By: D. Jeffrey Demanes M.D., FACRO, FACR
California Endocurietherapy (CET) Cancer Center
Reprinted from PCRI Insights August, 2007 v 10.3
Brachytherapy is a potentially curative treatment for prostate cancer. There are two methods of brachytherapy used: high dose rate (HDR) and permanent seeds. High dose rate brachytherapy is highly effective, yet less well known than permanent seeds because remote afterloading technology and the high intensity radiation source currently used for HDR were not generally available until some time after permanent seeds were developed. HDR is applicable to virtually all stages of localized prostate and many other types of cancer as well. It may be given as the only treatment (called HDR monotherapy) or it may be used with external radiation therapy. This article briefly describes and compares the treatment alternatives of surgery, external beam radiation, and brachytherapy for prostate cancer and highlights the advantages of HDR brachytherapy.
Radical prostatectomy is surgery designed to remove cancer in the prostate and seminal vesicles. It may be performed through a conventional surgical incision or with a robotic device that uses small scopes inserted through the abdominal wall (robotic prostatectomy)1. Surgery is completed in one session and provides valuable prognostic information.
The published literature shows that surgery is no more or less effective than radiation therapy, and elderly or medically frail patients may not be optimal candidates. Surgery is associated with significant risks of urinary incontinence and erectile dysfunction. The prostate surrounds the urethra (the urinary channel), and it is situated between the bladder and the urinary sphincter (that controls involuntary urine flow). Removal of the prostate from this strategic location, or damage to the sphincter muscle or nerves can lead to temporary or permanent urinary incontinence (involuntary urine leaking). Sexual function may be also disturbed due to injury of the neurovascular tissue that runs along side the prostate. Nerve-sparing operations reduce the incidence erectile dysfunction, but they should be performed only when there is a high probability that this approach will not compromise complete tumor removal.
External Beam Radiation Therapy
As the name indicates, external beam radiation involves the delivery of radiation from outside the body into the prostate. Standard external-beam linear accelerator therapy has historically been given with doses of 65-70 Gy with limited success. The advent of computer-assisted three-dimensional treatment planning, however, made it possible to deliver higher and more effective doses (75-78 Gy) to the prostate but with higher rectal doses and, consequently, more rectal complications2,3. A further technology refinement called intensity-modulated radiation therapy (IMRT) was subsequently developed to modulate the intensity of the beam and improve control of the target shape. Therefore, IMRT can selectively deliver higher radiation doses to the prostate and give lower doses to the bladder and rectum4. Proton beam external beam radiation is another form of advanced external beam technology with precise targeting of the prostate cancer5. The problems with highly targeted external-beam radiation, however, are (1) variable day-to-day targeting accuracy due to patient set-up and organ motion, (2) deposition of radiation into normal tissue before it gets to the target, and (3) the fact that none of the external-beam delivery systems have achieved the same high tumor dose, or offer as fine a level of dose distribution control within the prostate as brachytherapy.
Brachytherapy is an ideal way to treat prostate cancer because the prostate is a well-defined organ located between two important organs, the bladder and rectum. With brachytherapy, most of the radiation dose is delivered to the target and not the surrounding organs because the dose from a source of radiation within the prostate decreases very rapidly (i.e the inverse square law). The result is high tumor control and low complication rates.
Permanent seed brachytherapy, either alone or with external-beam radiation, has been successfully used in the treatment of prostate cancer for many years. When accurately performed, permanent seed implants deliver a safe and effective dose of radiation to the prostate. The benefits of prostate seed brachytherapy have been previously described in Insights in an article entitled Prostate Seed Implantation for Prostate Cancer by Grimm, Blasko, Sylvester et al that appeared in the November 2003 issue6. HDR brachytherapy is similar in principle, and it has the advanced features of robotic delivery and intensity modulation. The remainder of this article will describe the methods and relative advantages of HDR brachytherapy.
High Dose Rate (HDR) Brachytherapy
HDR doesn’t just describe the rate at which the radiation is given; it is a completely different process for delivering brachytherapy radiation. Instead of having a large number of uniform strength seeds that are inserted into the prostate permanently (as individual free seeds or connected by strands of absorbable material), HDR uses a single high-intensity radiation source on the end of a thin cable that is inserted temporarily. Table 1 summarizes the advantages of HDR Brachytherapy.
Table 1. Advantages of HDR Brachytherapy
• Short course compared to other types of radiation treatment (1 week)
• Preservation of organ structure and function
• Few side effects
• Excellent coverage of microscopic extension of cancer
• Knowledge of radiation dose distribution before treatment is given
• Accuracy and precision of tumor-specific radiation dose delivery
• Optimal radiation dose uniformity (avoids hot and cold spots)
• Organ motion (target movement) is not a problem for HDR as with external beam radiation
• Effective treatment for cancer recurrence (termed “salvage” therapy)
• No radiation source (seed) migration into other organs
• No radiation exposure to other people.
There are four basic steps to HDR brachytherapy. They are (1) image-guided applicator insertion, (2) image acquisition of the completed implant (simulation), (3) dose distribution calculations (computerized dosimetry), and (4) treatment delivery7,8. As shown in Figure 1, the first step is the placement of thin hollow close-ended catheters (like thin straws) under image- (ultrasound, CT, or MRI) and cystoscopy-guidance into and around the prostate. The images of the final implant position are acquired and downloaded into a treatment planning computer to create a virtual image of the implant and surrounding normal structures. The treatment planning computer is then used to calculate a highly patient-specific three-dimensional dose distribution (individually tailored isodose cloud) with specific dose constraints imposed on normal tissues.
|Figure 1 Illustration of the implant catheters entering the perineum going into the prostate and seminal vesicles.|
The data is viewed as isodose curves overlaid on an image such as a CT scan (see Figure 2) and as a three dimensional virtual image of the prostate tumor target and surrounding structures (see Figure 3 later). Once completed, the instructions on how long and where the source should be positioned within the implanted catheters are sent to the robotic delivery device called the “remote afterloader”. A trained therapist delivers treatments over a 15-20 minute period as the remote afterloader sequentially inserts the radiation source into “dwell positions” within each of the implant channels (catheters). Unlike brachytherapy seeds, the source is removed upon completion of the HDR treatment cycle so there is no residual radiation or radioactivity.
|Figure 2. CT cross section of the pelvis with implant catheter positions in the prostate and
the radiation isodose curves covering the target.
The radiation oncologist and the urologist typically perform the outpatient applicator insertion procedure together. They share their knowledge and skills to ensure optimal placement of the implant in the prostate and avoid injury to the bladder, urethra, and rectum. The radiation oncologist also works closely with other members of the HDR team consisting of a brachytherapy nurse, therapists, dosimetrist, and medical physicist during subsequent steps of the complex treatment process. Upon completion of treatment, the implant is removed, and the patient is discharged to go home.
HDR is frequently given in a series of implants (catheter placement procedures) with one or more treatments (radiation source delivery sessions called “fractions”) per implant. HDR treatments are often given twice daily. The total number and sequence of implants and treatments vary between centers and depend, in part, upon whether or not the patient also receives external-beam radiation therapy. The implant catheters are removed upon completion of the each of treatment series so they are not left in place when the patient goes home between treatments.
Since there is no incision and no surgical wound to heal, recovery from the procedure is rapid. Temporary urinary irritation, frequency, and urgency are to be expected for 1-2 weeks after the implant. Most patients have no major difficulties with urination after the procedure, but upon occasion, due either to prostate swelling or blood clots in the bladder, the patient may find it difficult to urinate after the procedure. Such urinary outflow problems are most common in patients with preexisting symptomatic BPH. The outflow problems that are directly related to the procedure typically occur within the first 24 hours after the implanted catheters have been removed. Urinary outflow problems after all forms of brachytherapy are best managed with medications or, if necessary, a temporary urinary catheter.
California Endocurietherapy (CET) Cancer Center Protocol
The treatment protocol at California Endocurietherapy (CET) Cancer Center in Oakland California is based upon risk group classification shown in Table 2. It consists of a series of two implants performed approximately one week apart. Either two or three treatments are given during each implant, depending upon whether external-beam radiation is used. Low- and “favorable” intermediate-risk group patients are treated with HDR monotherapy consisting of two implants with a total of six HDR treatments. Patients who are in either the “less favorable” intermediate-or high-risk groups are treated with a combination of HDR brachytherapy consisting of two implants with a total of four HDR treatments, followed approximately two weeks later by external-beam radiation therapy.
The theory of HDR monotherapy is that local treatment will eradicate early disease (cancer confined to the prostate gland and immediate surrounding tissue), and the normal tissue injury from the brachytherapy will be kept to a minimum. In the case of more aggressive or extensive disease, a somewhat larger area should be treated with external beam radiation, and HDR brachytherapy is used to more safely apply the high doses to the strategically located primary tumor. Dividing the implants into two separate sessions with multiple treatments best allows recovery of normal tissue and lessens the likelihood of normal tissue injury.
CET HDR Brachytherapy Results
At CET, we have treated 1650 patients with prostate cancer from 1991-June 2007. Our outcome studies have confirmed that HDR brachytherapy is a safe and effective treatment for prostate cancer. Ten-year results were published in 20059. The study population consisted of the first 209 patients from all risk groups treated with combined HDR and EBRT. We separately analyzed another group of patients who received androgen deprivation therapy (ADT) to avoid confounding the results. General clinical control (no clinical or PSA evidence of disease) was 90%, and the cause-specific survival was 97%. The PSA control rates according to risk group were 90% for low-risk patients, 87% for intermediate-risk patients, and 69% for high-risk patients. There were no statistically significant differences in outcome between the low- and intermediate-risk group patients. There were only 2% grade 1 rectal complications, 2% grade 2 rectal complications, and no grade 3 or 4 rectal complications. Grade 3-4 urinary effects were consistent with other forms of radiation therapy at 7.7%. These results are among the best reported in the literature. Rectal complications have remained low, and urinary complications have decreased as we gained experience in treatment delivery and post-treatment care.
We also reported results in 200510 on a total of 411 patients from that same period, comparing patients who did or did not receive ADT. There was no difference in outcome with ADT-treated patients. The 10-year PSA control rates (freedom from evidence of disease and no rise in PSA according to standard definitions) were 93% for the low-risk group, 87% for the intermediate-risk group, and 70% for the high-risk group. Local tumor control was 98% across all risk groups. These findings bring into question the need for ADT when high doses of radiation are given to the prostate and surrounding tissue.
Based upon the favorable experiences with both HDR and permanent seed brachytherapy without external beam radiation in early stage disease, we began offering HDR monotherapy as the only HDR treatment to low-risk patients and some-intermediate risk patients (T1 or T2, PSA <15, and Gleason 7 or less). We observed control of disease in 96% of cases (PSA progression-free survival) and low complications11. To confirm that the external beam radiation did not influence the outcome, we performed a matched-pair analysis that compared the results of like patients who received HDR plus EBRT with those who received HDR monotherapy. For low- and early intermediate-risk group patients, HDR monotherapy was as effective as treatment with both HDR plus EBRT. Our conclusion is that for early cancer of the prostate, HDR-monotherapy is both ample and the preferred treatment.
The HDR Brachytherapy Literature
Table 3 shows the results from the literature of HDR in combination with EBRT in patients with low-risk disease. The mean PSA progression-free survival (survival with no clinical, radiological, or PSA signs of disease progression) was over 90% with most patients having five or more years of follow-up (F/U in years).
Tables 4 and 5 show HDR brachytherapy and EBRT outcomes in patients with intermediate- and high-risk group disease based upon the length of follow-up. The distinction between intermediate and high-risk group patients varies in the prostate literature. It is a significant point of interest because upgrading patients to the high-risk group can exaggerate the efficacy of therapy. In any case, landmark studies by Martinez et al18 revealed that dosage dramatically affects tumor control. Patients who received the higher doses had an 87% control rate compared to 52% in patients who received lower doses. The 5-year control rates also correlate with the dosage delivered, and they range from 70-90% in patients who received higher doses.
Table 6 shows the results of multi-institutional studies that were published to address the benefits treatment of ADT and radiation of pelvic lymph nodes. Neither a short course (< 6 months) of ADT nor irradiation of pelvic lymph nodes was demonstrated to be of additional benefit21,22. They confirmed, however, the excellent results of HDR brachytherapy across all risk groups including patients with Gleason grades 8-1023.
Finally, as shown in Table 7, the results of HDR monotherapy for low-risk and early intermediate-risk groups in the literature are excellent24-26. A study of 294 patients from CET and William Beaumont Hospital showed the 5-year control rates to be 94%, the cause-specific survival to be 100%, and the fact that no patients had distant metastasis. The rectal complication rates were < 1% and there were < 5 % grade 3 urinary complications.
Beneficial Characteristics of HDR brachytherapy
HDR is “intensity modulated” and offers fine control of dose distribution The longer the HDR radiation source resides in a particular location, the greater the effective intensity of radiation will be. Intensity modulation comes from adjusting the source dwell times at each position within the catheter matrix. The distribution of radiation in and around the target can thereby be shaped to fit the target.
This capacity-to-intensity modulation is the functional equivalent of having an unlimited range of seed activity at every source position. The combination of infinitely variable source strength and precise source position control in and around the target volume permits dosimetry refinements that are possible only with HDR brachytherapy. Moreover, “intensity-modulated” HDR brachytherapy does not have the patient set-up and prostate motion problems associated with intensity modulated external-beam radiation therapy (IMRT.)
HDR is delivered with great precision.
Permanent seeds (with uniform activity) are manually inserted into deformable soft tissue, either as free seeds or in strands, according to provisional, or more recently, real-time dosimetry. The problem with any form of seed implant is that the final locations of the sources are different than planned. Because of limitations in the accuracy of the manual source insertion process, the ideal permanent seed implant (all of the sources with uniform activity placed exactly as planned) is virtually never achieved. Even if an ideal implant were accomplished, prostate swelling and seed migration after insertion might result in sub-optimal dosimetry.
In contrast, the single high-intensity HDR source is delivered according to manufacturer’s specifications and daily measurements are made with millimeter precision. The implant catheters can be placed anywhere in or around the prostate gland to create a stable matrix; then the source can be positioned as desired within the brachytherapy catheters. Hence, the positions of the treatment catheters in relationship to the target are checked carefully before treatment delivery. The HDR source does not shift or migrate.
HDR dosimetry is dynamic and prospective.
With permanent seed brachytherapy, the needle and source insertion are contemporaneous. It is thus a static process, and the actual radiation dose given to the patient is retrospectively determined. Seed insertion is static because, even though the needles move to the target, the seeds cannot be moved or adjusted once they are deposited. With permanent seed placement, the final dosimetry (the actual dose given to the patient) is retrospective because the final source positions in the patient are determined sometime after seeds are deposited. The consequence may be suboptimal dosimetry that may be identified too late to modify the dose (after the insertion procedure is finished). The problems associated with soft tissue deformity, manual seed insertion, and seed migration all potentially contribute to suboptimal dosimetry.
Conversely, HDR dosimetry is prospective, and HDR source delivery is dynamic. The distribution of the interstitial implant catheters and the relationship to the prostate and normal anatomy are known in advance of dosimetry calculations. The potential source positions within each catheter and the “dwell times” (the duration each source will spend at a particular location) are then selected to create the optimal dosimetry to conform to the target volume and normal tissue constraints. Hence, HDR brachytherapy differs from seed brachytherapy because the final HDR dosimetry is completed and approved by the physician before rather than during or after the source is administered. In other words, the radiation distribution in the patient is accurately represented by the HDR planning dosimetry. The relationships of the implant to the patient’s anatomy are known and maintained during the HDR source delivery.
An ideal radiation delivery system should establish and maintain the anatomic relationships to the target and the adjacent normal tissues throughout treatment. Although unintentional, doses can vary substantially during the time it takes a permanent seed implant to emit the dose, or due to patient motion or organ deformation during EBRT. There can be seed loss, prostate swelling, or other anatomical changes that impact the dose delivery. Conversely, the precise sequence of HDR simulation, dosimetry, and dose delivery, in conjunction with the short treatment duration, permits accurate representations and treatment delivery.
As with other forms of highly targeted radiation therapy, fiducial reference markers and image guidance are valuable components of the HDR process. Although it is necessary to confirm and sometimes to adjust the relationship of the applicator to the target between HDR fractions, these adjustments can be reliably and comfortably accomplished with the proper clinical management. Correct and reproducible geometric plan-to-target and source-to-target relationships are readily achieved with HDR brachytherapy.
HDR is user-friendly and forgiving of suboptimal brachytherapy catheter placement and not constrained by restrictive bone anatomy.
Inevitably in some cases, brachytherapy needle or catheter placement will be suboptimal. The possible reasons include prostate size or shape, a restrictive pubic arch, operator error, or poor imaging. The sequencing of HDR permits the physician to discover and improve suboptimal positioning and dosimetry either by moving the catheters to better positions or by utilizing the computer software (dwell time adjustment) to optimize the dosimetry. In our experience, relatively large prostates (up to approximately 100cc) can be treated with HDR, often without the need for ADT to downsize the prostate.
HDR reliably treats cancer that extends beyond the prostate.
HDR brachytherapy has a “scaffolding matrix” feature that provides both general stability and the ability to place catheters at or beyond the prostate capsule and into the seminal vesicles without the concern for source loss or migration to other organs. Figure 3 shows the 100% therapeutic isodose line extending beyond the prostate capsule. Our high local tumor control rates in all risk groups confirm the efficacy of HDR to control disease both in and around the prostate9,10.
|Figure 3 Three-dimensional virtual image of the pelvic anatomy with the prostate (dark red)
covered by the radiation isodose cloud (blue).
Control of normal tissue doses is predictable with HDR brachytherapy.
Not only does HDR permit dose control and target dose escalation, it also permits reliable control of normal tissue doses. The dose to the bladder and rectum can routinely be kept within prescribed constraints (typically 75-80% at CET)9. It is a subtle but significant fact that at large fraction sizes, the biological differences (as described by the linear quadratic equation of biological dose equivalence) are more pronounced than the percentages would imply. Thus, the biological doses to the bladder and rectum are actually less than the nominal percentages. Dose limits are readily achieved by avoiding the urethra and rectum during catheter insertion and by making dwell time adjustments during the dosimetry calculations. The ability to control the dose to normal tissues means that prior procedural interventions for BPH do not preclude the use of HDR brachytherapy after a suitable period of healing.
Radiobiological advantages for HDR in the treatment of prostate cancer
It has been established that the a/ß ratio (or repair of sub-lethal damage) for prostate cancer cells of 1.5- 3.0 is comparatively lower than previously thought.27-32 Such a low a/ß ratio suggests that the large fraction size and the rapidly accelerated course of treatment associated with HDR confers a biological advantage to this treatment for the relatively common low- and intermediate-risk groups. In cases of moderate to poorly differentiated prostate cancers where more rapid tumor doubling times are expected, the accelerated course of treatment with HDR is desirable so that repopulation of cancer cells is avoided. In other words, HDR brachytherapy, with and without EBRT, has radiobiological advantages for the entire range of prostate cancers.
Radiation safety is excellent.
Radiation exposure to people other than the patient does not occur with HDR brachytherapy. Although the total exposures rates are not high, permanent seed implants require time and distance restrictions. Even though total doses are low, population calculations (for infants, children or pregnant women) predict some risk of serious consequences. While the high-activity HDR source must be carefully monitored and regulated, exposure risks after seed implantation are eliminated with HDR. Furthermore, complicated seed accounting measures are not relevant to HDR. HDR typically has no seed loss, and there is no exposure of unwanted radiation to the environment, medical personnel, or family members.
HDR causes a comparatively short period of acute symptoms.
All forms of radiation therapy cause transient acute inflammation of pelvic structures that result in temporary irritation of bowel or bladder function. The duration of these symptoms depend upon how long it takes to deliver the radiation, the total dosage of radiation, and the volume of tissue irradiated. HDR brachytherapy limits the time, dose, and volume of radiation to normal structures so that the symptoms are of relatively short duration compared to external-beam radiation (approximately two months of treatment) and to permanent seeds (2-3 months of active radiation depending upon the radiation source used).
Unlike external-beam radiation, the physical advantages of brachytherapy require placement of applicators directly into and around the prostate. While neither permanent seeds nor HDR brachytherapy have excessive operative side effects, there are risks of urinary bleeding, outflow obstruction, anesthesia, and other events related to each procedure. Like surgery, good results from all forms of highly targeted radiation therapy depend upon the skill and expertise of the operator. The acute inflammatory period for the HDR procedure and the radiation effects is approximately two to three weeks.
HDR has low chronic rectal and urinary complication rates.
Side effects of prostate irradiation are related to the total dose administered and the volume of the normal structures treated. At CET, we use the gradient effect of brachytherapy (dose decreases rapidly from the implanted area) to minimize the dose impinging on surrounding tissue (1) by giving a large percentage of the dose with HDR (the EBRT is limited to 39.6Gy for combined therapy with additional radiation to pelvic lymph nodes applied with shielding of the implant region and normal structures) or (2) by giving the dose entirely with HDR monotherapy. Consequently, the rectal complications rates with combined HDR and EBRT at CET were 2% grade 1 and 2% grade 29, are even lower (<1%)26 from HDR monotherapy.
Chronic urinary side effects are related to (1) the presence of underlying benign prostate hyperplasia (symptomatic BPH), (2) the technical aspects of the implant, and (3) how outflow and other urinary symptoms are managed after the procedure. They occur in less than 10% of patients9. Avoidance of surgical intervention after radiation therapy is very important. In most cases, a conservative approach is preferable because transurethral surgery, while immediately effective in opening the urinary tract, results in chronic fibrosis, bladder neck contracture, and potentially urinary incontinence. Medications, temporary or intermittent catheterization, and patience will usually permit resolution of the symptoms. The rates of urinary incontinence for patients who do not have surgical intervention are <1%.
HDR is a reusable resource
HDR is appealing because the source is both reusable and can be applied to many different kinds of cancer other than prostate. The single source can be used for many prostate cancer patients, and the source is available even in remote areas at any time without the logistics of source delivery or stock inventory.
Follow up medical care and PSA testing after therapy
Most patients are back to baseline status within a month of treatment. It is particularly important that chronic bowel or bladder symptoms be properly managed conservatively. Proposed interventions such as biopsies or other procedures on the prostate, rectum, or bladder should be performed only by experienced physicians after careful consideration of indications and risks. The CET protocol for long-term PSA monitoring is testing every three months for two years and then every six months thereafter. If a rise is detected, more frequent testing is carried out. We caution patients must that a rise in PSA after HDR with or without EBRT does not necessarily mean that the cancer has recurred. Transient rises called PSA bounce can be seen months to years after treatment and should not be misinterpreted as treatment failures33. Biopsies within two years of treatment may not be reliable indicators of persistent disease, and they should be carefully interpreted, particularly if there is not a rising PSA.
HDR brachytherapy is a safe and effective treatment of localized prostate cancer. It combines the best characteristics of permanent seed brachytherapy and the intensity modulation that typifies IMRT. It has great precision, and it is a dynamic process that permits excellent control of radiation dose distribution The relationships of the implant and the dosimetry to patient anatomy are known in advance of treatment so the dosimetry is prospective and hence modifiable. HDR reliably treats local extension of disease beyond the prostate. Normal tissue dose constraints are readily attainable, predictable, and reliable. There is a radio- biological advantage to the HDR fractionation and the accelerated treatment course. Radiation safety is optimal. Acute radiation side effects are of short duration and chronic effects are relatively few. HDR may be safely and effectively applied to all risk groups either as monotherapy for early to intermediate disease or in combination with EBRT for intermediate-to-high disease. It can also be safely and effectively applied to patients with larger glands often without the need for ADT for downsizing the prostate. Like any fine tool, the accuracy resides with the knowledge of when and how to use it.
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33. Horwitz E, Levy L, A. Martinez A et al, The Post-Treatment PSA Bounce for Prostate Cancer Patients Treated With External Beam RT or Permanent Brachytherapy Alone Is Not Biochemically or Clinically Significant: A Multi-Institutional Pooled Analysis of More Than 7500 Patients International Journal of Radiation Oncology*Biology*Physics, Volume 66, Issue 3, Supplement 1, 1 November 2006, Page S205