Gil'ad N. Cohen

Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging

PURPOSE Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. METHODS MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. RESULTS The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using (125)I seeds. The preset dose bounds of 100-150% to the prostate and 100-120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. CONCLUSIONS Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for (125)I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal ultrasound-guided prostate brachytherapy.

PURPOSE We have developed an intraoperative three-dimensional (3D) conformal treatment planning system for permanent prostate implantation in an effort to reduce toxicity further and improve the accuracy of this procedure. We report the preliminary outcome of patients with localized prostate cancer treated with this approach. METHODS AND MATERIALS Two hundred forty-eight patients with clinically localized prostate cancer were treated with transperineal ultrasound-guided permanent prostate implantation using a real-time intraoperative 3D conformal technique (I-3D) between 1997 and 2001. A genetic algorithm optimization program intraoperatively evaluated the dose deposited throughout the entire 3D volume for multiple seed configurations to identify which seed-loading pattern adhered best to the predetermined target, urethral and rectal dose constraints. The median follow-up time in these patients was 27 months (range 12-51). The dosimetric outcome and acute toxicity profile of these 248 patients were compared with those of patients who were treated between 1988 and 1996 at our institution with a preplanned transperineal implantation technique (PP). RESULTS Postimplantation dosimetric analysis of the I-3D group demonstrated that the median value of the percentage of the target volume treated to at least the prescription dose (V(100)) was 96%, and the target coverage with the prescription dose (PD) was </=90% in only 3% of these patients. In contrast, among patients treated with the PP method, the median V(100) was 88% and the target coverage with the PD was </=90% in 60% of these patients (p < 0.001). For the I-3D patients, the median and maximal dose to the urethra was 140% and 170% of the PD, respectively, compared with 263% and 532%, respectively, for patients treated with the PP technique. The percentage of urinary symptom resolution at 6, 12, 18, and 24 months for the I-3D cohort was 39%, 72%, 90%, and 97%, respectively. In contrast, the percentage of symptom resolution at the same intervals for patients treated with the PP technique was 12%, 20%, 31%, and 42% (p < 0.001). Multivariate analysis demonstrated that the I-3D technique was an independent predictor of improved target coverage, reduced urethral dose, and more rapid resolution of urinary-related symptoms. The improved dosimetric conformity with the I-3D technique did not compromise the biochemical outcome, as the 4-year actuarial prostate-specific antigen relapse-free survival rate for this group was 97%. CONCLUSION The integration of an intraoperative optimization program with 3D dose evaluation throughout the target volume for prostate brachytherapy has consistently achieved excellent target coverage with the PD, and the dose levels to normal tissues were effectively restricted to tolerance ranges. These changes have led to a more favorable acute toxicity profile for patients treated with this technique without compromising biochemical control.

Postimplantation dosimetric analysis of permanent transperineal prostate implantation: improved dose distributions with an intraoperative computer-optimized conformal planning technique.

PURPOSE To compare the target coverage and dose to normal tissues after I-125 transperineal permanent implantation (TPI) of the prostate in 90 patients treated with one of three different transperineal techniques. METHODS AND MATERIALS Detailed postimplant dosimetric evaluations of permanent I-125 implantation procedures were performed on 30 consecutive patients treated between 1995-1996 who underwent TPI using a preplanning CT-based technique, on 30 consecutive patients treated in 1997-1998 who underwent an ultrasound-guided approach with intraoperative determination of seed distribution based on an I-125 nomogram, and on 30 consecutive patients in 1998-1999 who underwent TPI with intraoperative computer-based 3-dimensional conformal optimization. For all three techniques, postimplant CT scans were obtained 4-6 hours after TPI. Dosimetric parameters included V(100), V(90), V(150), D(100), D(90), D(80), as well as maximal and average doses to the urethra and rectal wall. These parameter outcomes are reported as a percentage of the prescription dose. RESULTS The intraoperative 3D-optimized technique (I-3D) provided superior target coverage with the prescription dose for all dosimetric variables evaluated compared to the other treatment techniques. The median V(100), V(90), and D(90) values for the I-3D technique were 96%, 98%, and 116%, respectively. In contrast, the V(100), V(90), and D(90) values for the CT preplan and ultrasound manual optimization approaches were 86%, 89%, and 88%, respectively and 88%, 92%, and 94%, respectively (I-3D versus other techniques: p < 0.001). The superior target coverage with the I-3D technique was also associated with a higher cumulative implant activity required by the optimization program. A multivariate analysis determined that the treatment technique (I-3D versus other approaches) was an independent predictor of improved target coverage for each parameter analyzed (p < 0.001). In addition, higher cumulative implant activities and smaller prostate target volumes were independent predictors of improved target coverage. The maximum and average urethral doses were significantly lower with the I-3D technique compared to the other techniques; a modest increase in the average rectal dose was also observed with this approach. CONCLUSION Three-dimensional intraoperative computer optimized TPI consistently provided superior target coverage with the prescription dose and significantly lower urethral doses compared to two other techniques used. These data provide proof-of-principle that improved therapeutic ratios can be achieved with the integration of more sophisticated intraoperative planning for TPI and may potentially have a profound impact on the outcome of patients treated with this modality.

Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.

To compare tumour control and toxicity outcomes with the use of high‐dose intensity‐modulated radiation therapy (IMRT) alone or brachytherapy combined with IMRT (combo‐RT) for patients with intermediate‐risk prostate cancer.

Comparison of Tumor Control and Toxicity Outcomes of High Dose Intensity-Modulated Radiotherapy and Brachytherapy for Patients with Favorable Risk Prostate Cancer

OBJECTIVES To compare the long-term, prostate-specific antigen relapse-free survival outcome and incidence of toxicity for patients with low-risk prostate cancer who underwent brachytherapy or intensity-modulated radiotherapy (RT). METHODS A total of 729 consecutive patients underwent brachytherapy (n = 448; prescription dose 144 Gy) or intensity-modulated RT alone (n = 281; prescription dose 81 Gy). The prostate-specific antigen relapse-free survival using the nadir plus 2 ng/mL definition and late toxicity using the National Cancer Institutes Common Terminology Criteria for Adverse Events were determined. RESULTS The 7-year prostate-specific antigen relapse-free survival rate for the brachytherapy and intensity-modulated RT groups was 95% and 89% for low-risk patients, respectively (P = .004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival, even after adjustment for other variables. The incidence of metastatic disease between treatment sessions was low for both treatment groups. Late grade 2 gastrointestinal toxicity was observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated RT groups, respectively (P = .02). No significant differences were seen between treatment groups for late grade 3 or greater rectal complications (brachytherapy 1.1% and intensity-modulated RT 0%; P = .19). Late grade 2 urinary toxicity occurred more often in the brachytherapy group than in the intensity-modulated RT group (15.6% and 4.3%, respectively; P < .0001). No significant differences were seen between the 2 treatment groups for late grade 3 urinary toxicity (brachytherapy 2.2% and intensity-modulated RT 1.4%; P = .62). CONCLUSIONS Among low-risk prostate cancer patients, the 7-year biochemical tumor control was superior for intraoperatively planned brachytherapy compared with high-dose intensity-modulated RT. Although significant toxicities were minimal for both groups, modest, but significant, increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated RT.

Operator-free, film-based 3D seed reconstruction in brachytherapy.

In brachytherapy implants, the accuracy of dose calculation depends on the ability to localize radioactive sources correctly. If performed manually using planar images, this is a time-consuming and often error-prone process-primarily because each seed must be identified on (at least) two films. In principle, three films should allow automatic seed identification and position reconstruction; however, practical implementation of the numerous algorithms proposed so far appears to have only limited reliability. The motivation behind this work is to create a fast and reliable system for real-time implant evaluation using digital planar images obtained from radiotherapy simulators, or mobile x-ray/fluoroscopy systems. We have developed algorithms and code for 3D seed coordinate reconstruction. The input consists of projections of seed positions in each of three isocentric images taken at arbitrary angles. The method proposed here consists of a set of heuristic rules (in a sense, a learning algorithm) that attempts to minimize seed misclassifications. In the clinic, this means that the system must be impervious to errors resulting from patient motion as well as from finite tolerances accepted in equipment settings. The software program was tested with simulated data, a pelvic phantom and patient data. One hundred and twenty permanent prostate implants were examined (105 125I and 15 103Pd) with the number of seeds ranging from 35 to 138 (average 79). The mean distance between actual and reconstructed seed positions is in the range 0.03-0.11 cm. On a Pentium III computer at 600 MHz the reconstruction process takes 10-30 s. The total number of seeds is independently validated. The process is robust and able to account for errors introduced in the clinic.

Combined brachytherapy with external beam radiotherapy for localized prostate cancer: Reduced morbidity with an intraoperative brachytherapy planning technique and supplemental intensity-modulated radiation therapy

PURPOSE To report the acute and late treatment-related toxicities of combined permanent interstitial (125)I implantation delivered via real-time intraoperative planning and supplemental intensity-modulated radiotherapy (IMRT) for patients with clinically localized prostate cancer. METHODS AND MATERIALS One hundred twenty-seven patients were treated with a combined modality (CM) regimen consisting of (125)I implantation (110Gy) using a transrectal ultrasound-guided approach followed 2 months later by 50.4Gy of IMRT directed to the prostate and seminal vesicles. Late toxicity was scored according to the NCI Common Terminology Criteria for Adverse Events toxicity scale. The acute and late toxicities were compared to a contemporaneously treated cohort of 216 patients treated with (125)I alone to a prescribed dose of 144Gy. RESULTS The incidence of Grade 2 acute rectal and urinary side effects was 1% and 10%, respectively, and 2 patients developed Grade 3 acute urinary toxicities. The 4-year incidence of late Grade 2 gastrointestinal toxicity was 9%, and no Grade 3 or 4 complications have been observed. The 4-year incidence of late Grade 2 gastrourinary toxicities was 15% and 1 patient developed a Grade 3 urethral stricture, which was corrected with urethral dilatation. The percentage of patients who experienced resolution of late rectal and urinary symptoms was 92% and 65%, respectively. Multivariate analysis revealed that in addition to higher baseline International Prostate Symptom Score, those patients treated with implant alone compared to CM were more likely to experience Grade 2 acute urinary symptoms. Increased Grade 2 late rectal toxicities were noted for CM patients (9% vs. 1%; p=0.001) as well as a significant increase for late Grade 2 urinary toxicities (15% vs. 9%; p=0.004). CONCLUSIONS Adherence to dose constraints with combination real-time brachytherapy using real-time intraoperative planning and IMRT is associated with a low incidence of acute and late toxicities. Acute urinary side effects were significantly less common for CM patients compared to those treated with implantation alone. Late Grade 2 rectal and urinary toxicities were more common for patients treated with CM compared to implant alone.

Reirradiation of Locally Recurrent Nasopharynx Cancer With External Beam Radiotherapy With or Without Brachytherapy

PURPOSE To determine survival rates of patients with locally recurrent nasopharynx cancer (LRNPC) treated with modern therapeutic modalities. METHODS AND MATERIALS From July 1996 to March 2008, 29 patients were reirradiated for LRNPC. Thirteen patients received combined-modality treatment (CMT), consisting of external beam radiotherapy (EBRT) followed by intracavitary brachytherapy, whereas 16 received EBRT alone. The median age was 50 years, 59% were male, 38% were Asian, 69% had World Health Organization Class III histology, and 86% were treated for their first recurrence. Nine, 6, 8, and 6 patients had recurrent Stage I, II, III, and IV disease, respectively. Patients in the EBRT-alone group had more advanced disease. Median time to reirradiation was 3.9 years. In total, 93% underwent imaging with positron emission tomography and/or magnetic resonance imaging before reirradiation, 83% received intensity-modulated radiotherapy, and 93% received chemotherapy, which was platinum-based in 85% of cases. RESULTS The median follow-up for all patients was 45 months and for surviving patients was 54 months. Five-year actuarial local control, event-free survival, and overall survival rates were 52%, 44%, and 60%, respectively. No difference was observed between patients treated with EBRT or CMT. Overall survival was superior in patients who achieved local control (p = 0.0003). The incidence of late Grade > or =3 events in patients re-treated with EBRT alone was significantly increased compared with those receiving CMT (73% vs. 8%; p = 0.005). CONCLUSIONS In this modern reirradiation series of patients with LRNPC, favorable overall survival compared with historical series was achieved. Patients treated with CMT experienced significantly fewer severe late effects compared with those treated with EBRT.

Impact of intraoperative edema during transperineal permanent prostate brachytherapy on computer-optimized and preimplant planning techniques.

The purpose of this study was to prospectively evaluate intraoperative prostatic edema during prostate brachytherapy with real-time ultrasound imaging and assess its impact upon the postimplant dosimetry of computer-optimized intraoperatively planned patients. Fifty consecutive patients with early-stage favorable risk adenocarcinoma of the prostate underwent transperineal ultrasound-guided I125 brachytherapy. Ultrasound volume studies of the prostate were performed immediately before and after placement of brachytherapy needles in the operating room. Twenty-five patients underwent intraoperative computer-optimized treatment planning using a genetic algorithm. Twenty-five patients underwent preimplant ultrasound studies for preimplant treatment planning. Postimplant dosimetry was performed on computed tomography scans obtained after the implant. Statistical analysis was performed taking into account patient age, preneedle volume, increase in intraoperative edema, use of hormonal therapy, type of isotope, number of needles or seeds used, and seed activity. For the intraoperatively planned patients, a median increase of 30% in intraoperative volume was found for the entire group. No correlation between the extent of intraoperative edema and %D90 (percentage of prescribed dose that covers 90% of the target volume) was found. None of the other analyzed variables correlated with %D90. Patients whose treatment was planned preoperatively experienced a median increase of 18.4% in target volume. A negative correlation between the amount of edema and the %D90 was found to be statistically significant (-0.55, P = 0.0047). All patients who underwent prostate brachytherapy experienced intraoperative prostatic edema. When planned intraoperatively, the amount of edema had no impact on the %D90. This may be because of the ability of intraoperative computer-optimized treatment planning to account for edema related to the procedure. Preplanned patients who encountered a greater degree of intraoperative edema had less %D90 target coverage.

Dose to the Bladder Neck Is the Most Important Predictor for Acute and Late Toxicity After Low-Dose-Rate Prostate Brachytherapy: Implications for Establishing New Dose Constraints for Treatment Planning

PURPOSE To identify an anatomic structure predictive for acute (AUT) and late (LUT) urinary toxicity in patients with prostate cancer treated with low-dose-rate brachytherapy (LDR) with or without external beam radiation therapy (EBRT). METHODS AND MATERIALS From July 2002 to January 2013, 927 patients with prostate cancer (median age, 66 years) underwent LDR brachytherapy with Iodine 125 (n=753) or Palladium 103 (n=174) as definitive treatment (n=478) and as a boost (n=449) followed by supplemental EBRT (median dose, 50.4 Gy). Structures contoured on the computed tomographic (CT) scan on day 0 after implantation included prostate, urethra, bladder, and the bladder neck, defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. AUT and LUT were assessed with the Common Terminology Criteria for Adverse Events, version4. Clinical and dosimetric factors associated with AUT and LUT were analyzed with Cox regression and receiver operating characteristic analysis to calculate area under the receiver operator curve (ROC) (AUC). RESULTS Grade ≥2 AUT and grade ≥2 LUT occurred in 520 patients (56%) and 154 patients (20%), respectively. No grade 4 toxicities were observed. Bladder neck D2cc retained a significant association with AUT (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.03-1.04; P<.0001) and LUT (HR, 1.01; 95% CI, 1.00-1.03; P=.014) on multivariable analysis. In a comparison of bladder neck with the standard dosimetric variables by use of ROC analysis (prostate V100 >90%, D90 >100%, V150 >60%, urethra D20 >130%), bladder neck D2cc >50% was shown to have the strongest prognostic power for AUT (AUC, 0.697; P<.0001) and LUT (AUC, 0.620; P<.001). CONCLUSIONS Bladder neck D2cc >50% was the strongest predictor for grade ≥2 AUT and LUT in patients treated with LDR brachytherapy. These data support inclusion of bladder neck constraints into brachytherapy planning to decrease urinary toxicity.