Hypofractionated conformal HDR brachytherapy in hormone naïve men with localized prostate cancer. Is escalation to very high biologically equivalent dose beneficial in all prognostic risk groups?

PURPOSE: To analyze the long-term effect of local dose escalation using conformal hypofractionated high-dose-rate brachytherapy (HDR-BT) boost and pelvic external-beam radiation therapy (EBRT) in hormone-naïve men with localized prostate cancer. PATIENTS AND METHODS: A total of 579 men were consecutively treated with pelvic EBRT and dose escalating HDR-BT since 1986 in two prospective trials: 378 patients at William Beaumont Hospital (1991-2002), and 201 patients at Kiel University (1986-1999). BT optimization was done modulating both, the dwell times and spatial source positions. A short course of neoadjuvant/concurrent androgen deprivation therapy was given to 222 patients. Hormone-naïve patients only (n = 324) with a follow-up > or = 18 months were analyzed. All patients had at least one poor prognostic factor (stage > or = T2b, Gleason Score > or = 7, pretreatment prostate-specific antigen [PSA] > or = 10 ng/ml): any one factor 122 patients, any two factors 122 patients, and three factors 80 patients. This cohort was stratified by equivalent dose (ED): dose level 1, < or = 94 Gy, n = 58, and dose level 2, > 94 Gy, n = 266, assuming an alpha/beta ratio of 1.2. The ASTRO definition for biochemical failure was used. RESULTS: Mean follow-up was 5.3 years (1.5-13.9 years). For all 324 patients, the 5-year biochemical control (BC) rate was 79%. Cancer-specific survival was 98%, and overall survival 90%. Similar analysis by institution demonstrated no difference in outcomes. For the entire cohort of hormone-naïve men, dose escalation to > 94 Gy resulted in a better 5-year BC of 59% versus 85% (p < 0.001). Discriminating by risk group a striking dose escalation effect was seen in the groups with two or three poor prognostic factors (p = 0.022 and < 0.001, respectively). In the group with only one poor prognostic factor, no statistical difference could be detected questioning the need for ED > 94 Gy. CONCLUSION: The results demonstrate that conformal HDR-BT is a successful method for delivering very high radiation dose to the prostate. The ability to escalate dose to ED > 94 Gy was reflected in improved long-term outcomes in terms of BC, significantly for those patients with two or three poor prognostic factors reaching BC rates of 85%.

Accelerated partial breast irradiation: a dosimetric comparison of three different techniques.

PURPOSE: We report the first single-institutional dosimetric comparison of patients treated with three forms of accelerated partial breast irradiation: interstitial HDR brachytherapy, the MammoSite balloon apparatus, and 3D conformal external beam quadrant irradiation (3D-CRT). METHODS: A retrospective dosimetric comparison of interstitial HDR brachytherapy, MammoSite balloon brachytherapy, and 3D-CRT was performed. Thirty patients including 10 from each treatment technique were included for a dosimetric comparison of the dose received by the ipsilateral breast, PTV, heart, and ipsilateral lung. Interstitial patients were treated with 4 Gy in 8 fractions to 32 Gy, and the MammoSite patients were treated with 3.4 Gy in 10 fractions to 34 Gy. 3D-CRT patients were treated with 3.85 Gy in 10 fractions to 38.5 Gy using multiple isocentric beams. The CT images from simulation or implant evaluation were transferred into our 3D treatment planning software. The lumpectomy cavities were outlined for every patient, except the MammoSite patients, where the cavity was defined by the balloon edge. The PTV was constructed as a uniform expansion of 1.5 cm for all interstitial HDR patients, 1.0 cm for the MammoSite patients, and a 1.0 cm expansion in addition to the CTV expansion of 1.0 cm (n=2), and 1.5 cm (n=8) for the 3D-CRT patients. The CTV expansion for 3D-CRT and the PTV expansion for the brachytherapy patients were limited to the chest wall and skin. Normal structures including both ipsilateral lung and breast and heart for left-sided lesions were outlined. The lumpectomy cavity was subtracted from the PTV and normal breast tissue for evaluation. To evaluate dose to the ipsilateral breast and lung, PTV, and heart, a dose-volume histogram (DVH) analysis was performed. All histograms were normalized to the volume of the structure (i.e., expressed as percent volume). RESULTS: The average percentage of the breast receiving 100% and 50% of the prescribed dose (PD) was higher in the 3D-CRT group (24% and 48%, respectively) compared with the MammoSite (5% and 18%, respectively) and interstitial patients (10% and 26%, respectively). Improved coverage of the PTV was noted in the 3D-CRT plans compared with the MammoSite and interstitial HDR plans. With the interstitial HDR technique, 58% of the PTV received 100% of the PD compared with 76% with MammoSite and 100% with 3D-CRT techniques. The percentage of the PTV receiving 90% of the PD was 68%, 91%, and 100% for the interstitial HDR, MammoSite, and 3D-CRT patients, respectively. The ipsilateral lung V20 was slightly higher for 3D-CRT at 5% compared with 0% for both brachytherapy techniques. CONCLUSION: In those treated with 3D-CRT, coverage of the PTV was better with 3D-CRT but varied with the definition used. At the coverage at 90% of the PD, no difference was observed between 3D-CRT and MammoSite (which were both better than interstitial). 3D-CRT resulted in better coverage of the PTV compared with MammoSite or interstitial brachytherapy techniques. Better PTV coverage with 3D-CRT came at the cost of a higher integral dose to the remaining normal breast. Dosimetrically, the best partial breast irradiation technique appears to depend on the clinical situation. Of the brachytherapy techniques, MammoSite appears to be superior in PTV coverage. When comparing MammoSite vs. 3D-CRT PTV coverage at 90% of the PD, the difference was not significantly different.

Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer.

PURPOSE: The aim of this study is to analyze, during the prostate-specific antigen (PSA) era, the long-term outcome of patients treated with conformal high-dose-rate (HDR) brachytherapy boost to the prostate with or without androgen deprivation therapy (ADT) when patients are stratified by risk factors for failure. METHODS AND MATERIALS: Between 1986 and 2000, 611 patients were treated for clinically localized prostate cancer in three prospective trials of external beam radiation therapy (EBRT) and dose-escalating HDR brachytherapy (BT) boost. There were 104 patients treated at Seattle, 198 at Kiel University, and 309 at William Beaumont Hospital. Of the 611 patients, 177 received a short course of neoadjuvant/concurrent ADT. The patients were divided into three risk groups. Group I, comprised of 46 patients, had stage < or =T2a, Gleason score (GS) < or = 6, and initial PSA (iPSA) < or = 10 ng/mL. Group II comprised 188 patients with stage > or =T2b, GS > or = 7, and iPSA > or = 10, with any one factor higher. Group III included 359 patients with any two risk factors higher. The American Society for Therapeutic Radiology and Oncology definition for biochemical failure was used. RESULTS: The mean follow-up was 5 years (range, 0.2-15.3). For the 611 patients, the 5-year and 10-year biochemical control (BC) rates were 77% and 73%, disease-free survival (DFS) was 67% and 49%, and cause-specific survival (CSS) was 96% and 92%, respectively. BC at 5 years for Group I patients was 96%, for Group II 88%, and for Group III patients 69%. CSS at 5 years was 100% in Group I, 99% in Group II, and 95% in Group III patients. In univariate and multiple regression analyses for BC, risk group, stage, iPSA, and GS were significant in predicting failure. However, age, follow-up interval, and ADT did not. CONCLUSIONS: EBRT with HDR-BT produced excellent long-term outcomes in terms of BC, DFS, and CSS in patients with prostate cancer even for those at highest risk. Conformal HDR-BT is both a precise dose delivery system and an effective treatment for both favorable and unfavorable prostate cancer. The addition of a short course of neoadjuvant/concurrent ADT failed to improve outcome. The results were similar at all three institutions, giving credence to the reproducibility of the brachytherapy treatment.

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.

High dose rate brachytherapy in the treatment of prostate cancer.

The optimal treatment of patients with localized prostate cancer remains controversial. Significant clinical data are available, however, demonstrating that patients treated with radiation therapy (RT) have a significantly better outcome as the dose to the gland is increased. What remains debatable, however, is how to best deliver these higher doses of RT without significantly increasing normal tissue toxicities. Conformal high dose rate brachytherapy (C-HDR BT) represents an alternative means of precise dose delivery that offers similar tumoricidal effects as three-dimensional (3D) conformal external beam radiotherapy (EBRT) or permanent interstitial prostate seed implants with potential additional advantages. Since C-HDR BT consists of temporarily placing afterloading needles or catheters directly into the prostate gland under real-time ultrasound guidance, a steep dose gradient between the prostate and adjacent normal tissues can be generated that is minimally affected by organ motion and edema or treatment setup uncertainties. The ability to control the amount of time the single HDR radioactive source "dwells" at each position along the length of each brachytherapy catheter further enhances the conformity of the dose. In addition, recent radiobiological data on prostate cancer treatment suggest that C-HDR BT should produce tumor control and late normal tissue side effects that are at least as good as achieved with conventional fractionation, with the additional possibility that acute side effects might be reduced. Published data from several groups performing C-HDR BT as boosts in patients with locally advanced disease have supported these assumptions. Combined with the physical advantages discussed above, C-HDR BT should provide similar tumor control as 3D conformal EBRT with the added advantages of reduced treatment times, less acute toxicity, and no additional technological requirements to account and correct for treatment setup uncertainties and organ motion. Due to the success of C-HDR BT as boost treatment in locally advanced disease, this form of radiation treatment has recently been applied to low-risk prostate cancer patients as an alternative brachytherapy technique to permanent interstitial seed implantation. Advantages in this setting include an improved ability to define and deliver the prescribed dose, a significantly shortened treatment schedule compared to 3D conformal EBRT, and the fact that patients are not radioactive after implantation.

The role of high-dose rate brachytherapy in locally advanced prostate cancer.

Although the optimal management of patients with locally advanced prostate cancer remains undefined, sufficient clinical data have emerged showing that patients treated with radiation therapy (RT) have a significantly better outcome as the dose to the gland is escalated. What remains unresolved, however, is how to best deliver these higher tumoricidal doses of RT. Conformal high-dose rate brachytherapy (C-HDR BT) is an alternative means of precise dose escalation that offers similar tumoricidal effects as 3-dimensional (3D) conformal external beam radiotherapy (EBRT) with potential additional advantages. By placing HDR afterloading needles directly into the prostate gland under real-time ultrasound guidance, a steep dose gradient between the prostate and adjacent normal tissues can be generated that is unaffected by organ motion and edema or treatment setup uncertainties. The ability to control the amount of time the single radioactive source dwells at each position along the length of each brachytherapy catheter further enhances the conformity of the dose. In addition, recent radiobiologic data on prostate cancer treatment suggest that the alpha/beta ratio for tumor control is similar to (or possibly even smaller) than that for surrounding late-responding normal tissues. If true, hypofractionation (as practiced with C-HDR BT combined with EBRT) would be expected to produce tumor control and late sequelae that are at least as good as achieved with conventional fractionation, with the additional possibility that early sequelae might be reduced. Recent data from several groups performing C-HDR BT in patients with locally advanced disease have confirmed these assumptions. Combined with the physical advantages discussed earlier, C-HDR BT as a means of dose escalation should provide similar tumor control as 3D conformal EBRT with the added advantages of reduced treatment times, less acute toxicity, and no additional technological requirements to account and correct for treatment setup uncertainties and organ motion. The issues that remain unresolved with this technique (as with other methods of dose escalation) revolve around the amount of additional dose required to provide optimal tumor control, the role of androgen deprivation in the management of patients with locally advanced disease, and whether the regional lymphatics should be irradiated.

An Internet-ready database for prospective randomized clinical trials of high-dose-rate brachytherapy for adenocarcinoma of the prostate.

PURPOSE: To demonstrate a new interactive Internet-ready database for prospective clinical trials in high-dose-rate (HDR) brachytherapy for prostate cancer. METHODS AND MATERIALS: An Internet-ready database was created that allows common data acquisition and statistical analysis. Patient anonymity and confidentiality are preserved. These data forms include all common elements found from a survey of the databases. The forms allow the user to view patient data in a view-only or edit mode. Eight linked forms document patient data before and after receiving HDR therapy. The pretreatment forms are divided into four categories: staging, comorbid diseases, external beam radiotherapy data, and signs and symptoms. The posttreatment forms separate data by HDR implant information, HDR medications, posttreatment signs and symptoms, and follow-up data. The forms were tested for clinical usefulness. CONCLUSION: This Internet-based database enables the user to record and later analyze all relevant medical data and may become a reliable instrument for the follow-up of patients and evaluation of treatment results.

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.

Dosimetric characteristics of the MammoSite RTS, a new breast brachytherapy applicator.

PURPOSE: A new device has been developed with the goal of making breast-conserving therapy more widely available, by making breast brachytherapy as monotherapy simpler and more accurate. This is the first published report on the dosimetric characteristics of this device. MATERIALS AND METHODS: The experience of a single institution participating in a multi-institutional trial is reported. Twelve patients were enrolled, of whom 8 were treated. Computed tomography scans of all 12 patients were obtained before initiation of treatment. A commercial three-dimensional planning system was used for retrospective detailed analysis of dosimetry, including dose-volume histograms and, in selected patients, skin dose distributions. These data were compared to those of a similar group of patients, analyzed previously, that was treated with interstitial high-dose-rate brachytherapy. RESULTS: Compared with interstitial brachytherapy, the MammoSite device resulted in a treatment dose that was less uniform, with a mean dose homogeneity index of 0.77 vs. 0.93. Coverage and reproducibility were improved, with a mean D90 (minimum dose to 90% of target volume) of 90.0% of prescribed dose (SD 0.5, range: 89.2-90.8%) vs. 69.8% (SD 7.3, range: 61.1-83.5%) for interstitial brachytherapy. CONCLUSIONS: Reproducible placement was easily achieved in this very early experience, indicating a much smaller "learning curve" than for interstitial brachytherapy. Because skin doses can be increased with the use of this device, caution is indicated, although simple maneuvers can significantly reduce skin dose.

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

PURPOSE: A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low alpha/beta ratio), more typical of the surrounding late-responding normal tissue. METHODS AND MATERIALS: Earlier estimates of alpha/beta 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 alpha/beta 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 alpha/beta value is considerably less than typical values for tumors (> or =8 Gy), and more comparable to values in surrounding late-responding normal tissues. CONCLUSIONS: This analysis provides strong supporting evidence that alpha/beta 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.

The emerging role of brachytherapy in the management of patients with breast cancer.

Brachytherapy remains an important treatment option in the overall management of patients with breast cancer. In patients treated with breast conserving therapy (BCT), prospective randomized trials have established the advantage of a boost in most patients. Interstitial brachytherapy has consistently been shown to provide an important option to boost patients, and in certain clinical settings it may provide a more appropriate means of dose delivery. The concept of delivering partial breast irradiation with accelerated treatment schedules has now provided brachytherapy a new and exciting role in the management of patients treated with BCT. There are now data available from several phase I/II studies suggesting that brachytherapy alone can be used safely and reproducibly in this setting in order to reduce the time, inconvenience, and toxicity associated with traditional radiation therapy. Although preliminary results with brachytherapy alone are encouraging, proper patient selection and optimal dosimetric guidelines must be employed in order to achieve success when used in this setting.