Vrinda Narayana

AAPM recommendations on dose prescription and reporting methods for permanent interstitial brachytherapy for prostate cancer: Report of Task Group 137

During the past decade, permanent radioactive source implantation of the prostate has become the standard of care for selected prostate cancer patients, and the techniques for implantation have evolved in many different forms. Although most implants use I125 or P103d sources, clinical use of C131s sources has also recently been introduced. These sources produce different dose distributions and irradiate the tumors at different dose rates. Ultrasound was used originally to guide the planning and implantation of sources in the tumor. More recently, CT and/or MR are used routinely in many clinics for dose evaluation and planning. Several investigators reported that the tumor volumes and target volumes delineated from ultrasound, CT, and MR can vary substantially because of the inherent differences in these imaging modalities. It has also been reported that these volumes depend critically on the time of imaging after the implant. Many clinics, in particular those using intraoperative implantation, perform imaging only on the day of the implant. Because the effects of edema caused by surgical trauma can vary from one patient to another and resolve at different rates, the timing of imaging for dosimetry evaluation can have a profound effect on the dose reported (to have been delivered), i.e., for the same implant (same dose delivered), CT at different timing can yield different doses reported. Also, many different loading patterns and margins around the tumor volumes have been used, and these may lead to variations in the dose delivered. In this report, the current literature on these issues is reviewed, and the impact of these issues on the radiobiological response is estimated. The radiobiological models for the biological equivalent dose (BED) are reviewed. Starting with the BED model for acute single doses, the models for fractionated doses, continuous low-dose-rate irradiation, and both homogeneous and inhomogeneous dose distributions, as well as tumor cure probability models, are reviewed. Based on these developments in literature, the AAPM recommends guidelines for dose prescription from a physics perspective for routine patient treatment, clinical trials, and for treatment planning software developers. The authors continue to follow the current recommendations on using D90 and V100 as the primary quantities, with more specific guidelines on the use of the imaging modalities and the timing of the imaging. The AAPM recommends that the postimplant evaluation should be performed at the optimum time for specific radionuclides. In addition, they encourage the use of a radiobiological model with a specific set of parameters to facilitate relative comparisons of treatment plans reported by different institutions using different loading patterns or radionuclides.

Source placement error for permanent implant of the prostate

The performance of ultrasound (US) and fluoroscopic-guided permanent 125I source implant of the prostate using CT identification of the source positions has been evaluated. Marker seeds were implanted during the planning study to assist in the alignment of the US and CT prostate volumes for treatment planning and to guide the placement of needles. The relative positions of the needles and marker seeds were checked by fluoroscopy. A postimplant CT study was used to input the radioactive source positions and to register the sources relative to the preimplant CT and US prostate volumes and the planned source distribution. Source placement errors observed were categorized as: (1) source-to-source spacing differences; (2) needle placement error, both depth and position; and (3) seed splaying, particularly near the prostate periphery. Errors due to source splaying and spacing were in part attributed to prostate motion. Later refinements included fixed-spaced string sources, for which placement errors were smaller than for unattached sources. However, source placement errors due to needle placement error and prostate motion remained unchanged.

Impact of differences in ultrasound and computed tomography volumes on treatment planning of permanent prostate implants

PURPOSE Both ultrasound (US) and computerized tomography (CT) images have been used in the planning of prostate interstitial therapy. Ultrasound images more clearly define the apex and capsule of the prostate, while CT images define seed positions for postimplant dosimetry. Proper registration of the US volume with the CT volume is critical to the assessment of dosimetry. We therefore compared US and CT prostate volumes to determine if differences were significant. METHODS AND MATERIALS Ten consecutive patients entered in an interstitial implant program were studied by pretreatment US. In addition, pretreatment CT scans were obtained and three physicians independently outlined the dimensions of the prostate on these images. The patients subsequently underwent placement of radioactive 125I or 103Pd. Postimplant CT images were obtained the next day and the postimplant prostate volumes were outlined by the same three physicians. Seven of 10 patients underwent late CT scans 9-14 months postimplant for comparison of preimplant and immediate postimplant CT studies. RESULTS There were differences between US and CT volumes. Although the physician-to-physician variation was significant, the trends were consistent, with US prostate volume typically smaller (47%) than the preimplant CT volume and markedly smaller (120%) than the postimplant CT volume. Prostate volumes derived from late CT images did not consistently return to preimplant levels. CONCLUSIONS Significant differences in volume of the prostate structure were found between US and CT images. The data suggests that: (a) Implants planned on CT tend to overestimate the size of the prostate and may lead to unnecessary implantation of the urogenital diaphragm and penile urethra. (b) Registration of initial US and postimplant CT prostate volumes required for accurate dosimetry is difficult due to the increased volume of prostate secondary to trauma. (c) Further study to determine the optimal time for the postimplant CT is necessary.

Impact of ultrasound and computed tomography prostate volume registration on evaluation of permanent prostate implants

PURPOSE Ultrasound (US)-guided permanent prostate implants typically use US prostate volumes to plan the implant procedure and CT prostate volumes for 3D dosimetric evaluation of the implant. Such a protocol requires that CT and US prostate volumes be registered. We have studied the impact of prostate volume registration on postimplant dosimetry for patients with low-grade prostate cancer treated with combined US and fluoroscopic-guided permanent implants. METHODS AND MATERIALS A US image set was obtained with the patient in the lithotomy position to delineate the prostate volume that was subsequently used for treatment planning. Each plan was customized and optimized to ensure complete coverage of the US prostate volume. After implant, a CT scan was obtained for postimplant dosimetry with the patient lying supine. Sources were localized on CT by interactively creating orthogonal images of small cubes, whose dimensions were slightly larger than the source, to assure unique identification of each seed. Ultrasound and CT 3D surfaces were registered using either (a) the rectal surface and base of the prostate, or (b) the Foley balloon and urethra as the alignment reference. A dose distribution was assigned to the US prostate volume based on the CT source distribution, and the dose-volume histogram (DVH) was calculated. RESULT Prostate volumes drawn from US images differ from those drawn from CT images with the CT volumes being typically larger than the US volumes. Urethral registration of the prostate volume based on aligning the prostatic urethra generates a dose distribution that best follows the preimplant plan and is geometrically the preferable choice for dosimetry. CONCLUSION The dose distribution and the DVH for the US prostate is sensitive to the mode of registration limiting the ability to determine if acceptable dose coverage has been achieved.

Radiographic and Anatomic Basis for Prostate Contouring Errors and Methods to Improve Prostate Contouring Accuracy

PURPOSE Use of highly conformal radiation for prostate cancer can lead to both overtreatment of surrounding normal tissues and undertreatment of the prostate itself. In this retrospective study we analyzed the radiographic and anatomic basis of common errors in computed tomography (CT) contouring and suggest methods to correct them. METHODS AND MATERIALS Three hundred patients with prostate cancer underwent CT and magnetic resonance imaging (MRI). The prostate was delineated independently on the data sets. CT and MRI contours were compared by use of deformable registration. Errors in target delineation were analyzed and methods to avoid such errors detailed. RESULTS Contouring errors were identified at the prostatic apex, mid gland, and base on CT. At the apex, the genitourinary diaphragm, rectum, and anterior fascia contribute to overestimation. At the mid prostate, the anterior and lateral fasciae contribute to overestimation. At the base, the bladder and anterior fascia contribute to anterior overestimation. Transition zone hypertrophy and bladder neck variability contribute to errors of overestimation and underestimation at the superior base, whereas variable prostate-to-seminal vesicle relationships with prostate hypertrophy contribute to contouring errors at the posterior base. CONCLUSIONS Most CT contouring errors can be detected by (1) inspection of a lateral view of prostate contours to detect projection from the expected globular form and (2) recognition of anatomic structures (genitourinary diaphragm) on the CT scans that are clearly visible on MRI. This study shows that many CT prostate contouring errors can be improved without direct incorporation of MRI data.

Use and uncertainties of mutual information for computed tomography/magnetic resonance (CT/MR) registration post permanent implant of the prostate

Post-implant dosimetric analysis for permanent implant of the prostate benefits from the use of a computed tomography (CT) dataset for optimal identification of the radioactive source (seed) positions and a magnetic resonance (MR) dataset for optimal description of the target and normal tissue volumes. The CT/MR registration process should be fast and sufficiently accurate to yield a reliable dosimetric analysis. Since critical normal tissues typically reside in dose gradient regions, small shifts in the dose distribution could impact the prediction of complication or complication severity. Standard procedures include the use of the seed distribution as fiducial markers (seed match), a time consuming process that relies on the proper identification of signals due to the same seed on both datasets. Mutual information (MI) is more efficient because it uses image data requiring minimal preparation effort. A comparison of MI registration and seed-match registration was performed for twelve patients. MI was applied to a volume limited to the prostate and surrounding structures, excluding most of the pelvic bone structures (margins around the prostate gland were approximately 2 cm right-left, approximately 1 cm anterior-posterior, and approximately 2 cm superior-inferior). Seeds were identified on a 2 mm slice CT dataset using an automatic seed identification procedure on reconstructed three-dimensional data. Seed positions on the 3 mm slice thickness T2 MR data set were identified using a point-and-click method on each image. Seed images were identified on more than one MR slice, and the results used to determine average seed coordinates for MR images and matched seed pairs between CT and MR images. On average, 42% (19%-64%) of the seeds (19-54 seeds) were identified and matched to their CT counterparts. A least-squares method applied to the CT and MR seed coordinates was used to produce the optimum seed-match registration. MI registration and seed match registration angle differences averaged 0.5 degrees, which was not significantly different from zero. Translation differences averaged 0.6 (1.2 standard deviation) mm right-left, -0.5(1.5) mm posterior-anterior, and -1.2(2.0) mm inferior-superior. Registration error estimates were approximately 2 mm for both the MI and seed-match methods. The observed standard deviations in the offset values were consistent with propagation of error. Registration methods as applied here using mutual information and seed matching are consistent, except for a small systematic difference in the inferior-superior axis for a minority of cases (approximately 15%). Cases registered with mutual information and with bony anatomy misregistration of greater than approximately 5 mm should be evaluated for rescan or seed-match registration. The improvement in efficiency of use for the MI registration method is substantial, approximately 30 min compared to several hours using seed match registration.

Comparison of MRI pulse sequences in defining prostate volume after permanent implantation

PURPOSE To determine the relative value of three MRI pulse sequences in defining the prostate volume after permanent implantation. METHODS AND MATERIALS A total of 45 patients who received a permanent 125I implant were studied. Two weeks after implantation, an axial CT scan (2 mm thickness) and T1-weighted, T1-weighted fat saturation, and T2-weighted axial MRI (3-mm) studies were obtained. The prostate volumes were compared with the initial ultrasound planning volumes, and subsequently the CT, T1-weighted, and T1-weighted fat saturation MRI volumes were compared with the T2-weighted volumes. Discrepancies in volume were evaluated by visual inspection of the registered axial images and the registration of axial volumes on the sagittal T2-weighted volumes. In a limited set of patients, pre- and postimplant CT and T2-weighted MRI studies were available for comparison to determine whether prostate volume changes after implant were dependent on the imaging modality. RESULTS T1-weighted and T1-weighted fat saturation MRI and CT prostate volumes were consistently larger than the T2-weighted MRI prostate volumes, with a volume on average 1.33 (SD 0.24) times the T2-weighted volume. This discrepancy was due to the superiority of T2-weighted MRI for prostate definition at the following critical interfaces: membranous urethra, apex, and anterior base-bladder and posterior base-seminal vesicle interfaces. The differences in prostate definition in the anterior base region suggest that the commonly reported underdose may be due to overestimation of the prostate in this region by CT. The consistent difference in volumes suggests that the degree of swelling observed after implantation is in part a function of the imaging modality. In patients with pre- and postimplant CT and T2-weighted MRI images, swelling on the T2-weighted images was 1.1 times baseline and on CT was 1.3 times baseline, confirming the imaging modality dependence of prostate swelling. CONCLUSION Postimplant T2-weighted MRI images provided superior prostate definition in all critical regions of the prostate compared with CT and the other MRI sequences tested. In addition to defining an optimal technique, these findings call two prior observations into question. Under dosing at the anterior base region may be overestimated because of poor definition of the prostate-bladder muscle interface. The swelling observed after implantation was lower on T2-weighted images as well, suggesting that a fraction of postimplant swelling is a function of the imaging modality. These findings have implications for preimplant planning and postimplant evaluation. As implant planning techniques become more conformal, and registration methods become more efficient, T2-weighted MRI after implantation will improve the accuracy of postimplant dosimetry.

Greater Postimplant Swelling in Small-Volume Prostate Glands: Implications for Dosimetry, Treatment Planning, and Operating Room Technique

PURPOSE Postimplant prostatic edema has been implicated in suboptimal permanent implants, and smaller prostates have been reported to have worse dosimetric coverage. In this study we compare the degree of postimplant edema between larger and smaller prostates and examine the effects of prostate size on the dose delivered to 90% of the prostate (D90). METHODS AND MATERIALS From September 2003 to February 2006, 105 hormone-naive patients underwent permanent prostate brachytherapy with (125)I Rapid Strand (Oncura Inc., Arlington Heights, IL). All patients underwent pelvic magnetic resonance imaging (MRI) within 3 weeks before implant, transrectal ultrasound at the time of implant, and both computed tomography and MRI 2.5 to 3 weeks after implant. Prostates were divided into 5 subgroups based on preimplant MRI volumes: less than 25 mL, 25 to 35 mL, 35 to 45 mL, 45 to 55 mL, and greater than 55 mL. Prostate swelling was assessed by use of preimplant and postimplant MRI volumes. Postimplant dosimetry was determined by MRI and compared between the subgroups. RESULTS All prostates showed postimplant swelling on MRI when compared with preimplant MRI, with a mean increase of 31% ± 31% (p < 0.0001). The greatest swelling was noted in small prostates (volume less than 25 mL), with a mean increase of 70% ± 36%. The degree of swelling in the group with a volume less than 25 mL was significantly larger than the degree of swelling in all other prostate subgroups (p < 0.003). Transrectal ultrasound significantly overestimates the prostate volume when compared with MRI by a mean of 15% ± 25% (p = 0.0006) and is more pronounced for smaller prostates. Although prostates with volumes less than 25 mL did not have significantly worse D90 compared with larger prostates, they had the largest percent of suboptimal implants by the standard ratio of D90 divided by the prescription dose. CONCLUSIONS Although small prostates have the greatest postimplant edema, planning ultrasound at the time of implant overestimates the volumes of smaller prostates to a greater degree than larger prostates, which may minimize the effects of edema on postimplant dosimetry.

Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5

PURPOSE To investigate the impact of Gleason pattern 5 (GP5) prostate cancer after either external beam radiotherapy (EBRT) or the combination of EBRT with low-dose rate brachytherapy boost (combo). METHODS AND MATERIALS Between 1998 and 2008, 467 patients with National Comprehensive Cancer Network high-risk prostate cancer were treated with EBRT (n = 326) or combo (low-dose rate to 90-108 Gy using I-125 followed by EBRT) (n = 141). Freedom from biochemical failure, freedom from metastasis (FFM), cancer-specific survival (CSS), and overall survival were evaluated. RESULTS Combo patients were younger (66 vs. 72 years, p < 0.001) and had fewer comorbidities (Charlson comorbidity index 3.7 vs. 4.4, p < 0.001). EBRT patients had higher tumor stages (T3-4: 30% vs. 21%, p = 0.03) and lower Gleason scores (8-10: 61% vs. 75%, p = 0.01). Androgen deprivation therapy use was similar between cohorts (85% vs. 87%, p = 0.5), but EBRT patients had longer androgen deprivation therapy use (median 14 vs. 12 months, p = 0.05). GP5 predicted worse FFM (p < 0.001, hazard ratio [HR] 3.3, 95% confidence interval [CI]1.8-6.2]) and CSS (p < 0.001, HR 5.9, 95% CI 2.7-12.9) for the EBRT group, but not for the combo group (p = 0.86, HR 0.48, 95% CI 0.1-2.4 for metastasis and p = 0.5, HR 1.6, 95% CI 0.33-8.0 for CSS). In those with GP5 (n = 143), combo was associated with improved outcomes in all endpoints. On univariate analysis, 5-year outcomes for combo vs. EBRT were as follows: freedom from biochemical failure 89% vs. 65%, FFM 89% vs. 67%, CSS 93% vs. 78%, and overall survival 88% vs. 67% (p < 0.05 for all). CONCLUSION Combo was associated with improved outcomes for men with GP5 prostate cancer. This highlights the importance of local therapy, especially in patients with the highest pathologic grade disease.

Vessel-sparing Radiotherapy for Localized Prostate Cancer to Preserve Erectile Function: A Single-arm Phase 2 Trial

BACKGROUND Erectile dysfunction remains the most common side effect from radical treatment of localized prostate cancer. We hypothesized that the use of vessel-sparing radiotherapy, analogous to the functional anatomy approach of nerve-sparing radical prostatectomy (RP), would improve erectile function preservation while maintaining tumor control for men with localized prostate cancer. OBJECTIVE To determine erectile function rates after vessel-sparing radiotherapy. DESIGN, SETTING, AND PARTICIPANTS Men with localized prostate cancer were enrolled in a phase 2 single-arm trial (NCT02958787) at a single academic center. INTERVENTION Patients received vessel-sparing radiotherapy utilizing a planning MRI and MRI-angiogram to delineate and avoid the erectile vasculature. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Both physician- and patient-reported inventories were used to capture erectile function at baseline and at 2 and 5 yr after treatment. Validated model-based comparisons were performed to compare vessel-sparing results to nerve-sparing RP and conventional radiotherapy. RESULTS AND LIMITATIONS From 2001 to 2009, 135 men underwent vessel-sparing radiotherapy. After a planned interim analysis, the trial was stopped after meeting the primary endpoint. The median follow-up was 8.7 yr, with a ≥94% response rate to all inventories at each time point. At 5 yr, 88% of patients were sexually active with or without the use of sexual aids. The 2-yr erectile function rates were significantly improved with vessel-sparing radiotherapy (78%, 95% confidence interval [CI] 71-85%) compared to modeled rates for convention radiotherapy (42%, 95% CI 38-45%; p<0.001) or nerve-sparing prostatectomy (24%, 95% CI 22-27%; p<0.001). At 2 yr after treatment, 87% of baseline-potent men retained erections suitable for intercourse. The 5- and 10-yr rates of biochemical relapse-free survival were 99.3% and 89.9%, and at 5 yr the biochemical failures were limited to the National Comprehensive Cancer Network high-risk group. The single-arm design is a limitation. CONCLUSIONS Vessel-sparing radiotherapy appears to more effectively preserve erectile function when compared to historical series and model-predicted outcomes following nerve-sparing RP or conventional radiotherapy, with maintenance of tumor control. This approach warrants independent validation. PATIENT SUMMARY In this interim analysis we looked at using a novel approach to spare critical erectile structures to preserve erectile function after prostate cancer radiotherapy. We found that almost 90% of patients at 5 yr after treatment remained sexually active, significantly higher than previous studies with surgery or radiotherapy.