Gregory K. Edmundson

Direct evidence that prostate tumors show high sensitivity to fractionation (low α/β ratio), similar to late-responding normal tissue

Abstract Purpose : A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low α/β ratio), more typical of the surrounding late-responding normal tissue. Methods and Materials : Earlier estimates of α/β for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. Results : The estimated value of α/β from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This α/β value is considerably less than typical values for tumors (≥8 Gy), and more comparable to values in surrounding late-responding normal tissues. Conclusions : This analysis provides strong supporting evidence that α/β values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.

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.

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

PURPOSE To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. METHODS AND MATERIALS Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. RESULTS The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. CONCLUSION Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

INTRAOPERATIVE PLANNING AND EVALUATION OF PERMANENT PROSTATE BRACHYTHERAPY: REPORT OF THE AMERICAN BRACHYTHERAPY SOCIETY

PURPOSE The preplanned technique used for permanent prostate brachytherapy has limitations that may be overcome by intraoperative planning. The goal of the American Brachytherapy Society (ABS) project was to assess the current intraoperative planning process and explore the potential for improvement in intraoperative treatment planning (ITP). METHODS AND MATERIALS Members of the ABS with expertise in ITP performed a literature review, reviewed their clinical experience with ITP, and explored the potential for improving the technique. RESULTS The ABS proposes the following terminology in regard to prostate planning process: *Preplanning--Creation of a plan a few days or weeks before the implant procedure. *Intraoperative planning--Treatment planning in the operating room (OR): the patient and transrectal ultrasound probe are not moved between the volume study and the seed insertion procedure. * Intraoperative preplanning--Creation of a plan in the OR just before the implant procedure, with immediate execution of the plan. *Interactive planning--Stepwise refinement of the treatment plan using computerized dose calculations derived from image-based needle position feedback. *Dynamic dose calculation--Constant updating of dose distribution calculations using continuous deposited seed position feedback. Both intraoperative preplanning and interactive planning are currently feasible and commercially available and may help to overcome many of the limitations of the preplanning technique. Dosimetric feedback based on imaged needle positions can be used to modify the ITP. However, the dynamic changes in prostate size and shape and in seed position that occur during the implant are not yet quantifiable with current technology, and ITP does not obviate the need for postimplant dosimetric analysis. The major current limitation of ITP is the inability to localize the seeds in relation to the prostate. Dynamic dose calculation can become a reality once these issues are solved. Future advances can be expected in methods of enhancing seed identification, in imaging techniques, and in the development of better source delivery systems. Additionally, ITP should be correlated with outcome studies, using dosimetric, toxicity, and efficacy endpoints. CONCLUSION ITP addresses many of the limitations of current permanent prostate brachytherapy and has some advantages over the preplanned technique. Further technologic advancement will be needed to achieve dynamic real-time calculation of dose distribution from implanted sources, with constant updating to allow modification of subsequent seed placement and consistent, ideal dose distribution within the target volume.

Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial-breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy ☆

PURPOSE We present our ongoing clinical experience utilizing 3D conformal radiation therapy (3D-CRT) to deliver partial-breast irradiation (PBI) in patients with early-stage breast cancer treated with breast-conserving therapy. MATERIALS AND METHODS Thirty-one patients referred for postoperative radiation therapy after lumpectomy were treated with PBI using our previously reported 3D-CRT technique. Ninety-four percent of patients had surgical clips outlining the lumpectomy cavity (mean: 6 clips). The clinical target volume (CTV) consisted of the lumpectomy cavity plus a 10-mm margin in 9 patients and 15-mm margin in 22 (median: 15 mm). The planning target volume consisted of the CTV plus a 10-mm margin for breathing motion and treatment setup uncertainties. The prescribed dose (PD) was 34 or 38.5 Gy (6 patients and 25 patients, respectively) in 10 fractions b.i.d. separated by 6 h and delivered in 5 consecutive days. Patients were treated in the supine position with 3-5 beams (mean: 4) designed to irradiate the CTV with <10% inhomogeneity and a comparable or lower dose to the heart, lung, and contralateral breast compared with standard whole-breast tangents. The median follow-up duration is 10 months (range: 1-30 months). Four patients have been followed >2 years, 6 >1.5 years, and 5 >1 year. The remaining 16 patients have been followed <12 months. RESULTS No skin changes greater than Grade 1 erythema were noted during treatment. At the initial 4-8-week follow-up visit, 19 patients (61%) experienced Grade 1 toxicity and 3 patients (10%) Grade 2 toxicity. No Grade 3 toxicities were observed. The remaining 9 patients (29%) had no observable radiation effects. Cosmetic results were rated as good/excellent in all evaluable patients at 6 months (n = 3), 12 months (n = 5), 18 months (n = 6), and in the 4 evaluable patients at >2 years after treatment. The mean coverage of the CTV by the 100% isodose line (IDL) was 98% (range: 54-100%, median: 100%) and by the 95% IDL, 100% (range: 99-100%). The mean coverage of the planning target volume by the 95% IDL was 100% (range: 97-100%). The mean percentage of the breast receiving 100% of the PD was 23% (range: 14-39%). The mean percentage of the breast receiving 50% of the PD was 47% (range: 34-60%). CONCLUSIONS Utilizing 3D-CRT to deliver PBI is technically feasible, and acute toxicity to date has been minimal. Additional follow-up will be needed to assess the long-term effects of these larger fraction sizes on normal-tissue sequelae and the impact of this fractionation schedule on treatment efficacy.

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.

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont Phase II dose-escalating trial

PURPOSE We analyzed our institutions experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach. METHODS AND MATERIALS From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) >/= 10.0 ng/ml, Gleason score >/= 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS The pretreatment PSA level was >/= 10.0 ng/ml in 51% of patients. The biopsy Gleason score was >/= 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2-4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity. CONCLUSION Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.

Low-dose-rate brachytherapy as the sole radiation modality in the management of patients with early-stage breast cancer treated with breast-conserving therapy: Preliminary results of a pilot trial

PURPOSE We present the preliminary findings of our in-house protocol treating the tumor bed alone after lumpectomy with low-dose-rate (LDR) interstitial brachytherapy in selected patients with early-stage breast cancer treated with breast-conserving therapy (BCT). METHODS AND MATERIALS Since March 1, 1993, 60 women with early-stage breast cancer were entered into a protocol of tumor bed irradiation only using an interstitial LDR implant with iodine-125. Patients were eligible if the tumor was < or = 3 cm, margins were > or = 2 mm, there was no extensive intraductal component, the axilla was surgically staged, and a postoperative mammogram was performed. Implants were placed using a standardized template either at the time of reexcision or shortly after lumpectomy. A total of 50 Gy was delivered at 0.52 Gy/h over a period of 96 h to the lumpectomy bed plus a 2-cm margin. Perioperative complications, cosmetic outcome, and local control were assessed. RESULTS The median follow-up for all patients is 20 months. Three patients experienced minimal perioperative pain that required temporary nonnarcotic analgesics. There have been four postoperative infections which resolved with oral antibiotics. No significant skin reactions related to the implant were noted and no patient experienced impaired would healing. Early cosmetic results reveal minimal changes consisting of transient hyperpigmentation of the skin at the puncture sites and temporary induration in the tumor bed. Good to excellent cosmetic results were noted in all 19 patients followed up a minimum of 24 months posttherapy. To date, 51 women have obtained 6-12-month follow-up mammograms and no recurrences have been noted. All patients currently have no physical signs of recurrence, and no patient has failed regionally or distantly. CONCLUSION Treatment of the tumor bed alone with LDR interstitial brachytherapy appears to be well tolerated, and early results are promising. Long-term follow-up of these patients is necessary to establish the equivalence of this treatment approach compared to standard BCT, however.

Dose-volume analysis for quality assurance of interstitial brachytherapy for breast cancer

PURPOSE/OBJECTIVE The use of brachytherapy in the management of breast cancer has increased significantly over the past several years. Unfortunately, few techniques have been developed to compare dosimetric quality and target volume coverage concurrently. We present a new method of implant evaluation that incorporates computed tomography-based three-dimensional (3D) dose-volume analysis with traditional measures of brachytherapy quality. Analyses performed in this fashion will be needed to ultimately assist in determining the efficacy of breast implants. METHODS AND MATERIALS Since March of 1993, brachytherapy has been used as the sole radiation modality after lumpectomy in selected protocol patients with early-stage breast cancer treated with breast-conserving therapy. Eight patients treated with high-dose-rate (HDR) brachytherapy who had surgical clips outlining the lumpectomy cavity and underwent computed tomography (CT) scanning after implant placement were selected for this study. For each patient, the postimplant CT dataset was transferred to a 3D treatment planning system. The lumpectomy cavity, target volume (lumpectomy cavity plus a 1-cm margin), and entire breast were outlined on each axial slice. Once all volumes were entered, the programmed HDR brachytherapy source positions and dwell times were imported into the 3D planning system. Using the tools provided by the 3D planning system, the implant dataset was then registered to the visible implant template in the CT dataset. The distribution of the implant dose was analyzed with respect to defined volumes via dose-volume histograms (DVH). Isodose surfaces, the dose homogeneity index, and dosimetric coverage of the defined volumes were calculated and contrasted. All patients received 32 Gy to the entire implanted volume in 8 fractions of 4 Gy over 4 days. RESULTS Three-plane implants were used for 7 patients and a two-plane implant for 1 patient. The median number of needles per implant was 16.5 (range 11-18). Despite visual verification by the treating physician that surgical clips (with an appropriate margin) were within the boundaries of the implant needles, the median proportion of the lumpectomy cavity that received the prescribed dose was only 87% (range 73-98%). With respect to the target volume, a median of only 68% (range 56-81%) of this volume received 100% of the prescribed dose. On average, the minimum dose received by at least 90% of the target volume was 22 Gy (range 17.3-26.9), which corresponds to 69% of the prescribed dose. CONCLUSION Preliminary results using our new technique to evaluate implant quality with CT-based 3D dose-volume analysis appear promising. Dosimetric quality and target volume coverage can be concurrently analyzed, allowing the possibility of evaluating implants prospectively. Considering that target volume coverage may be suboptimal even after radiographically verifying accurate implant placement, techniques similar to this need to be developed to ultimately determine the true efficacy of brachytherapy in the management of breast cancer.

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.