD; and source-to-surface distance (SSD), fixed-beam therapy at 90 cm SCD. In all positions, its leaves could be used for unmodulated or intensity-modulated therapy. Our goal in the present work is to describe the general characteristics of the eMLC and to demonstrate that its leakage characteristics and dosimetry are adequate for SSD, fixed-beam therapy as an alternative to Cerrobend cutouts with applicators once the prototypes leaves are motorized. Our eMLC data showed interleaf electron leakage at 15 MeV to be less than 0.1% based on a 0.0025 cm manufacturing tolerance, and lateral electron leakage at 5 and 15 MeV to be less than 2%. X-ray leakage through the leaves was 1.6% at 15 MeV. Our data showed that beam penumbra was independent of direction and leaf position. The dosimetric properties of square fields formed by the eMLC were very consistent with those formed by Cerrobend inserts in the 20 x 20 cm2 applicator. Output factors exhibited similar field-size dependence. Airgap factors exhibited almost identical field-size dependence at two SSDs (105 and 110 cm), consistent with the common assumption that airgap factors are applicator independent. Percent depth-dose curves were similar, but showed variations up to 3% in the buildup region. The pencil-beam algorithm (PBA) fit measured data from the eMLC and applicator-cutout systems equally well, and the resulting two-dimensional (2-D) dose distributions, as predicted by the PBA, agreed well at common airgap distance. Simulating patient setups for breast and head and neck treatments showed that almost all fields could be treated using similar SSDs as when using applicators, although head and neck treatments require placing the patients head on a head-holder treatment table extension. The results of this work confirmed our design goals and support the potential use of the eMLC design in the clinical setting. The eMLC should allow the same treatments as are typically delivered with the electron applicator-cutout system currently used for fixed-beam therapy.