Donald S. Brabbins

An off-line strategy for constructing a patient-specific planning target volume in adaptive treatment process for prostate cancer

PURPOSE To improve the efficacy of dose delivery and dose escalation for external beam radiotherapy of prostate cancer, an off-line strategy for constructing a patient-specific planning target volume is developed in the adaptive radiotherapy process using image feedback of target location and patient setup position. MATERIALS AND METHODS We hypothesize that a patient-specific confidence-limited planning target volume (cl-PTV), constructed using an initial sequence of daily measurements of internal target motion and patient setup error, exists and ensures that the clinical target volume (CTV) in the prostate cancer patient receives the prescribed dose within a predefined dose tolerance. A patient-specific bounding volume to correct for target location and compensate for target random motion was first constructed using the convex hull of the first k days of CT measurements. The bounding volume and the initial days of CT measurements were minimized based on a predefined dosimetric criterion. The hypothesis was tested using multiple daily CT images by mimicking the actual treatment of both conventional 4-field-box and intensity-modulated radiotherapy (IMRT) on each of 30 patients with prostate cancer. For each patient, a patient-specific setup margin was also applied to the bounding volume to form the final cl-PTV. This margin was determined using the random setup error predicted from the initial days of portal imaging measurements and the residuals after correcting for the systematic setup error. RESULTS The bounding volume constructed using daily CT measurements in the first week of treatment are adequate for the conventional beam delivery to achieve maximum dose reduction in the CTV of 2% or less of the prescription dose, for at least 80% of patients (p = 0.08), and 4.5% or less for 95% of patients (p = 0.1). However, for IMRT delivery, 2 weeks of daily CT measurements are required to achieve a similar level of the dosimetric criterion, otherwise the maximum dose reduction of 7%, on average, in the CTV is expected. Furthermore, the patient-specific setup margin required for the IMRT treatment is at least twice larger than that for the conventional treatment, to maintain the same dosimetric criterion. As compared to the conventional PTV, the volume of cl-PTV is significantly reduced, while maintaining the same dosimetric criterion. CONCLUSION The cl-PTV for prostate treatment can be constructed within the first week of treatment using the feedback of imaging measurements. The cl-PTV has the capability to exclude the systematic variation and compensate for the patient-specific random variation on target location and patient setup position. This implies that in the current off-line image feedback adaptive treatment process, a single plan modification can be performed within the second week of treatment to improve the efficacy of dose delivery and dose escalation for external beam therapy of prostate cancer.

PHASE II PROSPECTIVE STUDY OF THE USE OF CONFORMAL HIGH- DOSE-RATE BRACHYTHERAPY AS MONOTHERAPY FOR THE TREATMENT OF FAVORABLE STAGE PROSTATE CANCER: A FEASIBILITY REPORT

PURPOSE To evaluate the technical feasibility and tolerance of image-guided transperineal conformal high-dose-rate (C-HDR) brachytherapy as the sole treatment modality for favorable, localized cancer of the prostate, and to analyze possible intrafraction and interfraction volume changes in the prostate gland which may affect dosimetric quality. METHODS AND MATERIALS Patients were eligible for this prospective Phase II trial if they had biopsy proven adenocarcinoma of the prostate with favorable prognostic factors (Gleason score < or =7, PSA < or =10 ng/ml and Stage < or =T2a). The technique consisted of a transperineal implant procedure using a template with transrectal ultrasound (TRUS) guidance. An interactive on-line real-time planning system was utilized with geometric optimization. This allowed dosimetry to be generated and modified as required intraoperatively. Prescription was to the minimum dose point in the implanted volume, assuring conformal coverage of the prostate at its widest dimension with no margin. Total dose was 3800 cGy in 4 fractions of 950 cGy each, delivered twice a day over 2 days. The dose to any segment of rectum and urethra was limited to < or =75% and < or =125% of the prescription dose, respectively. Before each fraction, needle positions were verified under fluoroscopy and adjusted as required. For the last 10 patients, the adjustments required were measured in a prospective fashion in representative extrema of the gland. TRUS images were recorded for all patients before any needle manipulation, again just before delivering the first fraction and immediately after the last fraction. This typically meant approximately 36 h to pass between the first and last measurements. Implant quality was assessed via dose-volume histograms (DVH). RESULTS Between 3/99 and 6/00, 41 patients received C-HDR interstitial brachytherapy as their only treatment for prostate cancer at our institution. Median age was 64 years (range 51-79). Stage distribution was 27 T1c patients and 14 T2a patients. Three patients had Gleason score (GS) of 5; 34 had GS of 6; 4 patients had GS of 7. Median pretreatment PSA was 4.7 ng/ml (range 0.8-13.3). All patients tolerated the treatment well with minimal discomfort. For 23 patients, data on volume changes in the gland during the implant were tabulated. They demonstrated a mean prostate volume of 30.7 cc before any manipulation with needles, 37.0 cc at the end of fraction 1, and 38.2 cc at the end of fraction 4. In addition, for those 10 patients prospectively evaluated for required adjustments, the overall mean adjustment between fraction 1 and fraction 2 was 2.0 cm, between fraction 2 and 3 was 0.4 cm, and between fractions 3 and 4 was 0.4 cm. For 10 consecutive patients, the average prescriptions dose -D90 for fractions 1 and 4 were 104% and 100%, respectively. The corresponding average urethral D10 for fractions 1 and 4 were 122% and 132%. CONCLUSION Our protocol using C-HDR interstitial brachytherapy as monotherapy for early cancer of the prostate was feasible and well tolerated by 41 patients treated. Changes in interfraction prostate volume do not appear to be significant enough to warrant modification of dosimetry for each fraction. Both excellent dose coverage of the prostate gland and low urethral dose are achieved as measured by DVH. However, paramount attention should be given to needle displacement before each fraction. Needle movement is most significant between fractions 1 and 2. Acute toxicity (RTOG) has been modest. Late toxicity and tumor control rates will be reported as longer follow-up allows.

Improvement in dose escalation using the process of adaptive radiotherapy combined with three-dimensional conformal or intensity-modulated beams for prostate cancer☆

PURPOSE Advances in technology allow the creation of complex treatment plans with tightly conforming doses. However, variations in positioning of the organ/patient with respect to treatment beams necessitate the use of an appreciable margin, potentially limiting dose escalation in many patients. To (1) reduce this margin and (2) test the hypothesis that the achievable level of dose escalation is patient dependent, a patient-specific, confidence-limited planning target volume (cl-PTV) was constructed using an adaptive radiotherapy (ART) process for prostate cancer treatment developed in-house. The potential dose escalation achievable with this ART process is quantified for both conformal radiotherapy (CRT) delivery and intensity-modulated radiotherapy (IMRT) delivery. MATERIAL AND METHODS Patients with organ confined prostate cancer were entered prospectively into an ART process developed in-house. This ART process has been designed to improve accuracy and precision of dose delivery, consequently enhancing dose escalation. In this process, a cl-PTV is constructed for each patient in the second week of treatment based upon on-line portal and CT images acquired during the first week of treatment. The treatment prescription dose, defined as the minimum dose to the cl-PTV, is selected based on predefined dose-volume constraints for rectum/bladder and derived from the pretreatment planning CT image. In addition, the treatment modality (CRT or IMRT) is determined based on the level of dose escalation achievable and the risk of inaccurate targeting. The potential for both dose escalation and the application of IMRT was evaluated by comparing the prescription doses delivered using the ART process, with the cl-PTV, to those in the traditional treatment process, with a conventional generic PTV. In addition, the distributions of potential geometric target underdosing and normal tissue overdosing were also calculated to evaluate the quality of the conventional treatment plans. RESULTS One hundred and fifty patients have been treated with the ART process. When compared to the treatment dose delivered with the conventional treatment process (generic PTV), an average 5% (2.5--10%) more dose could be delivered using the ART process with CRT, and 7.5% (2.5--15%) more dose could be delivered with IMRT. Of the 150 patients, 70% were treated to a minimum cl-PTV dose > or = 77.4 Gy (81.3 Gy ICRU isocenter dose). Dosimetric analysis revealed that 81 Gy to the cl-PTV (or 86.7 Gy ICRU) could be prescribed to at least 50% of patients if IMRT was applied using the ART process. In contrast, IMRT did not yield an obvious dose escalation gain if patients were treated using the generic PTV. Our results also demonstrate that the cl-PTV is significantly smaller than the conventional generic PTV for most patients, with a mean volume reduction of 24% (range, 5--43%). CONCLUSION These results support our hypothesis that the achievable level of dose escalation using ART is patient dependent. By using the ART process to develop a cl-PTV, one can (1) optimize the dose level, (2) increase the applicability of IMRT, and (3) improve the quality of dose delivery. The ART process provides the foundation to identify a suitable option (CRT or IMRT) for the delivery of a safe treatment and dose escalation. It is now our standard of practice for prostate cancer treatment.

The use of adaptive radiation therapy to reduce setup error: a prospective clinical study

PURPOSE Adaptive Radiation Therapy (ART) is a feedback treatment process that optimizes a patients treatment according to the patient specific information measured during the course of treatment. Utilizing an electronic portal imaging device (EPID) and a computer-controlled multileaf collimator (MLC), the ART process is currently being implemented in our clinic to improve the treatment accuracy by compensating for the treatment setup error. A prospective study was conducted to evaluate the feasibility and efficacy of the ART process for clinical use. METHODS AND MATERIALS The prospective study included 20 patients who underwent conventional radiotherapy on a linear accelerator equipped with an EPID and a MLC. No specific changes were made in the routine clinical procedures except daily portal images were obtained for each treatment field. Two-dimensional setup error for each treatment field was then measured offline using a software tool. The measured setup errors from initial treatment days were used to predict the systematic and random setup errors for each treatment field. An adjustment decision was made if the predicted systematic error was larger than or equal to 2 mm. Furthermore, the treatment field was extended if the predicted random setup error could not be effectively compensated by the predefined treatment setup margin. Instead of the conventional approach of patient repositioning, setup adjustment was implemented by reshaping the MLC field. The entire process from measuring setup error to reshaping the MLC field was performed offline through a computer network. After completion of a patients treatment, the systematic and random setup errors after adjustment were compared with those predicted prior to the adjustment. The accuracy of the adjustment, and the reliability and stability of the process were analyzed. RESULTS Treatment fields of 13 patients were modified to correct for systematic errors. The mean systematic error was 4 mm with a range of 2 to 7 mm before adjustment. It was reduced to 0.5 mm with a range of 0.2 to 1.4 mm after adjustment. There was no significant difference in random setup errors before and after adjustment. The ART process was found to be stable, as more than 95% of patient specific setup margins were predictable within 1 mm using the first four to nine fractions of treatment, confirming the feasibility of treatment plan reoptimization with the ART process. CONCLUSIONS The prospective study demonstrates that the ART process can be effectively implemented in routine clinical practice to improve treatment accuracy. This process is also ready to be further extended to reoptimize the treatment plan by incorporating the predicted patient specific setup variation.

Matched-Pair Analysis of Conformal High–Dose-Rate Brachytherapy Boost Versus External-Beam Radiation Therapy Alone for Locally Advanced Prostate Cancer

PURPOSE We performed a matched-pair analysis to compare our institutions experience in treating locally advanced prostate cancer with external-beam radiation therapy (EBRT) alone to EBRT in combination with conformal interstitial high-dose-rate (HDR) brachytherapy boosts (EBRT + HDR). MATERIALS AND METHODS From 1991 to 1998, 161 patients with locally advanced prostate cancer were prospectively treated with EBRT + HDR at William Beaumont Hospital, Royal Oak, Michigan. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen (PSA) level of >/= 10.0 ng/mL, Gleason score >/= 7, or clinical stage T2b to T3c. Pelvic EBRT (46.0 Gy) was supplemented with three (1991 through 1995) or two (1995 through 1998) ultrasound-guided transperineal interstitial iridium-192 HDR implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant. Each of the 161 EBRT + HDR patients was randomly matched with a unique EBRT-alone patient. Patients were matched according to PSA level, Gleason score, T stage, and follow-up duration. The median PSA follow-up was 2.5 years for both EBRT + HDR and EBRT alone. RESULTS EBRT + HDR patients demonstrated significantly lower PSA nadir levels (median, 0.4 ng/mL) compared with those receiving EBRT alone (median, 1.1 ng/mL). The 5-year biochemical control rates for EBRT + HDR versus EBRT-alone patients were 67% versus 44%, respectively (P <.001). On multivariate analyses, pretreatment PSA, Gleason score, T stage, and the use of EBRT alone were significantly associated with biochemical failure. Those patients in both treatment groups who experienced biochemical failure had a lower 5-year cause-specific survival rate than patients who were biochemically controlled (84% v 100%; P <.001). CONCLUSION Locally advanced prostate cancer patients treated with EBRT + HDR demonstrate improved biochemical control compared with those who are treated with conventional doses of EBRT alone.

Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer

OBJECTIVES To determine the factors associated with outcome by reviewing our institutions experience treating patients with external beam radiation therapy (RT) after radical prostatectomy. METHODS Sixty-one patients received RT to the prostatic fossa after radical prostatectomy for prostate cancer (median dose 59.4 Gy). Thirty-eight patients received adjuvant RT within 6 months of surgery for adverse pathologic findings only. Therapeutic RT was administered to 23 patients either for a persistently elevated postoperative prostate-specific antigen (PSA) level (n = 2), a rising PSA level more than 6 months after surgery (n = 9), or a biopsy-proven local recurrence (n = 12). Preoperative and preradiation PSA values, Gleason score, pathologic findings, patient age, total RT dose, and indication for RT were analyzed for their impact on biochemical control. The median follow-up was 48 months. RESULTS Patients treated with adjuvant RT achieved 3 and 5-year biochemical control rates of 84% and 67%, respectively. Multiple clinical, pathologic, and treatment-related factors were analyzed for an association with biochemical control. No variable was associated with 5-year outcome. The 5-year actuarial rate of biochemical control for patients treated with therapeutic RT was 16%. Multiple clinical, pathologic, and treatment-related factors were analyzed for an association with biochemical control. Only a pre-RT PSA level of 2 ng/mL or less was associated with an improved rate of biochemical control at 3 years (80% versus 27%, P = 0.001). However, at 5 years, this difference was not statistically significant. A separate analysis was performed to determine the prognostic factors associated with outcome for the entire group of patients. Only the indication for RT (adjuvant versus therapeutic) was associated with 5-year outcome. Patients treated with adjuvant RT had a statistically significant improvement in 5-year actuarial rates of biochemical control (67% versus 16%, P <0.001) and disease-free survival (66% versus 46%, P = 0.037) but not in overall survival. There were no statistically significant differences between patient groups with respect to age, preoperative PSA, Gleason score, pathologic T stage, median follow-up, and total RT dose. CONCLUSIONS At our institution, patients treated with adjuvant RT after prostatectomy for adverse pathologic findings achieved excellent rates of biochemical control that were significantly better than that of similar patients treated therapeutically for persistent or rising PSA or clinical local recurrence.

Conformal prostate brachytherapy: Initial experience of a phase I/II dose-escalating trial

PURPOSE To improve treatment results on prostatic adenocarcinoma, conformal radiation therapy (CRT) has been used. Two major drawbacks of external CRT are: (a) internal organ motion/daily set-up variations, and (b) exclusion of several patients for CRT based on poor geometrical relationships as identified by three dimensional (3D) treatment planning. To overcome the above problems, we began the first prospective Phase I/II dose-escalating clinical trial of conformal brachytherapy (CB) and concurrent external beam irradiation. METHODS AND MATERIALS Fifty-nine patients with T2b-T3c prostatic adenocarcinoma received 176 transperineal ultrasound-guided conformal high-dose rate (HDR) boost implants. All patients received concomitant external beam pelvic irradiation. Dose escalation of the three HDR-CB fractions proceeded as follows: 5.5 Gy (30 patients), 6 Gy (20 patients), and 6.5 Gy (9 patients). The CB dose was prescribed to the prostate contour as outlined using an online biplanar transrectal ultrasound probe. The urethra, anterior rectal wall, and prostate boundaries were identified individually and outlined at 5 mm intervals from the base to the apex of the gland. The CB using real-time ultrasound guidance with interactive online isodose distributions was performed on an outpatient basis. As needles were placed into the prostate, corrections for prostate displacement were recorded and the isodose distributions were recalculated to represent the new relationship between the needles, prostate, and normal structures. No computerized tomography (CT) planning or implant preplanning was required. RESULTS No patient was rejected based on poor geometrical relation of pelvic structures. In every implant performed, prostate displacement was noted. Craniocaudal motion of the gland ranged from 0.5-2.0 cm (mean = 1.0 cm), whereas lateral displacement was 0.1-0.4 cm. With the interactive online planning system, organ motion was immediately detected, accounted for, and corrected prior to each HDR treatment. The rectal dose has ranged from 45 to 87%, and the urethral dose from 97 to 112% of the prostate dose. It is significant to note that operator dependence has been completely removed because the interactive online planning system uniformly guides the physicians. CONCLUSIONS With ultrasound guidance and the interactive online dosimetry system, organ motion (as compared to external beam) is insignificant because it can be corrected during the procedure without increasing target volume margins. Common pitfalls of brachytherapy, including operator dependence and difficulty with reproducibility, have been eliminated with the intraoperative online planning system.

Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a phase I/II clinical trial.

PURPOSE To improve results for locally advanced prostate cancer, a prospective clinical trial of concurrent external beam irradiation and fractionated iridium-192 (Ir-192) high dose rate (HDR) conformal boost brachytherapy was initiated. METHODS AND MATERIALS Between November 1991 and February 1994, 99 implants were performed on 33 patients with prostatic adenocarcinoma at William Beaumont Hospital. Using AJCC staging criteria, 9 patients had T2b tumors, 17 patients had T2c tumors, and 7 patients had T3 disease. Patients were treated with (a) 45.6 Gy whole pelvis external irradiation and (b) three HDR fractions of 5.5 Gy each (18 patients) or 6 Gy each (15 patients) to the prostate. Transperineal needle implants using real-time ultrasound guidance with interactive on-line isodose distributions were performed on an outpatient basis during weeks 1, 2, and 3 of external irradiation. Acute toxicity was scored using the Radiation Therapy Oncology Group (RTOG) morbidity grading system. RESULTS This technique of concurrent external pelvic irradiation and conformal HDR brachytherapy was well tolerated. No significant intraoperative or perioperative complications occurred. Three patients (9%) experienced Grade 3 acute toxicity (two dysuria and one diarrhea). All toxicities were otherwise Grades 1 or 2 and were primarily as expected from pelvic external irradiation. Persistent implant-related toxicities included Grades 1-2 perineal pain (12%) and hematospermia (15%). Median follow-up time was 13 months. Serum prostatic-specific antigen (PSA) levels normalized in 91% of patients (29 out of 32) within 1-14 months (median 2.8 months) after irradiation. PSA levels were progressively decreasing in the other three patients at last measurement. Prospectively planned prostatic rebiopsies done at 18 months in the first 10 patients were negative in 9 out of 10 (90%). CONCLUSIONS Acute toxicity has been acceptable with this unique approach using conformal high dose rate Ir-192 boost brachytherapy with concurrent external irradiation. The initial tumor response as assessed by serial PSA measurement and rebiopsy is extremely encouraging. Dose escalation will proceed in accordance with the protocol guidelines. Further patient accrual and longer follow-up will allow comparison to other techniques.

Comparison of acute and late toxicities for three modern high-dose radiation treatment techniques for localized prostate cancer.

PURPOSE We compared acute and late genitourinary (GU) and gastrointestinal (GI) toxicities in prostate cancer patients treated with three different high-dose radiation techniques. METHODS AND MATERIALS A total of 1,903 patients with localized prostate cancer were treated with definitive RT at William Beaumont Hospital from 1992 to 2006: 22% with brachytherapy alone (BT), 55% with image-guided external beam (EB-IGRT), and 23% external beam with high-dose-rate brachytherapy boost (EBRT+HDR). Median dose with BT was 120 Gy for LDR and 38 Gy for HDR (9.5 Gy × 4). Median dose with EB-IGRT was 75.6 Gy (PTV) to prostate with or without seminal vesicles. For EBRT+HDR, the pelvis was treated to 46 Gy with an additional 19 Gy (9.5 Gy × 2) delivered via HDR. GI and GU toxicity was evaluated utilizing the NCI-CTC criteria (v.3.0). Median follow-up was 4.8 years. RESULTS The incidences of any acute ≥ Grade 2 GI or GU toxicities were 35%, 49%, and 55% for BT, EB-IGRT, and EBRT+HDR (p < 0.001). Any late GU toxicities ≥ Grade 2 were present in 22%, 21%, and 28% for BT, EB-IGRT, and EBRT+HDR (p = 0.01), respectively. Patients receiving EBRT+HDR had a higher incidence of urethral stricture and retention, whereas dysuria was most common in patients receiving BT. Any Grade ≥ 2 late GI toxicities were 2%, 20%, and 9% for BT, EB-IGRT, and EBRT+HDR (p < 0.001). Differences were most pronounced for rectal bleeding, with 3-year rates of 0.9%, 20%, and 6% (p < 0.001) for BT, EB-IGRT, and EBRT+HDR respectively. CONCLUSIONS Each of the three modern high-dose radiation techniques for localized prostate cancer offers a different toxicity profile. These data can help patients and physicians to make informed decisions regarding radiotherapy for prostate andenocarcinoma.

Adjuvant whole abdominopelvic irradiation for high risk endometrial carcinoma

Fifty-six patients with surgical Stage III or IV endometrial carcinoma, or earlier stage disease with two or more risk factors for peritoneal recurrence, were given postoperative whole abdomino-pelvic irradiation (WAPI) with nodal and vaginal boosts between November 1981 and May 1989. Mean age at diagnosis was 63 years. Twenty-seven patients were surgical Stage I-II, 17 Stage III, and 12 Stage IV. Thirty-seven (66%) had deep myometrial involvement, 34 (61%) had positive peritoneal cytology, 31 (55%) had high grade lesions, 20 (36%) had either serous-papillary or adenosquamous histologic variants, and 13 (23%) had up to 2 cm residual disease remaining after surgery. Mean overall follow-up was 45 months. The 7-year actuarial survival was 63.8% with a 7-year disease-free survival (DFS) of 60.9%. By surgical stage, the 7-year DSF was 77.1% for Stage I-II, 57.8% for Stage III, and 25.0% for Stage IV (p = 0.006). The 7-year DSF was 79.8% for those with lesions of Broders grade 1 or 2, and 46.9% for grades 3 or 4 (p = 0.001). Multivariate analysis demonstrated that of all covariates considered, only surgical stage and histologic grade had prognostic significance for survival and disease-free survival. Acute toxicity has been common but mild; chronic toxicity has been almost entirely subclinical with the exception of three cases of moderate to severe bowel toxicity. These results suggest that post-operative WAPI is a safe and efficacious treatment alternative for patients with surgical Stage I through III high-risk endometrial carcinoma.