Revised 29 July 2009

Eligibility Criteria

1. Low-risk disease (clinical stage T2a, iPSA =10.0 ng/ml^-1and Gleason Score (GS) =6)
2. ‘Low tier’ intermediate risk patients (= T2c and iPSA 10-15 ng/ml^-1 with GS=6 or GS=7 with iPSA<10 ng ml^-1)
3. 'High-tier' intermediate risk patients (clinical stage = T2c, iPSA 15-20 ng ml^-1 and GS=6 or 7)

Patients with 50% positive cores or/ and two or three risk factors ( T2c, GS7 and PSA 15-20) may receive three months of neoadjuvant and three months of adjuvant hormone therapy (HT) (LHRH agonist, with four weeks non-steroidal antiandrogen) together with prostate brachytherapy (PB).

Prostate brachytherapy’s use in high risk disease [CS T3a, (disease palpable outside of the prostate) initial PSA >20 or GS 8] disease is restricted to patients enrolled in a BC Cancer Agency led multicentre randomized trial (ASCENDE-RT), comparing a brachytherapy boost to an external beam conformal boost, after pelvic external beam radiation, with 12 months of neoadjuvant androgen suppression.

Use of Hormone Therapy Together with Prostate Brachytherapy

Hormone therapy (HT) is used in conjunction with PB in order to downsize prostate gland and reduce pubic arch interference (make the implant technically easier/ possible). The additional benefit of HT on improving long term PSA outcome is unclear. Patients who have implants with less than optimal dosimetry coverage of the prostate (D90< 130Gy), or those with high risk prostate cancer, may benefit from the addition of HT (1). The addition of HT to prostate brachytherapy had produced a small additional benefit to PSA recurrence-free survival in some series, including ours (2,3), but not in others (4-6).

Use of HT is associated with a higher risk of cardiovascular morbidity including sudden cardiac death, glucose intolerance and diabetes, osteoporosis (and diabetes mellitus), muscle mass wasting, fatigue, decrease in QOL, decrease in sexual function (7).

The potentially small additional benefit of HT in increasing PSA recurrence-free survival must be weighted against potentially significant adverse side effects.

Use of Androgen Suppression for Cytoreduction

Cytoreduction can be accomplished using LHRH agonist with antiandrogen for at least three months prior to implant. Antiandrogen should be given concurrently with LHRH agonist for one to three months. Total Androgen Blockade (TAB) has been shown to reduce prostate volume faster to a greater degree than LHRH agonist alone. Cytoreduction can also be accomplished using combination of Avodart 0.5 mg with Casodex 50 mg daily for at least three months prior to implant.

Patients with relatively large prostates ( 50 cc) may have increased urinary morbidity with prostate brachytherapy (8)(9). HT may be employed to reduce the prostate volume; however, the morbidity of prostate brachytherapy may be more closely correlated with the pre-cytoreduced volume than the post-cytoreduced volume. Men with median lobes that project superiorly into the bladder are difficult to implant and may have a high risk of acute and prolonged urinary retention. The use of peri- and post-operative dexamethasone may reduce the incidence of acute urinary retention in men with large prostates and/or high IPSS scores.

Anticoagulants

Patients on coumadin are suitable for brachytherapy, provided they are judged able to safely stop the coumadin therapy for at least six days. Documentation as to the safety of such an interruption in anticoagulation therapy must be provided by an appropriate specialist physician (usually a cardiologist or hematologist).

TUPR

Selected men who have had one TUPR, who are left with a small defect on ultrasound and who are at least two years out from TUPR can be considered for brachytherapy. Patients with significant urinary symptoms requiring therapeutic TURP, are also eligible for prostate brachytherapy four to five months after the TURP, providing they are left with a small tissue defect.

References:

1. Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the management of intermediate- to high-risk prostate cancer treated with permanent radioactive seed implantation. International Journal of Radiation Oncology, Biology, Physics 2002;52(2):444-52.
2. Merrick GS, Butler WM, Wallner KE, Galbreath RW, Lief JH, Allen Z, et al. Impact of supplemental external beam radiotherapy and/or androgen deprivation therapy on biochemical outcome after permanent prostate brachytherapy. Int.J.Radiat.Oncol.Biol.Phys. 2005 Jan 1;61(1):32-43.
3. Morris WJ, Keyes M, Palma D, Spadinger I, McKenzie MR, Agranovich A, et al. Population-based Study of Biochemical and Survival Outcomes After Permanent (125)I Brachytherapy for Low- and Intermediate-risk Prostate Cancer. Urology 2009 Jan 23.
4. Potters L, Morgenstern C, Calugaru E, Fearn P, Jassal A, Presser J, et al. 12-Year Outcomes Following Permanent Prostate Brachytherapy in Patients with Clinically Localized Prostate Cancer. J.Urol. 2008 May;179(5 Suppl):S20-4.
5. Zelefsky MJ, Kuban DA, Levy LB, Potters L, Beyer DC, Blasko JC, et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. International Journal of Radiation Oncology, Biology, Physics 2007;67(2):327-333.
6. Stone NN, Potters L, Davis BJ, Ciezki JP, Zelefsky MJ, Roach M, et al. Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes. Int.J.Radiat.Oncol.Biol.Phys. 2007 Dec 1;69(5):1472-1477.
7. Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J.Clin.Oncol. 2006 Sep 20;24(27):4448-4456.
8. Keyes M, Miller S, Moravan V, Pickles T, McKenzie M, Pai H, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: long-term outcome in 712 consecutive patients. Int.J.Radiat.Oncol.Biol.Phys. 2009 Mar 15;73(4):1023-1032.
9. Keyes M, Schellenberg D, Moravan V, McKenzie M, Agranovich A, Pickles T, et al. Decline in urinary retention incidence in 805 patients after prostate brachytherapy: the effect of learning curve? Int.J.Radiat.Oncol.Biol.Phys. 2006 Mar 1;64(3):825-834.
   

BC Cancer Agency Prostate Brachytherapy Outcomes - June 2009

Prostate brachytherapy is a standard treatment for early stage, localized prostate cancer. The Provincial Prostate Brachytherapy Program was established 11 years ago. Within the BC Cancer Agency umbrella, over 2,500 patients have been implanted using common selection criteria, treatment algorithms, and quality control. The procedure is done using a real-time ultrasound guidance and fluoroscopy, as originally developed by the Seattle group, 20 years ago. Most implants are done with general or spinal anaesthesia, all as a day-care procedure, over a period of one hour. Most men return to their usual daily activity within days after the procedure.

BC Cancer Agency Prostate Brachythereapy PSA Outcomes

The BC Cancer Agency Brachytherapy Program has recently published biochemical control rates of the first consecutive 1,006 patients (1,2). Of those: 58% had low-risk and 42% had low-tier intermediate-risk disease and 65% received androgen suppression for six months together with the implant (no longer a routine policy).

The results show that after a median follow up of five years (and maximal follow up ten years), 95.6% of patients have a very low PSA (median PSA at last follow up of 0.04) which indicates an excellent long term outcome and potential cancer cure. We have only one patient who has relapsed after the six-year mark (out of 300 at risk with follow-up > 72m). Projected ten-year PSA recurrence free survival rate is 93.3%. These results confirm the findings from other institutions that PB outcomes are durable. Patients who have PSA 0.2 ng/ml at 5 years after PB have only a 1- 2% chance of subsequent recurrence (3). The seven-year actuarial overall survival is 93.4%.

Kaplan-Meier plot of PSA recurrence free survival for 1277 men implanted between July 20, 1998 - Feb. 28, 2005. 5 year bNED is 96.0 ±1.4%; 8 year bNED is 94.1 ±2.0% .
Results updated March 2009

Prostate Brachytherapy and External Beam Radiation Therapy for Localized Prostate Cancer

A recent BC Cancer Agency matched-pair analysis shows that men treated with PB have superior outcomes for PSA control when compared to external beam radiation (EBRT)(4). Five year PSA recurrence free rates are 95% (BT) and 85% (EBRT). After seven years, the BT result was unchanged, but the EBRT had fallen to 75%. Toxicity rates in this study show worse late urinary toxicity with BT, but worse bowel toxicity with EBRT.

It could be argued that striving for high cure rates in all patients is unnecessary, as most patients with localized prostate cancer will die of other causes. However, younger patients with long life expectancy are those most likely to benefit from curative treatment, avoiding difficult issues with disease recurrence and need for secondary intervention with lifelong androgen suppression.

Prostate Brachytherapy Side Effects:

The recovery time after the procedure is short. Most men return to their usual daily activity within days after the procedure. Severe long term side effects are rare.

Urinary Side Effects:

Most men will experience some urinary symptoms after the procedure; about 50% will have moderate obstructive and/or irritative urinary symptoms lasting several months. By 12 months, 90% of the patients’ urinary symptoms will return to baseline (5). At seven years after PB, the majority of patients (92.5%) will have very little or no urinary symptoms.

Patients with larger prostate volume, worse baseline urinary function, and those given hormone therapy are more likely to have more irritative and obstructive urinary symptoms after PB. Five to ten percent of patients will require a Foley catheter for urinary obstruction (most for <1 week, 3% of all patients for several weeks or months)(6); again this is more often seen in patients with worse baseline urinary function and those with larger prostate size before implant.

Patients implanted in more recent years have less long term urinary toxicity and less urinary obstruction compared to patients implanted earlier on in the program. For example, the temporary urinary retention rate decreased from 17% to 6% comparing the first two years after the program inception with subsequent experience (5,6).

Long-term, < 3% of men will require urethral dilatation or a TURP (transurethral resection of the prostate) to relieve obstructive urinary symptoms. With greater experience in the program, the overall rate of urinary side effects has declined.

Rectal Side Effects:

Mild self-limiting rectal irritation affects 20% of patients. 1-5% of patients will have rectal bleeding requiring a laser photocoagulation procedure (7). Serious rectal injury has occurred in four patients out of more than 2,500 men treated with brachytherapy at the BC Cancer Agency. Three of these four patients required a major surgical intervention such as colostomy.

It is important to ask our advice before any procedure (such as a biopsy) in the rectum, as after high dose radiation to the rectum even a relatively small tissue trauma, like biopsy, can precipitate development of rectal fistulae. Similarly, laser coagulation is only undertaken when conservative measures have failed.

Sexual Function:

Erectile dysfunction (ED) rates in our experience mirror that of elsewhere: after three years, 63% of patients who were previously potent remain so. Younger patients and those with better pre-treatment erectile function are likely to do better after the treatment (8). Many patients will have improvement in their function with oral GMP-specific phosphodiesterase inhibitors (PDE5 inhibitors: Sildenafil, Verdanefil, Tadalafil).

Implant Procedure:

The prostate brachytherapy implant is a surgical day-care procedure taking about 45 minutes. Patients are discharged home two to three hours later. The radiation oncologist places the radioactive seeds into the prostate through the perineum, using between 20-28 needles, each carrying two to six seeds. The seeds are 0.5 cm titanium shells that contain I¹²⁵ (Iodine ¹²⁵) radioactive gas. The half life of I¹²⁵ is 60 days. As radioactive decay is an exponential function, 50% of the radioactivity is released by two months, 88% by six months, 99% by 12 months.

The procedure is done using a real-time ultrasound guidance and fluoroscopy. Seed placement is guided using three-dimensional co-ordinates predetermined by a customized planning algorithm using computer modelling leaving 90-150 seeds permanently in the prostate (figure 2). Most implants are done with general or spinal anaesthesia (occasionally under local anaesthesia). After the procedure a CT scan of the prostate is performed to ensure accurate position of the seeds and adequate radiation dose distribution within the prostate. This is a rigorous QA procedure that was built into our program as a standard practice from the outset. Very rarely, (1 in 200) men may be asked to come and have a second procedure done, where additional seeds may be placed in the prostate.

References:

1. Morris WJ, Keyes M, Palma D, Spadinger I, McKenzie MR, Agranovich A, et al. Population-based Study of Biochemical and Survival Outcomes After Permanent (125)I Brachytherapy for Low- and Intermediate-risk Prostate Cancer. Urology 2009 Jan 23.
2. Morris WJ, Keyes M, Palma D, McKenzie M, Spadinger I, Agranovich A, et al. Evaluation of dosimetric parameters and disease response after 125 iodine transperineal brachytherapy for low- and intermediate-risk prostate cancer. Int.J.Radiat.Oncol.Biol.Phys. 2009 Apr 1;73(5):1432-1438.
3. Stock RJ, Klein TJ, Cesaretti JA, Stone NN. Prognostic significance of 5-year PSA value for predicting prostate cancer recurrence after brachytherapy alone and combined with hormonal therapy and /or external beam radiotherapy. IJROBP 2009(in press. available on line January 2009).
4. Tom Pickles, Mira Keyes, W J Morris. Brachytherapy or Conformal External RT for Prostate Cancer: A single-institution matched-pair analysis. Radiother Oncol 2008 CARO 2008. International Journal of Radiation Oncology, Biology, accepted for publication
5. Keyes M, Miller S, Moravan V, Pickles T, McKenzie M, Pai H, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: long-term outcome in 712 consecutive patients. Int.J.Radiat.Oncol.Biol.Phys. 2009 Mar 15;73(4):1023-1032.
6. Keyes M, Schellenberg D, Moravan V, McKenzie M, Agranovich A, Pickles T, et al. Decline in urinary retention incidence in 805 patients after prostate brachytherapy: the effect of learning curve? Int.J.Radiat.Oncol.Biol.Phys. 2006 Mar 1;64(3):825-834.
7. Keyes M, Moravan V, Liu M, Jankovic B, Morris J. Rectal toxicity after I 125 permanent prostate implants in 445 patients: Is rectal and prostate dosimetry related to toxicity? Radiotherapy and Oncology 2005;76.
8. Macdonald AG, Keyes M, Kruk A, Duncan G, Moravan V, Morris WJ. Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important? International Journal of Radiation Oncology, Biology, Physics 2005;63(1):155-163.