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Neoadjuvant and adjuvant approaches
Outcomes of radiotherapy in patients with intermediate or high-risk prostate cancer have benefited from neoadjuvant hormonal ablation. In a randomized trial, Pilepich et al found that subjects randomized to receive luteinizing hormone–releasing hormone and flutamide in addition to EBRT showed improved local control and survival (in patients with higher-grade disease) compared with those treated with radiation alone.10
In the adjuvant setting, Laverdiere et al compared patients with localized prostate cancer treated with EBRT or EBRT with combined with androgen blockade in terms of both PSA failure and persistence of the cancer on prostate biopsy specimens. One hundred and twenty subjects with clinical stage B1-T2a, B2-T2b/T2c, or C-T3/T4 adenocarcinoma of the prostate were entered in this prospective randomized study. The subjects were randomly allocated to EBRT alone (group 1); 3 months of neoadjuvant combination therapy (luteinizing hormone–releasing hormone agonist plus flutamide) prior to EBRT (group 2); and combination therapy 3 months before, during, and 6 months after EBRT (group 3). The 3 groups had no significant differences in age, disease stage, tumor grade, and pretreatment PSA levels.
TRUS-guided needle biopsies were performed 12 and 24 months after the end of EBRT. Serum PSA levels were measured at scheduled visits. While 62% of control subjects in group 1 disclosed residual neoplasm upon biopsy at 12 months, only 30% and 4% showed residual disease in groups 2 and 3, respectively. When assessed at 24 months, 65%, 28%, and 5% showed residual cancer for groups 1, 2, and 3, respectively. The PSA measurements at 12 months also indicated differences between the 3 groups, except at 24 months, when the difference between group 2 and 3 was no longer significant.
Another randomized study (Bolla et al) further showed that androgen suppression prior to, during, and following radiation therapy increased disease-free survival (DFS) and overall survival in patients with locally advanced disease undergoing EBRT.
A study by D'Amico et al compared patients treated with brachytherapy with those treated with brachytherapy and androgen ablation. They found no differences, except in patients with a Gleason score of 7. Whether this difference persisted over time is unclear. Several other reports analyzing subsets of intermediate- or high-risk patients have failed to confirm a benefit.
Salvage brachytherapy
Recurrent disease and residual disease after therapy are fairly common in patients with prostate cancer, with rates ranging from 25-85% depending on initial therapy and disease type. The National Cancer Institute's Physician Data Query (ie, PDQ - NCI's Comprehensive Cancer Database, formerly known as CancerNet) reports that approximately 10% of patients initially treated with radiation experience relapse. Local recurrence presents a difficult challenge because the therapeutic options are limited.
In the past, additional EBRT was rarely an option because of the limits on cumulative doses. Hormonal therapy is not curative, and salvage prostatectomy has limited efficacy with significant adverse effects. Estimated 5-year survival rates for salvage prostatectomy range from 25-65%. Over the past few years, salvage brachytherapy and salvage cryotherapy have been increasingly advocated as therapeutic options in addition to salvage prostatectomy. A 2003 series by Koutrouvelis et al reported success with salvage brachytherapy after prior brachytherapy, but note that this success was reported in only one study with 31 patients12 ; therefore, such a treatment plan must be considered with caution. The tables presented below summarize some of the pertinent literature pertaining to these newer modalities.
Table 1. Salvage Cryotherapy
| Authors and Years |
No. of Patients |
Mean Age of
Patients (Range) |
Disease-Free Survival |
Mean Follow-Up (Range) |
| de la Taille et al, 2000 13 |
43 |
69.4 y (48.1-83.6 y) |
79% DFS at 6 mo, 66% at 12 mo |
21.9 mo (1.2-54 mo) |
| Perrotte et al, 1999 14 |
112 |
63 y (45-81 y) |
. . . |
16.7 mo (0.5-31.5 mo) |
| Greene et al, 1998 15 |
146 |
Not reported |
40% DFS (PSA <0.5 ng/mL), 78% DFS (biopsy) |
21 mo (3-47 mo) |
| Pisters et al, 1999 16 |
145 |
Not reported |
74% DFS at 24 mo (PSA <10 ng/mL), 28% DFS at 24 mo (PSA >10 ng/mL), 58% DFS (Gleason score <8), 29% DFS (Gleason >9) |
24 mo (3-48 mo) |
| Chin et al, 2000 (abstr) |
118 |
<78 y |
78% DFS |
3-60 mo |
| Lee et al, 1999 (abstr) 17 |
56 |
Not reported |
2-y actuarial DFS in low-risk, 56%; moderate-risk, 44%; high-risk, 14% |
12 mo (3-72 mo) |
| Cohen et al (unpublished data) |
104 |
>65 y |
At 5 y, 20 of 53 had PSA <0.5 ng/mL |
|
| Authors and Years |
No. of Patients |
Mean Age of
Patients (Range) |
Disease-Free Survival |
Mean Follow-Up (Range) |
| de la Taille et al, 2000 13 |
43 |
69.4 y (48.1-83.6 y) |
79% DFS at 6 mo, 66% at 12 mo |
21.9 mo (1.2-54 mo) |
| Perrotte et al, 1999 14 |
112 |
63 y (45-81 y) |
. . . |
16.7 mo (0.5-31.5 mo) |
| Greene et al, 1998 15 |
146 |
Not reported |
40% DFS (PSA <0.5 ng/mL), 78% DFS (biopsy) |
21 mo (3-47 mo) |
| Pisters et al, 1999 16 |
145 |
Not reported |
74% DFS at 24 mo (PSA <10 ng/mL), 28% DFS at 24 mo (PSA >10 ng/mL), 58% DFS (Gleason score <8), 29% DFS (Gleason >9) |
24 mo (3-48 mo) |
| Chin et al, 2000 (abstr) |
118 |
<78 y |
78% DFS |
3-60 mo |
| Lee et al, 1999 (abstr) 17 |
56 |
Not reported |
2-y actuarial DFS in low-risk, 56%; moderate-risk, 44%; high-risk, 14% |
12 mo (3-72 mo) |
| Cohen et al (unpublished data) |
104 |
>65 y |
At 5 y, 20 of 53 had PSA <0.5 ng/mL |
|
In December 2000, the Health Care Financing Administration (Coverage Analysis Group file no. 00064) revised the national noncoverage policy for cryosurgical salvage therapy to allow coverage only for patients with localized disease (1) in whom a trial of radiation therapy failed as their primary treatment and (2) who meet one of the following conditions: stage T2B or below, Gleason score less than 9, and PSA level less than 8 ng/mL. Cryosurgical ablation as salvage therapy remains uncovered for all other patients.
Table 2. Salvage Brachytherapy
Authors and
Years |
No. of Patients |
Isotope (Dose) |
Disease-Free Survival |
Median Follow-Up (Range) |
| Koutrouvelis et al, 2003 12 |
31 |
Pd-103 in 26, I-125 in 5 |
87% (biochemical control) |
30 mo |
| Beyer, 1999 18 |
17 |
I-125 (120 Gy) in 15, Pd-103 (90 Gy) in 2 |
53% (5-y PSA progression by ASTRO* criteria) |
54 mo (23-147 mo) |
| Grado et al, 1999 19 |
49 |
I-125 or Pd-103 |
34% (5-y PSA progression by 2 successive rising PSA values above posttreatment PSA nadir) |
64 mo |
Authors and
Years |
No. of Patients |
Isotope (Dose) |
Disease-Free Survival |
Median Follow-Up (Range) |
| Koutrouvelis et al, 2003 12 |
31 |
Pd-103 in 26, I-125 in 5 |
87% (biochemical control) |
30 mo |
| Beyer, 1999 18 |
17 |
I-125 (120 Gy) in 15, Pd-103 (90 Gy) in 2 |
53% (5-y PSA progression by ASTRO* criteria) |
54 mo (23-147 mo) |
| Grado et al, 1999 19 |
49 |
I-125 or Pd-103 |
34% (5-y PSA progression by 2 successive rising PSA values above posttreatment PSA nadir) |
64 mo |
*American Society for Therapeutic Radiology and Oncology
Data on salvage brachytherapy are very immature but appear similar to those of cryotherapy. Larger studies and longer follow-up are needed before a definitive conclusion on the efficacy of this modality is established.
Overview of the permanent brachytherapy technique
A perineal template and TRUS guidance are used to guide placement of the needles into the prostate. Once the final needle position is established, the seeds are delivered. Postprocedure, a CT scan is repeated to confirm seed position and to generate imaging data for postimplant dosimetry.
Preoperative Details
Preoperative workup includes (1) bowel preparation, both mechanical and antibiotic; (2) prophylactic intravenous antibiotics at the time of the procedure and an oral course for several days afterward; (3) subcutaneous heparin if the patient has a history of deep vein thrombosis; and (4) stoppage of all anticoagulants, including aspirin, nonsteroidal anti-inflammatory drugs, and warfarin.
Intraoperative Details
TRUS-guided implantation technique
- Positioning: The lithotomy position is used. To differentiate the bladder from the prostate, use a urinary catheter to visualize the urethra or instill diatrizoate (Renografin) in the bladder. Secure the scrotum out of the perineal field with tape or towel clips.
- TRUS probe: A biplanar probe is best at 5, 6, or 7.5 MHz. Attach the probe to the stepping unit, which moves the probe in a cephalad or caudal direction at 0.5-cm intervals.
- Re-create planning images: Match the probe image to the planning image. Adjust the needle-guide template against the perineum, with 1-3 cm of space between the skin and the template. When intraoperative planning is being used, re-creation of the images is not necessary. The benefits of intraoperative planning are that optimal settings are determined in real time and variations are minimized (ie, no re-creation of prior plan). One drawback is that the operative time is longer, but the patient needs to come in only once.
- Needle insertion: The needle is inserted through holes in the template, then through skin. Watch for deflection, and reposition as needed. Avoid anterior pubic bones. Burnished-tip needles are easier to see when the sonogram becomes distorted by previously placed needles. Avoid piercing the urethra and ensure that no needle is closer than 0.5 cm to the rectal wall.
- Needle depth: Adjust the needle depth based on the preplan zero plane. Use a longitudinal ultrasonographic view. To mark the location of the bladder neck, perform fluoroscopy using a Foley balloon or instill diatrizoate.
- Source placement: Afterloading or Mick applicator techniques can be used. Remove the needle slowly to avoid source migration in the afterloading technique. Observe seed positioning under fluoroscopy.
- Postprocedure: Many brachytherapists perform cystoscopy to look for sources in the bladder or the urethra.
CT-guided implantation technique
- Planning: A planning CT scan is obtained several days before the procedure, with a urinary catheter in place. The catheter and diatrizoate serve to mark the bladder-prostate border. The prostate is scanned at 5-mm intervals with images that are 5 mm thick.
- Positioning: The patient is prone. A urethral catheter is placed that has wire through it and lead markers at 1-cm intervals. The template stand is mounted against the perineum. Most brachytherapists do not use a rectal marker.
- Needle placement: Initially, 2 needles are inserted simultaneously just posterior to the urethra on either side of the midline. Then, all anterior needles are inserted to limit prostate mobility. Anterior sources are placed first. Posterior needles are placed again, using 1-cm urethra markers for guidance.
- Source placement options: For the Mick applicator, pull the needle back from the zero plane at 5-mm intervals. Use preloaded needles. Rigid Absorbable Permanent Implant Device (RAPID; Amersham Health; Princeton, NJ) Strand seeds, ie, I-125 seeds adsorbed onto a silver rod are an option. Watch the placement of each source using repeat CT scanning. Perform a final CT scan of the prostate and postimplant dosimetry.
Postoperative Details
Allow the patient to recover from anesthesia. A final CT scan of the prostate and postimplant dosimetry are performed (only in TRUS-guided cases) from 1-30 days following the procedure. If a "cold spot" is observed, reimplantation can be performed. A voiding trial is initiated. If the patient cannot void, a catheter is reinserted and another trial is performed in 5-7 days.
Follow-up
Patients are discharged home the same day. Hematuria is expected for the first 1-2 weeks, and all patients experience dysuria. Most studies report urinary retention rates of less than 10%. However, if acute retention develops, a Foley catheter is inserted and alpha-blockers initiated. In most cases, perioperative edema resolves within the first 48 hours or certainly within the first week. A small subset of patients continue to have difficulty voiding beyond that period. These patients are taught the technique of clean intermittent catheterization. If voiding does not return within 3 months, urodynamics testing may be considered to ensure that this is truly obstruction rather than bladder dysfunction. In patients with true obstruction, transurethral resection of the prostate may be performed.
If obstructive symptoms are present, patients are started on alpha-blockers and maintained on this therapy for 9 months. Infection, perineal pain, and rectal bleeding are less common; nonsteroidal anti-inflammatory drugs and mesalamine (Rowasa) suppositories may help.
For excellent patient education resources, visit eMedicine's Prostate Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Prostate Cancer.
Tumor follow-up
PSA should be measured and a DRE should be performed every 3-6 months for 5 years and then yearly. If the PSA or DRE findings are abnormal at follow-up, appropriate increased follow-up frequency (PSA abnormality only) or biopsy (DRE abnormality) should be considered.
Definitions of biochemical failure
The PSA definition of disease freedom after radiotherapy for prostate cancer is still disputed. Historically, several different approaches have been used to define biochemical failure.
The first approach is to use absolute values to define failure, similar to the use of PSA levels following prostatectomy. Various cutoffs have been used, ranging from 4-0.2 ng/mL. The alternative approach is to use increasing values of PSA over time as a definition of failure. The ASTRO has proposed that 3 consecutive elevations should define failure if each elevation satisfies certain requirements. A principal rationale behind the ASTRO definition is the well-documented occurrence of benign spikes in PSA levels that can occur following brachytherapy; allowing for these spikes prevents an incorrect diagnosis of a recurrence.
Recent studies have shown that the ASTRO Consensus Panel definition of biochemical failure following radiation therapy correlates well with clinical distant metastases–free survival, DFS, and cause-specific survival. These findings suggest that this definition may be a surrogate for clinical progression and survival. However, determining the date of recurrence has been controversial. In the ASTRO definition, the date of failure is the point halfway between the nadir and first rise in PSA level. This ambiguity and the fact that the definition performed poorly in patients treated with hormone ablation has led to the development of a new definition. The Phoenix definition is characterized by a rise in PSA level of 2 ng/mL above the nadir. This is used to define biochemical failure after EBRT, with or without hormone ablation.
Both definitions are currently used in brachytherapy research protocols. Regardless of the definition used, the reported date of biochemical control should be cited as 2 years short of the median follow-up. In other words, prolonged follow-up is necessary in good studies.
The faster the PSA level nadir is reached, the better the outcomes.
The following are the PSA level nadir levels with the corresponding 5-year DFS rates:
- PSA level less than 0.5 ng/mL - 79%
- PSA level 0.5-0.99 ng/mL - 66%
- PSA level 1-1.99 ng/mL - 49%
- PSA level greater than 2 ng/mL- 25%
Complications
Needle puncture sites
The perineum is tender and bruised and may have slight bleeding from needle holes. Treatment is predominantly with ice and mild analgesics.
Urinary symptoms
Hematuria may be observed in the first 24 hours. Irritative symptoms such as dysuria, frequency, and urgency last from days to months. Studies have shown that 34-45% of patients have symptoms that persist for up to 1 year. The incidence rate of incontinence is 10-35% in the first few months, with few patients having any leakage at 1 year. As mentioned above, a small subset of patients may have persistant urinary retention, which is managed initially with a Foley catheter, then clean intermittent catheterization, and possibly transurethral resection of the prostate.
Reported rectal symptoms
As many as a third of patients report urge, diarrhea, and painful bowel movements. These symptoms improve over the first year. At 1 year, only 2% have persistent symptoms. Some studies report as many as 20% of patients have bright red blood per rectum. Symptoms have been reported to persist as long as 49 months after the procedure. Prostatorectal fistulas occur in 1-7% of all patients in published series. Recent data from the primary authors' institution suggest that, after brachytherapy, these fistulas result from biopsy of the anterior rectal wall by gastroenterologists. The wall likely appears irritated and ulcerated following brachytherapy, thus prompting the biopsy. Patients should be counseled to undergo colonoscopy prior to or one year after brachytherapy.
Sexual dysfunction
Generally, 33% of patients have a decrease in sexual function and activity. Decreased semen volume is observed. Results from studies on impotence vary, with rates as widely disparate as 2.5-25%. In some studies, 40% of the patients experienced some degree of erectile dysfunction following radiation therapy.
Quality of life
The ABS recommends using validated, patient-administered health-related quality-of-life methods to evaluate baseline and follow-up bowel, urinary, and sexual dysfunction. Recent studies have shown that, over time, quality of life among patients who have undergone radical prostatectomy is comparable with that of patients who have undergone brachytherapy alone. Initial differences in the adverse effect profile dissipate over time (2-4 y). However, the quality of life in patients treated with brachytherapy and EBRT was significantly worse at all time points compared with that in patients treated with radical prostatectomy and brachytherapy alone. The effect of androgen ablation on health-related quality of life is mixed, with some studies suggesting a worsening of health-related quality of life and others finding no discernible change.
Outcome and Prognosis
When compared with historical series using classic EBRT to treat prostate cancer, brachytherapy series appear to offer equivalent or better disease-specific survival as measured by biochemical failure rates. Patients must be appropriately selected and treated at an accredited institution. Although brachytherapy is still in its infancy, 5-, 7-, and 12-year follow-up studies suggest brachytherapy is equal to surgery in terms of biochemical recurrence.
A 12-year study by Ragde et al (2000) reported on patients treated with I-125 seeds, with or without additional EBRT.20 Of these patients, 66% and 79% of the brachytherapy alone and external radiation plus brachytherapy groups, respectively, were free of biochemical or clinical recurrence. Similarly, Kuban et al found no evidence of disease in only 64% of patients treated with I-125 at 10-year follow-up, but negative findings were found in all of these patients after posttreatment prostate biopsy.21 In patients with positive findings after prostate biopsies, only 19% remained actuarially disease-free at 10 years.
Polascik et al compared brachytherapy with radical prostatectomy and demonstrated that, at 7 years, surgery had an 87% progression-free survival rate versus 79% for brachytherapy in comparable patients.22 High-risk patients have been reported to have progression-free survival rates of 65-80%. When evaluating these control rates, careful attention must be given to variables such as the addition of EBRT or androgen ablation and length of follow-up.
However, no prospectively performed randomized studies have compared the efficacy of surgery with that of either brachytherapy or high dose external beam radiotherapy as delivered with modern treatment techniques. Because of a known migration in stage and histology between biopsy and prostatectomy specimens, any retrospective advantage must be interpreted with caution owing to differences in clinical versus pathologic staging.
The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis.
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