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The two forms of brachytherapy performed today for the treatment of prostate cancer are low dose rate in the form of permanent seeds and High Dose Rate (HDR) temporary implants or HDR Brachytherapy. Our physicians did hundreds of permanent seed implants before switching to HDR in 1991, for reasons explained elsewhere in this website. To date, our center has done over 3,000 HDR brachytherapy implants for prostate cancer.
HDR Monotherapy is used for patients whose disease is believed to be confined to the prostate or immediate surrounding tissues (just beyond the covering or "capsule" of the prostate). Our HDR Monotherapy prostate protocol was developed in 1996 for patients who, for one reason or another, were not candidates for combined HDR and EBRT. We reasoned that if permanent seeds could be used without EBRT so could HDR. We subsequently observed that HDR Monotherapy for prostate cancer was a safe and effective treatment and thus began our HDR Monotherapy program. We have treated nearly 500 patients with HDR Monotherapy and it is now a routinely recommended treatment option at CET. Our results have shown excellent clinical control of disease and few side effects.
Our protocol is designed to minimize side effects by giving treatment in a series of two "implant" procedures, performed approximately one week apart. Three HDR treatments (called "fractions") are given with each implant so a total of six fractions completes the course of treatment. Since the radiation is delivered quickly, the acute radiation reactions come and go quickly. The tumor control rate (patient without clinical evidence of disease or PSA progression) is more than 95%.
Combined HDR brachytherapy and EBRT is used for patients with locally more advanced disease within or around the prostate, those with higher PSA levels or higher pathology (Gleason 8-10) grade. Delivery of EBRT expands the area of treatment beyond the prostate into other regions of the pelvis where microscopic deposits of disease may be present but undetected. Combined HDR and EBRT therapy patients undergo two HDR implants a week apart with two HDR radiation treatments (also called fractions) per implant for a total of four HDR treatments. Approximately 2 weeks later a short (4-5 weeks) course of EBRT (Monday through Friday) is given.
Our published results on patients followed for 10 years are among the best reported in the literature. We have shown 90% clinical control of disease and high rates of freedom from PSA progression (a rising PSA) that vary according to the severity of disease.
Between January 1996 and December 2003, 117 consecutive patients (median age 64 years) were treated with a series of 2 HDR implants to minimize injury to normal tissue. The procedures were performed approximately 1 week apart to allow recovery of normal tissue effects of treatment. Three doses of HDR (6.75-7.25 Gy) were delivered during each implant. The risk group characteristics were T1c (82%) and T2 (18%), Gleason 6(94%) and 7(6%), PSA <10(84%) and 10-20(16%). The risk group profile was low in 75% and intermediate in 25% of cases. The total HDR dose was escalated from 36 to 43.5 Gy over the course of our experience, since we observed excellent tolerance to therapy. The planning volume was calculated at least 5mm beyond the prostate capsule in order to encompass possible microscopic extensions of disease. The posterior margin or treatment varied according to the proximity of the anterior rectal wall to minimize side effects. The normal tissue dose constraints (limits) were anterior rectum 80% (of the prescription dose), bladder 85%, and urethra 108%. Median follow-up duration was 2 years and the mean was 2.5 years. Three different definitions of PSA progression were studied. They were the ASTRO definition (3 consecutive rises), two consecutive rises of at least 0.5 ng/ml, and nadir +2 ng/ml. Morbidity analysis was based upon RTOG criteria.
The Kaplan Meier PSA progression free survival rates are identical at 5 and 8 years (0.96 ASTRO, 0.94 nadir + 2, and 0.98 two rises of >0.5 ng/ml). All but one patient had clinical disease control. Upon further follow-up, the two patients who were ASTRO definition failures did not have PSA progression. In other words, the PSA elevations were transient (PSA bounce) and not true failures. The cause specific survival was 100%. That means no one has died of prostate cancer. The Radiation Therapy Oncology Group (RTOG) grade 1-4 scale for measuring late morbidity revealed minimal GI side effects. Only one patient, who had ulcerative colitis before therapy, had grade 1 rectal symptoms. The late urinary morbidity was 2 grade 2, 4 grade 3 and zero grade 4. The grade 3 cases consisted of 1 patient who underwent urethral dilation for a stricture, 2 patients who performed self-catheterization, and 1 patient had a laser transurethral resection for benign prostate hypertrophy (BPH).
The CET HDR Monotherapy protocol is safe and effective therapy for low and early intermediate risk group prostate cancer.
HDR monotherapy reliably delivered the dose to the prostate target, known as the clinical treatment volume (CTV). The therapeutic dose known as the planning treatment volume (PTV) was delivered to a 5 mm margin beyond the prostate and it included part of the seminal vesicles closest to the prostate. The dose at the prostate capsule was approximately 110% of the target dose. The dose to the rectum, urethra, and bladder were given as prescribed.
Advantages of HDR Monotherapy
There appear to be fewer side effects with HDR monotherapy than with combined HDR and EBRT. A formal comparative statistical study is underway to confirm our impression. Doses to both the target and nearby tissues are known before radiation given and there is no radiation exposure to other persons. The treatment is accurately delivered in minutes with the patient and implant in the same position as when the planning images were obtained. The implant is checked with radiographs or fluoroscopy before each treatment to ensure catheter position is correct. HDR reliably delivers the dose to a prescribed distance beyond the prostate capsule and there is no concern about shifting or migrating seeds. The ability to control the HDR dwell times (the location and time the source spends at each location within the implant) is thus like having a supply of infinitely variable strength seeds to insert at precisely measured positions within the prostate. The dose to 90% of the prostate (called the D90 for permanent seeds) is always 105-120% with HDR. The volume of the prostate covered by the 100% dose (V100) is always 97% or better. A small volume (2-3%) is purposely given slightly lower doses to protect the urethra where it enters and leaves the prostate. Thus, unlike the permanent seeds literature, the measures of HDR dose always demonstrate complete coverage of the target and excellent protection of the normal organs.
The article describes a series of 209 consecutive patients treated with combined HDR brachytherapy and EBRT during years 1991 and 1998. The median follow-up was 7.25 years. None of the patients received androgen deprivation therapy (hormone therapy). The patients were divided for analysis into three risk groups:
Low (Stage T2a or less, Gleason score <6, and PSA <10 ng/mL)
Intermediate (Stage T2b or T2c, Gleason 7, or PSA 10–20 ng/mL)
High (Stage T3, Gleason score 8–10, and PSA level >20)
Four definitions of PSA progression were assessed and then compared for evidence of clinical failure. The rate of general clinical control for the entire group was 90% (188 of 209). The overall survival rate was 79%, and the cause-specific survival rate was 97%. The PSA progression free survival (ASTRO definition) rate was 90% for low, 87% for intermediate, and 69% for high-risk groups. The rate of late urinary morbidity was 6.7 Grade 3 was 1% Grade 4. There was no late Grade 3 or 4 rectal morbidity. The sexual potency preservation rate was 67%.
These 10 year results show that HDR and EBRT is safe and effective treatment for all stages and risk groups of prostate cancer and that the CET method compares favorably with other therapeutic alternatives.
Long Term Results With and Without Androgen Deprivation
We have presented the results of a study that compares the outcome of combined HDR and EBRT when a short course of androgen deprivation therapy was also used. It asks the question of whether androgen suppression improves the outcome with HDR brachytherapy and it also doubled the number of patients studied (with long term follow up) treated with the HDR and EBRT at California Endocurietherapy. The results have been presented at national meetings: 1) American Brachytherapy Society (ABS), San Francisco 2005 2) American Society for Therapeutic Radiation and Oncology, Denver 2005
LONG TERM RESULTS OF HIGH DOSE RATE BRACHYTHERAPY AND EXTERNAL BEAM WITH AND WITHOUT ANDROGEN SUPPRESSION FOR PROSTATE CANCER: D. Jeffrey Demanes, M.D., Gillian Altieri, C.M.D., David Brandt, M.A., Marie-Claire Barnaba, MSN., Pat Skoolisariyaporn M.S.., Lionel Schour, M.D. and Dennis R. Hill, M.D.
We reported the long term outcome of High Dose Rate (HDR) brachytherapy and external beam radiation therapy (EBRT) with and without short-term (6 months) neoadjuvant and concomitant androgen deprivation therapy (ADT).
Between Sept. 1991 and Dec. 1998, 411 consecutive patients were treated with 4 fractions HDR (5-6G) and 36-39.6Gy (the dose was increased over time as we observed that side effects were low). The study was prospective, but it was not randomized for androgen deprivation therapy (ADT). It compared patients treated with the same HDR and EBRT protocol with ADT as the only known variable. There were 200 patients in the "ADT group" (20% low, 48% intermediate, and 32% high risk) and 211 in the “no ADT "(33% low, 44% intermediate, 23% high risk). A comparison of treatment parameters revealed that patients who received ADT were more likely to be in a higher risk group. However, we divided patients into risk groups (called stratification) for analysis to balance the major prognostic factors. Also whole pelvic EBRT was given to 20% of the "ADT group" and 1.5% “no ADT group” (although other studies of HDR have shown no benefit to treatment of the whole pelvis compared to prostate only radiation therapy. The ASTRO definition of failure was used to define PSA progression. The median follow up was 7 years. General clinical failure end points were local or distant failure, PSA >25, or placement on androgen deprivation. General clinical control was the inverse.
The ASTRO PSA progression free survival (PSA-PFS) for all patients at 8 years was 85% and by risk group: low 93%, intermediate 86%, and high 71%. Low and intermediate risk groups were not statistically different from one another but they both did statistically better than the high risk group. An overall group comparison between "ADT group" and “no ADT group” revealed no significant difference in general clinical control (89% vs. 89%), PSA-PSF (86% vs. 83%) or cause specific survival (97% vs. 97%). The clinical local control (no evidence of recurrence in the prostate) rate was 99%. PSA progression was no difference between "ADT group" and “no ADT group” despite the higher rate of whole pelvic radiation for the "ADT group".
HDR brachytherapy and EBRT is a safe and effective treatment for all risk groups of patients with prostate cancer. Unlike the randomized trials that use EBRT without brachytherapy, the outcome stratified by risk group was not improved by the use of androgen deprivation therapy (ADT). Long term follow up of the CET HDR brachytherapy and EBRT patients shows the PSA progression free survival for low and intermediate risk group patients to be excellent. High risk group patients also have good control rates compared to other treatment approaches. Lack of randomization in the study means that some degree of case selection bias cannot be excluded, but our results suggest further study of ADT with HDR will be required to demonstrate which risk groups of patients, if any, will benefit from ADT.
1. Stage T1c, T2a, or small T2b (limited findings on digital rectal exam)
2. PSA < 15 (as long as the PSA doubling rate is > 1 year)
3. Gleason 2-7 (3+4 not 4+3 and it involves < 50% biopsy specimen)
The above criteria are applied to patients on an individual case basis. Most patients with low risk group disease (T1c or T2a, Gleason 6 or less, and PSA <10) will probably be candidates for HDR monotherapy. Some patients categorization as intermediate risk group will be also considered candidates. For example, a patient with Gleason score of 3+4=7, a small palpable tumor (T2a or T2b), and a PSA < 15 would be consider a candidate for HDR monotherapy, if a only small percentage of the biopsy specimen is positive and the MRI indicates a low volume of disease and no extracapsular extension.
Certain patients with prior radiation (external beam or permanent seeds) who have biopsy proven evidence of persistent disease may be candidates for "salvage" HDR monotherapy.
|Fig 1: This patient is receiving his treatment. The afterloader is in the lower right corner.|
|Fig 2: These four images are used to evaluate the implant using the 3D CT based software. The upper left image shows the implant in 3D. The physician can rotate the implant to assess the radiation coverage by the prescription dose "cloud" from any angle, and the proximity of the implant to other structures, such as the rectum and bladder. Clockwise, three CT images show the radiation dose levels at the top, middle and bottom of the gland.|
|Fig 3: This close-up 3-D image of the 100% isodose cloud, showing near complete coverage of not only the prostate plus 5mm margin, but also the proximal seminal vesicles, shown semi-transparently. Notice how the dose cloud is shaped posteriorly to spare the anterior rectal wall.|
|Fig 4: This view evaluates the implant from the top. The red areas are the small portions of the target volume that are spared the full prescription dose: the bladder neck and the lower bulbous urethra to prevent urinary incontinence and urethral stricture respectively.|
|Fig 5: This DVH shows that 97.4 % of the target volume is being encompassed by the prescription dose. 35% of the urethra received doses slightly higher than the prescription dose, with the maximum dose being around 110% of the prescription dose. The maximum anterior rectal wall dose our physicians allow is 75% of the prescription dose, versus up to 100% with seeds or external beam.|
|Fig 6: This is an "AP" (front view) radiograph of a CET prostate implant. The blue markings are the rectal outline and dose calculation points for the bladder, urethra and rectum. "Dummy" markers are inserted in the catheters. Contrast is introduced into the bladder (cystogram). Contrast is also used to inflate the foley balloons in the bladder and rectal catheters. The bladder catheter is made of a radio-opaque material to see the urethra clearly. Notice how the catheters can be made to flare in order to encompass any extracapsular extension.|
|Fig 7: This is a lateral (side view) of the CET prostate implant. The physicians try to lift the prostate away from the rectum to help achieve low rectal doses. Notice how the tips of the catheters are against the bladder. This ensures that any tumor in the base of the gland is adequately treated, yet by adjusting the time the source spends in the tip "dwell" positions, the bladder doses are controlled.|
|Fig 9: Specific Radiation Boosting: CET was the first center to realize and use the ability of the HDR system to send the source to specific positions in the catheters allowing us to give an additional "boost" dose to the cancer nodules. The image on the left shows the 3-D boosted area in blue at it extends out past and into the (red semi-transparent) prostate. The transverse view CT image with the isodose levels is on the right.|
|Fig 10: Composite Dose Distribution|
|This is the resulting isodose pattern of the initial whole gland plan combined with the boost, which we call the composite plan. The numbers are the isodose values in cGy (HDR). The highest dose areas are in the peripheral zone of the prostate, where most prostate tumors arise. Notice the larger boosted area that is covered by the 900 cGy (HDR) isodose line. The prescription dose, 600 cGy (HDR), is the inner red line going around the prostate. Note that the 600 cGy prescription is occurring 5mm out from the prostate capsule. If necessary, we can create an|
|Fig 11: HDR Conformity and Accuracy Sparing a TURP defect: This image shows how we can accurately shape the radiation dose (white line) to go around the contrast-filled TURP defect. This precision is not possible with EBRT or permanent seeds.|
|American Society for Therapeutic Radiology And Oncology
Chair - Health Policy and Economics Practice Management Subcommittee,
Chair - Regulatory Subcommittee, Member - Health Policy and Economic Committee,
Member - Health Policy and Economics Code Development and Valuation Subcommittee,
Member - Code Utilization and Application Subcommittee.
American Brachytherapy Society
Chair - Socioeconomic Committee.
American College of Radiation Oncology
President - 2005 to 2007
American College of Radiology
Fellow - 2007