Salvage High Dose Rate Brachytherapy For Recurrent Prostate Cancer After Radiation Therapy
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Paul Y. Song, M.D.
Valley Radiotherapy Associates, Inc.
Santa Monica & West Hills CA

Edited from PCRI Insights November, 2008 v 11.4

Recently reported estimates from the Surveillance, Epidemiology, and End Results (SEER) Program indicate that 186,320 men will be diagnosed with prostate cancer in the United States in 2008.1 Up to 80% of these men will present with localized disease, and about 30% will be initially managed with external beam irradiation.2,3 Based on long-term data, up to 13,500 men may be faced with a local recurrence after primary irradiation in the United States alone.1

Lee et al recently reported that of men who have a rising PSA after definitive radiation, approximately 26% will have clinical evidence of a local recurrence, and 47% will develop distant metastases within five years.4 With more and younger patients opting for radiation treatment, the number of patients for potential risk of failure may continue to increase. This, coupled with the stage migration toward early-stage, lower-PSA disease, may result in an increasing population of patients with perhaps more curable recurrent disease. Many of these patients will have local recurrence as the sole component of their disease and might indeed benefit from additional local treatment to their prostate.

Patients most likely to benefit from salvage local therapy after primary radiotherapy are those with the following:

1. Pathologically documented local failure
2. No clinical or radiographic evidence of distant metastases
3. Life expectancy > 5 to 10 years based on age and health
4. Disease-free interval of >2 years
5. PSA < 10 at time of salvage
6. Long PSA doubling time (> 9 months)
7. Gleason score at salvage of 6 or less.

There are a number of options in addition to radical prostatectomy and hormonal therapy. These options include cryoablation, thermoablation, and brachytherapy (both low-dose rate [LDR] and high-dose rate [HDR]). Of these techniques, prostatectomy and cryotherapy are perhaps the most widely used, but brachytherapy has garnered significant interest because of increased technologic advances in this field.

Cryoablation for radiation failures has been studied at numerous institutions with biochemical control ranging from 40% to 59%,5,6 however up to 10% develop incontinence and 90% report having severe erectile dysfunction.7

Fewer studies on thermoablation have been reported in the setting of radiation failures. With short follow-ups of one year, the disease-free survivals have been reported to be around 60%, with 36% requiring secondary procedures after salvage therapy for urinary complications.8,9

Both cryoablation and thermoablation have a gradual fall-off of the temperature gradient in the treated region so sparing of previously treated normal prostatic tissue is problematic; hence the increased risk of complications.

LDR Salvage Brachytherapy

Over the past 15+ years, there have been vast improvements in prostate seed brachytherapy due to the use of pre-planning, ultrasounds, a transperineal approach, and sophisticated treatment planning and dosimetry. With a long-term successful track record for early stage primary prostate cancer, it has now been successfully applied as salvage therapy for external beam radiation failures.

Several studies of salvage therapy with modern LDR brachytherapy techniques have been reported. Grado et al performed salvage brachytherapy in 46 patients who had a recurrence two to five years after conventional external beam irradiation (median dose of 6600 cGy). Implants were performed using either I-125 or Pd-103. Three- and five-year biochemical disease-free survival rates of 48% and 34% were achieved using a definition of failure that required two rising PSA values. Patients who had a PSA nadir of < 0.5 after salvage brachytherapy did substantially better. At five years, the biochemical disease-free survival was 56% for those who achieved this nadir compared to 15% for those who did not achieve it. No significant toxicity was reported.10

Beyer et al reported on 17 patients treated with salvage LDR brachytherapy with Pd-103 and I-125. The biochemical disease-free survival was 53% at five years with a cause-specific survival of 93%.11 A Gleason score of 6 or less or a PSA < 10 at the time of salvage predicted for low-risk patients and improved outcomes as 83% of these patients were still free of a second recurrence after salvage therapy. A recent update from Beyer et al with longer follow-up demonstrated that 60% of patients treated with their regimen were alive or died of something other than their prostate cancer.1

The toxicity of salvage LDR brachytherapy can be problematic. Urinary complications are demonstrably higher and have been reported with pelvic/penile pain in 6% of patients, hematuria in 4%, and urinary incontinence in 14-24%.11,12 Rectal complications with proctitis have been reported in up to 4% of patients. Bleeding or necrosis leading to the need for a colostomy is very variable, ranging from 0%11 to 5%.10 However, when reviewing LDR salvage brachytherapy complications, it is very important to note the work of Kuban et al, who documented an 18% risk of major urinary complications in patients with untreated recurrent prostate cancer as a direct result of disease progression.13

Like cryotherapy and thermoablation, there is a gradual fall-off of the therapeutic dose gradient which also increases the potential for complications with salvage LDR brachytherapy. In addition, there are some increased limitations associated with this technique including (1) the inability to reliably implant the seminal vesicles and extracapsular extension; (2) the inability to reposition seeds once implanted; and (3) seed migration in 5% to 10% of these patients.

High Dose Rate Brachytherapy

High Dose Rate (HDR) brachytherapy is already a well established and safe treatment for localized prostate cancer.14,15,16 It allows for the precise delivery of very high doses of radiation in a very short treatment time and is more conformal than seeds, protons, or IMRT. Not only does HDR brachytherapy not share these limitations, it also has the advantage of delivering the most conformal dose distribution compared to seeds, protons, and/or IMRT. (See Table 1)

Table 1. HDR Advantages vs. LDR (Summary)) 1. Radiation can be directed very precisely (conformal treatment) to the prostate thereby reducing side effects to the urethra, bladder, and rectum. Symptoms may be less than a permanent implant
2. Treatment is delivered in minutes over a period of days.
3. No permanent radioactivity remains inside the patient.
4. Extracapsular tissues and seminal vesicles can be treated.
5. Greater control of evenly distributed radiation doses throughout the intended target while minimizing exposure to the bladder and rectum.
6. Radiation dose can be modified after catheter insertion and before any radiation is delivered to the patient to insure an optimal implant.
7. Radiobiological advantage to the HDR fractionation and the accelerated treatment course.
8. Absolute knowledge of radiation dose distribution before the treatment is given.

HDR is a completely different method of delivering brachytherapy radiation. Instead of having a large number of uniform intensity seeds permanently inserted into the prostate, HDR uses a single high-intensity Iridium-192 source which is inserted temporarily and can be adjusted and customized to conform to each patient’s individual anatomy. Unlike the permanent seed implant process, which cannot be changed once the seeds have been placed, the ability to adjust and alter the HDR catheter dwell times prevents ever having a suboptimal implant (one that has regions of too much or too little radiation coverage).

HDR provides greater overall accuracy of dosimetry than with LDR brachytherapy without the radiation exposure to hospital staff and family members.17 Recent radiation biology studies suggest that prostate cancer cells may actually be more responsive to large fractions sizes of radiation delivered in fewer overall treatments than conventional radiation regimens.18,19,20

It appears from the LDR literature that the dose-limiting structure with salvage brachytherapy is the urethra and not the rectum. This is not very surprising as the dose to the urethra with a seed implant is usually substantially higher than the prescription dose to the entire prostate. The real potential promise of HDR brachytherapy when compared to LDR brachytherapy in the salvage setting is its unique ability to decrease the dose to the urethra while still maintaining adequate coverage of the prostate and limiting the dose to the bladder and rectum.

Although there have been few reported series of HDR salvage brachytherapy, those few appear to show great promise with better biochemical control and decreased toxicity when compared to LDR brachytherapy and cryotherapy.21 Lee et al reported on a series of 21 patients who were treated with 36 Gy in six fractions.21 With a median follow-up of 18.7 months, their two-year biochemical control after recurrence was 89%. Three patients (14%) developed grade 3 genitourinary toxicity. There was no rectal toxicity noted.

Tharp et al reported a 71% disease-free survival with a median follow-up of 58 months with no significant rectal toxicity, but did report increased urethral strictures requiring dilation in 71% of the patients.22

Gamie et al published a study on 35 patients treated with HDR and eight patients treated with LDR.23 With a median follow-up of 41 months, 18 of 43 patients (41%) remained without evidence of disease (by the ASTRO consensus definition). There was less toxicity seen in patients treated with HDR than with those treated with a seed implant.

Our Treatment Protocol

Drawing on the most recent published literature and with our prior experience with salvage LDR brachytherapy for patients with locally recurrent prostate cancer after external beam radiotherapy, we have developed and started to enroll patients in our very own treatment protocol using HDR salvage brachytherapy. Our protocol takes advantage of (1) increased technologic advances in imaging, (2) incorporation of the patient’s prior radiation therapy treatment and plan into our advanced treatment planning system, and (3) a dynamic multi-channel HDR machine.

Recognizing that approximately 26% of all radiation failures will be localized to strictly the prostate, our participating patients must first show pathologically documented evidence of recurrent prostate cancer. Patients with PSA < 10 ng/ml and a Gleason score of 6 or less are then asked to undergo a bone scan, a CT scan of the abdomen and the pelvis, and an MRI of prostate (figure 1a-b), (and sometimes a ProstaScint scan if the CT scan is found to be abnormal). Patients must also have a prostate volume of less than 60 cc and an American Urologic Association obstructive score < 10.

Figure 1a: MRI images are obtained to determine if extracapsular extension is present. Note darkened area in the right lateral posterior lobe of the prostate.

Figure 1b: MRI images are obtained to look for seminal vesicle involvement. Note involvement of right seminal vesicle (darkened).

Once patients are selected and enrolled in our protocol, they will be placed on a short four-month course of androgen ablation prior to the planning and treatment process. This course will be used in order to shrink the prostate and further reduce the radiation exposure to surrounding normal tissues.

Every attempt will be made to obtain each patient’s prior radiation treatment records. Using the latest technology, it is possible to recreate and closely estimate the prior radiation doses delivered to the rectum, bladder, and urethra and to incorporate this information into the salvage HDR treatment planning process (figures 2-4).

Figure 2: Initial radiation treatment fields and plans are reviewed to determine and/or reconstruct a close approximation of the prior radiation doses delivered to normal tissues.

Figure 3: Reconstructed radiation treatment plan which shows the original dose delivered to rectum and bladder.

Figure 4: Dose volume histograms (DVH) of the initial radiation treatment course are obtained and/or re-created and used to help determine normal tissue parameters for the salvage HDR treatment plan. The majority of all radiation failures were treated with older non-IMRT technology where lower total doses were used, but there was less sparing of the bladder and rectum.

After treatment planning parameters are met, patients will be placed under an epidural anesthesia and have between 14-24 temporary catheters placed transperineally under ultrasound guidance (figures 5-6).

Figure 5: Once patients are carefully selected and meet all criteria, they receive epidural anesthesia and have placement of temporary transperineal catheters under ultrasound guidance.

Figure 6: Actual catheters placed through the perineal template which is sutured to the skin.

After successful placement, a cystoscopy will be performed by the urologist to insure that the catheters are not protruding into the bladder. Patients will have a CT scan performed immediately after catheter placement and these images will be loaded into our treatment planning computer (figure 7).

Figure 7: CT images of catheter placement are obtained and downloaded into the treatment planning computer where the prostate, bladder, rectum, and urethra are defined and contoured by the physician.

The prostate, bladder, rectum, and urethra will be contoured by the physician (figure 8).

Figure 8: CT images are entered into the treatment planning computer. The prostate, rectum, urethra, and bladder are each contoured.

Great effort is needed to keep the urethral dose below 105% of the prescription dose with less than 1 cc of the urethra receiving 125%, and a three-dimensional dose distribution will be reconstructed (figure 9-10).

Figure 9: Three-dimensional dose distributions from individual catheter dwell times are created.

Figure 10: Treatment planning is performed and individual catheter dwell times calculated. Catheter dwell times can be customized to reduce the overall dose to the urethra which is believed to be the structure most at risk for increased toxicity.

Once all the treatment planning has been performed, the patient will then be brought to the treatment room. Patients will undergo fluoroscopy or x-rays prior to each treatment in order to make sure that the catheters have not been displaced or moved. If any movement is noted, the catheters can be readjusted to their correct positions. Patients will then be connected to the HDR machine, and a test run will be performed to insure that all the catheters are open and fully patent (figure 11a-b). Once all of these steps have been properly checked, the patient will be treated under epidural anesthesia with four fractions of 9.5 Gy over a two day period.

Figure 11a-b: Each temporary perineal catheter is attached to its own individual catheter station in the HDR machine which houses the Iridium-192 source.

 

Conclusions

HDR brachytherapy is already a well established and safe treatment for localized prostate cancer. It allows for the precise delivery of very high doses of radiation in a very short treatment time and is more conformal than seeds, protons, or IMRT. Up to 25% of all prostate cancer failures following definitive radiation therapy will be localized, and many of these men will be suitable candidates for salvage therapy.

While cryotherapy and LDR brachytherapy have been shown to be useful in a select population, both have been shown to have some significant associated complications and overall limitations due to the gradual fall-off of the therapeutic dose gradient. Based on published literature and our prior experience with HDR, we believe that HDR brachytherapy will allow for a more precise treatment option with less toxicity while taking advantage of the radiation biology of prostate cancer cells. This precision offered by HDR is especially appropriate for the salvage setting, given the potential danger around normal structures that have already previously received full-dose radiation during primary therapy. Salvage HDR prostate brachytherapy for biochemical failure after radiation therapy appears to be safe and well tolerated with promising results in carefully selected patients.

Editor’s note: For more information, see: High Dose Rate (HDR) Brachytherapy

References:

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2. Mettlin CJ, Murphy GP, McDonald CJ, et al: The National Cancer data base report on increased use of brachytherapy for the treatment of patients with prostate carcinoma in the U.S. Cancer 86:1877-1882, 1999

 

3. Moul JW: Treatment options for prostate cancer: Part I – Stage, grade, PSA, and changes in the 1990’s. Am J Managed Care 4:1031-1036, 1998.

 

4. Lee WR, Hank GE, Hanlon A. Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: Clinical observations. J Clin Oncol 15:230-238, 1997.

 

5. Izawa JI, Madsen LT, Scott SM, et al. Salvage cryotherapy for recurrent prostate cancer after radiotherapy: Variables affecting patient outcome. J Clin Ocolo 20:2664-2671, 2002.

 

6. Bahn DK, Lee F, Silverman P, et al. Salvage cryosurgery for recurrent prostate cancer after radiation therapy: A seven-year follow-up. Clin Prostate Cancer 2:111-114, 2003.

 

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10. Grado GL, Collins JM, Kriegshauser JS, et al: Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 53:2-10, 1999.

 

11. Beyer DC: Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology 54:880-883, 1999.

 

12. Loening SA, Turner JW: Use of percutaneous transperineal AU-198 seeds to treat recurrent prostate adenocarcinoma after failure of definitive radiotherapy. Prostate 23:283-290, 1993.

 

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14. Martinez A, Gonzalez, Spencer W, et al. Conformal high-dose brachytherapy improves biochemical control and causes specific survival in patients with prostate cancer and poor prognostic factors. J Urol 169:974-980, 2003.

 

15. Eulau SM, Hollebeke L, Cavanagh W, et al. High dose rate iridium 192 brachytherapy in localized prostate cancer: Results and toxicity with maximum follow-up of 10 years. Int J Radiat Oncol Biol Phys 48:149, 2000.

 

16. Demanes D, Rodriguez R, Schour L, et al. High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California Endocurietherapy’s 10-year results. Int J Radiat Oncol Biol Phys 61:1306-1316, 2005.

 

17. Demanes D, Rodriguez R, Altieri G: High dose rate brachytherapy: the California Endocurietherapy (CET) Method, Radiotherapy and Oncology 57:289-296, 2000.

 

18. Brenner DJ, Hall EJ: Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 43:1095-1101, 1999.

 

19. Wang JZ, Guerrero M, Allen X: How low is the alpha-beta ratio for prostate cancer. Int J Radiat Oncol Biol Phys 55:194-203, 2003.

 

20. Livesey JE, Cowan RA, Wylie JP, et al: Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis. Int J Radiat Oncol Biol Phys 57:1254-1259, 2003

 

21. Lee B, Shinohara K, Weinberg V, et al: Feasibility of high-dose rate brachytherapy salvage for local prostate cancer recurrence after radiotherapy: the University of California-San Francisco experience. Int J Radiat Oncol Biol Phys 67:1106-1112, 2007.

 

22. Tharp M, Hardacre M, Bennett R, et al: Prostate high-dose rate bracytherapy as salvage treatment of local failure after previous external or permanent seed irradiation for prostate cancer. Brachytherapy 7:231-236, 2008.

 

23. Gamie SH SN, Puthawala A, Mustafa E, et al: Re-irradiation for locally recurrent prostate cancer using temporary interstitial 1r-192 implant technique. American Brachytherapy Society 23rd Annual meeting (Abstracts), 2002:56.