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Brachytherapy for recurrent prostate cancer after radiation therapy
Brachytherapy for Recurrent Prostate Cancer After Radiation Therapy David C. Beyer Prostate cancer specialists routinely see patients with recurrent disease after external beam irradiation. Traditionally, only palliative treatments have been offered with hormonal intervention or simple observation. A significant, although as yet uncertain, percentage of these patients will have only locally recurrent cancer and thus are potentially candidates for curative salvage therapy. Permanent brachytherapy with 125I or 103Pd has been used in an attempt to eradicate the remaining prostate cancer and prevent the need for additional intervention. It is particularly critical in this population to identify those patients most likely to have distant metastases or who are unlikely to suffer death or morbidity from their local recurrence to avoid potential treatment morbidity in patients unlikely to benefit from any intervention. Review of the literature shows 5-year freedom from second relapse after salvage brachyther-
apy in approximately 50% of patients, although with careful case selection second relapse free survival rates of up to 83% may be achieved. A schema is presented, based on the available data, suggesting that it may be possible to identify those patients who are most likely to benefit from salvage treatment. These include men with the following: (1) histologically confirmed local recurrence, (2) no clinical or radiologic evidence of distant disease, (3) adequate urinary function (IPSS < 20), (4) age and overall health indicative of >5- to 10-year life expectancy, (5) prolonged disease-free interval (>2 years) from primary radiation therapy, (6) long prostate-specific antigen (PSA) doubling time (>6-9 months), (7) Gleason sum <6, and (7) PSA <10 ng/mL at the time of recurrence. © 2003 Elsevier Inc. All rights reserved.
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13,500 men may thus be faced with a recurrence after primary irradiation in the United States alone. Many of these patients have local recurrence as a component of their disease and might be considered for further treatment to the prostate. Although it has not been well documented, a significant percentage of these patients can be expected to have only a local recurrence with no distant disease. For many men, no further treatment is considered because of their advanced age or failing health. For others, the recurrent cancer might have a prolonged indolent course and not require intervention. Although the population of patients who may benefit from salvage therapy is thus reduced, it still represents a sizeable and growing group of men. This review is intended to help address this significant patient population, and in particular, to frame several important questions:
he management of prostate cancer is a subject of considerable debate among physicians. Treatment options including surgery, radiation, brachytherapy, watchful waiting, and hormonal ablation have proponents with good rationale and results published for each. Much less has been written regarding the care of patients who have failed initial treatment. In the United States alone, close to 190,000 patients are diagnosed each year with prostate cancer.1 In 1988, roughly half of all newly diagnosed prostate cancers were locally advanced or metastatic; however, close to 80% of men now present with clinically localized disease2 and are candidates for potentially curative therapy. Recent estimates from the National Cancer Data Base3 and the Surveillance, Epidemiology, and End Results program4 suggest that 30% of presenting patients are managed initially with external beam irradiation. Yet 10% of low-risk patients and as many as 50% of high-risk patients can be expected to suffer a failure of this primary treatment. Assuming an average case mix, up to
From the Arizona Oncology Services, Scottsdale, AZ. Address reprint requests to David C. Beyer, MD, FACR, 8994 East Desert Cove, Suite 100, Scottsdale, AZ 85260. E-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1302-0009$30.00/0 doi:10.1053/srao.2003.50015
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1. Can we identify those patients who are most likely to benefit from salvage treatment? 2. Can we identify those patients who are most likely to respond to salvage treatment? 3. What is the expected morbidity of salvage brachytherapy? 4. What other options should be considered? An American Society of Therapeutic Radiology and Oncology Consensus Panel acknowledged in 1997 that some component of local failure is common in irradiated patients with a rising
Seminars in Radiation Oncology, Vol 13, No 2 (April), 2003: pp 158-165
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prostate-specific antigen (PSA)5 and suggested a limited role for routine rebiopsy in patients experiencing a biochemical recurrence. Conservative therapy, with observation or hormonal intervention, is usually the treatment of choice for this population, and histologic confirmation offers little benefit. However, for the occasional patient being considered for any potentially aggressive local therapy, biopsy confirmation of prostatic recurrence is mandatory as a minimum requirement for local intervention. As with men evaluated for primary treatment, the age and overall health of the patient is the first and foremost factor in identifying appropriate candidates for salvage therapy. This requires an estimation of the individual’s likely mortality from other causes and the anticipated time to symptomatic progression of the cancer or death if left untreated. Unfortunately, neither will be known with any certainty, and as with primary treatment, one is unlikely to have much beyond “good clinical judgment” to guide this choice. With that being said, there are some data to serve as a guide. A few authors have written about the clinical course of recurrent disease after radiation therapy. In one report, Kuban et al6 showed that local recurrence diminishes the overall 5 year survival from 89% to 66%. Unfortunately, no PSA data were available during the years of this report, and their relevance in the PSA era is unclear. Lee et al7 reported a 5-year overall survival of 65% with a cause specific survival of 76% in 151 men after a PSA failure (defined as PSA ⬎1.5 with 2 consecutive rises). Local recurrence was documented in 26% with distant metastases in 47%. Pound et al8 reported on the natural history of recurrent disease after radical prostatectomy. After PSA failure, the median time to metastasis was 8 years, with death occurring an average of 5 years thereafter. The Gleason score, PSA doubling time, and interval between surgery and rising PSA were all significant factors predicting for a more aggressive disease course. Pound’s study represents a highly selected patient population and is perhaps not truly indicative of the average patient failing surgery or radiation therapy. The median age was not stated in the Pound series, but based on usual surgical criteria, might be expected to be at least a full decade younger than the average radiation therapy cohort. Until better data are available documenting the time
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to metastasis (or death) for radiation therapy populations, this might be considered a bestcase scenario, expecting the average patient to present with clinical progression less than 5 to 8 years after PSA failure. The risk of cancer progression must then be weighed against the individual patient’s life expectancy. Death from unrelated causes, including heart disease, other cancers, and a host of other illnesses, remains the leading causes of death in patients with prostate cancer. Age-specific actuarial life expectancy tables can be found for populations, although never for individuals. For older and sicker patients, intervention targeting locally recurrent prostate cancer will often be unnecessary. In clinical practice, however, one is often faced with relatively young and healthy patients who must be considered at risk for death or morbidity from recurrent prostate cancer. These patients would be candidates for intervention if the cancer would be expected to progress within their life expectancy. Historically, most radiation therapy practices have treated patients for primary prostate cancer who averaged over 70 years of age.9 Consequently, the typical patient showing a rising PSA several years after radiation might not have been a good candidate for aggressive second-line therapy. However, during the past decade, there has been a dramatic rise in the number of young prostate cancer patients (45-70 years of age),10 with almost a 2-fold increase in the number of younger men being treated with radiation therapy. Even if only a minority of the treated patients fail, many men will still be young enough to reasonably consider definitive salvage treatment. Local salvage treatment is not appropriate for patients with distant disease. Distant metastasis or complications of therapy will be the predominant cause of death. In these patients, local control is unlikely to affect survival. In the PSA era, however, most failures now present with only a rising PSA. Radionuclide bone scans, computed tomography scans, or magnetic resonance imaging studies may frequently miss subclinical deposits. There is, however, every reason to expect that the PSA may give some indication of the probability of occult distant metastases at the time of biochemical failure. In men irradiated for local recurrence after radical prostatectomy, both the absolute value of the PSA at the time of second-line therapy, and the interval from initial
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treatment to the biochemical failure predict for freedom from a second failure. Schild et al11 determined that grade, dose, and PSA ⬎1.1 ng/mL at the time of salvage irradiation independently identify patients at high risk of failing salvage therapy. Several other series confirm that delaying treatment after surgical failure for PSA levels ranging from 1.0 to 2.5 ng/mL will cause the 5-year biochemical no evidence of disease rates to fall by more than half compared with salvage started with lower PSA levels.12-14 Less information is available regarding the prognostic impact of the PSA level after radiation therapy. Given the nature of the treatments and differences in the definition of PSA failure between surgical and radiotherapy patients, one would reasonably expect that radiation patients would likely have a higher average PSA at the time of failure. Indeed, using the ASTRO definition of failure,5 which requires 3 rising intervals, few patients are likely to be identified as radiation failures while the PSA is still less than 2 ng/mL. Tefilli et al15 compared patients at a single institution having salvage radiotherapy after a radical prostatectomy with men having salvage prostatectomy after failed external beam and noted a significant difference in the serum PSA at the time second-line therapy was instituted. Patients having salvage radiation after surgery had a mean PSA of 1.1 ng/mL in contrast to 9.1 ng/mL for salvage after radiotherapy. Salvage treatment after radiation therapy was more likely to be delayed, averaging 15.6 months from the time of recurrence, compared with 4.9 months for patients receiving radiation after failing prostatectomy. There are limited data addressing the level of PSA at the time of salvage brachytherapy after external beam irradiation. One report suggests a PSA ⬎10 as indicative of a high risk of failure,16 although other levels were not addressed. It is not clear if this dramatic difference in the PSA cutpoint after surgery and radiation therapy is a reflection of a biologic difference between these 2 initial treatment modalities, a delay in recognition of recurrence, or simply a reflection of the paucity of studies looking at salvage brachytherapy. Most likely all 3 are true to some extent, although it seems reasonable to conclude that the risk of failing the second-line therapy does rise with PSA elevation.
The disease-free interval since initial treatment has also been suggested as an indicator of site of disease. After radical prostatectomy, patients who show signs of PSA failure within the first 24 months have a significantly increased risk of having distant metastases, whereas those with a later PSA failure are more likely to have only local failure.8 In addition, a PSA doubling time after initial therapy of less than 6 months has been suggested as a strong predictor of metastatic disease after prostatectomy.17 Similar results have been reported after radiation therapy. Pollack et al18 calculated the PSA doubling time in 119 men with a rising PSA after radiation therapy. Patients with a PSA doubling time of ⬍5 months had a 4-year freedom from metastasis of 69% compared with 100% in men with a PSA doubling time of ⬎12 months. This is consistent with other studies showing no clinical signs of progression seen at 28 months in patients with a PSA doubling time of more than 9 months.19 Thus, it appears that the patients most likely to benefit from additional local therapy after primary radiotherapy are those with the following: (1) pathologically documented local failure, (2) no clinical or radiologic evidence of distant metastases, (3) life expectancy ⬎5 to 10 years based on age and health, (4) disease-free interval ⬎2 years from primary radiation therapy, (5) PSA ⬍10 at the time of salvage, (6) long PSA doubling time (⬎6-9 months). Can We Identify Those Patients Who Are Most Likely to Respond to Salvage Treatment? The notion of using brachytherapy as a salvage treatment is not new. Shortly after the introduction of 125I as a clinically useful isotope for primary prostate cancer, Goffinet et al20 reported a small preliminary series of patients treated with retropubic implantation for recurrent disease. Implanting 14 to 23 mCi, they delivered 9,000 to 22,500 rads. Early results were encouraging with 11 of 14 patients locally controlled and 8 completely NED. This report is unfortunately limited by use of the now outdated retropubic technique, lack of PSA results, and short follow-up. Complications were modest, except in the group implanted with high activity (⬎0.5 mCi) sources. Wallner et al21 reported a unique series of 13 patients with locally recurrent disease after retropubic 125I implantation who underwent a sec-
Brachytherapy for Recurrent Prostate Cancer
ond implant with a median matched peripheral dose of 170 Gy (calculated before the introduction of TG-43). A variety of techniques including retropubic implantation, open perineal placement, and fluoroscopic and computed tomography– guided brachytherapy were used. Five-year freedom from local progression of 51% was achieved, although 10 of 13 patients developed distant metastases with 59% survival at the 5-year mark. By today’s standards, these would have been considered to be fairly advanced cancers. PSA was not yet available, most patients had moderately or poorly differentiated cancers, and all had palpable tumors larger than 1.5 cm or extra prostatic extension. Looking primarily at biopsy results, Loening and Turner22 reported on 31 patients treated with transperineal ultrasound and fluoroscopy guided 198Au brachytherapy for salvage. Implants used a mean of 146 mCi and delivered a calculated dose of 20,000 rads. Seventeen of the patients had stage C or D disease at the time of radiotherapy, which consisted of an average of 6,000 rads. Follow-up was short, and no PSA information was presented. Twenty-one patients had follow-up biopsy 12 to 24 months after implantation. Forty percent of biopsies were negative, and 33% showed cancer with radiation effect. Three patients developed metastases, and the 5-year survival rate was 67% with only 2 cancer-related deaths. Taken together, it appears from these early series that several conclusions can be made. First, before the introduction of PSA, it was difficult to select patients with truly localized disease, and overall survival of just over 50% at 5 years could be expected. Local control was generally in excess of 50% with salvage brachytherapy, although it remains difficult to accurately assess. Complications were relatively modest, although frequent enough to discourage widespread adoption of these procedures. During the past decade, there has been a virtual revolution in prostate brachytherapy with the introduction of transperineal ultrasoundguided techniques, improved dosimetry, and general acceptance of the procedure for early cancer. During the same years, the introduction of routine PSA testing in screening, pretreatment selection, and posttreatment evaluation have brought about parallel changes in our understanding of the disease and in the stage of newly
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diagnosed cancers. A few studies have now been published addressing the use of salvage brachytherapy in this more modern era, taking advantage of these advances in implantation and PSA evaluation. Grado et al23 performed salvage brachytherapy in 46 patients who had recurrence 2 to 5 years after conventional external beam irradiation (median 66 Gy) and in 3 patients with recurrence after a 125I implant (dose not stated). They implanted a median of 31.76 mCi 125I or 126 mCi 103Pd to deliver a median matched peripheral dose of 160 Gy and 120 Gy, respectively. All implants were performed before the introduction of TG-43 and NIST-1999. Three- and 5-year biochemical disease-free survival rates of 48% and 34% were achieved using a definition of failure that required 2 rising PSA values. Patients who reached a PSA nadir of ⬍0.5 after salvage brachytherapy (47% in this report) fared dramatically better than those who failed to do so. At 5 years, the biochemical disease-free survival was 56% for those who achieved this nadir and 15% for those who failed to do so. This series presents a mixed cohort of adversely selected patients. Four men had also previously undergone radical prostatectomy and had grossly palpable recurrence. Eleven cancers were hormone refractory and 16 patients had previously undergone a transurethral resection of the prostate. It is highly unlikely that any patient with hormone refractory disease or a palpable mass after radical prostatectomy has a solitary local recurrence. Cure with salvage local therapy is not possible in these men. It is encouraging, however, to look at the subgroup who achieved a PSA nadir of ⬍0.5 after salvage. One might presume that these patients were less likely to have metastatic disease and they did show a 5-year PSA-free tumor control of 56%. Our own initial results for salvage brachytherapy were published for the first 17 consecutively treated patients.16 Doses of 120 Gy before TG-43 (or 110 Gy after TG-43) were used for 125I and 90 Gy for 103Pd before NIST-99 (or 100 Gy after NIST-99). Compared with Grado et al,23 we report that slightly better overall results were achieved with 53% biochemical disease-free survival and 93% prostate cancer-specific survival seen at 5 years. A Gleason sum ⱕ6 or PSA ⬍10 at the time of salvage predicted for low-risk patients and improved outcomes, although not at a statis-
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Figure 1. Actuarial biochemical disease-free survival is shown for salvage brachytherapy. (A) This shows the impact of serum PSA at the time of salvage for PSA ⬍10 ng/mL (dashed curve) versus PSA ⱖ10 ng/mL (solid). (B) This shows the effect of grade at the time of salvage for Gleason 2 to 6 (dashed) verus Gleason 7 to 10 (solid).
tically significant level. It is encouraging to note that 83% of these low-risk patients (N ⫽ 6) are still free of a second recurrence 5 years after salvage therapy. With additional treated patients and longer follow-up, a retrospective review of our results confirms many of these initial impressions. Currently, 30 patients have been followed up to 125 months (median, 46 months). The biochemical disease-free survival is shown in Figure 1 for the same risk groups, consisting of PSA ⬍10 versus PSA ⱖ10 (Fig 1A) and Gleason 2 to 6 versus Gleason 7 to 10 (Fig 1B). As in the initial analysis, a lower break point for PSA failed to discriminate any better than PSA greater than or less than 10, although the size of the cohort remains too small to make any statistically significant claims.
As might be expected with more than 5 years follow-up, late prostate cancer deaths have been seen. At 10 years, the prostate cancer specific survival rate is 60%. At the time of salvage, the Gleason score and PSA both predict for survival as can be seen in Figure 2. No cancer deaths have been seen in patients having a Gleason score of 6 or less at the time of salvage brachytherapy. In conclusion, it appears that salvage brachytherapy with 125I prescribed to 110 to 145 Gy (accounting for TG-43) is effective as a secondline treatment for selected patients failing initial radiation therapy. Incorporating the recommendations of NIST-99, 103Pd, doses of 100 to 115 Gy would be an alternative. Overall, approximately 50% of patients should be locally controlled clinically and remain bNED. As with primary treatment, the PSA and Gleason score at the time of
Figure 2. Prostate cancer specific survival is shown for salvage brachytherapy. (A) This shows the impact of serum PSA at the time of salvage for PSA ⬍10 ng/mL (dashed curve) versus PSA ⱖ10 ng/mL (solid). (B) This shows the effect of grade at the time of salvage for Gleason 2 to 6 (dashed) versus Gleason 7 to 10 (solid) and is statistically significant at P ⫽ .05.
Brachytherapy for Recurrent Prostate Cancer
salvage can help select patients with better outcomes. Those most likely to respond are men with PSA ⬍10 and Gleason ⱕ6. What Is the Expected Morbidity of Salvage Brachytherapy? It is readily apparent from the preceding discussion that only a limited number of patients have been treated with salvage brachytherapy. All published series are retrospective in nature and no proper quality of life reports are available. All authors have addressed complications; however, only physician reported morbidity is noted and this might well underestimate the true risks. The earliest reports of brachytherapy for recurrent disease addressed the dangers of complications including urinary incontinence, proctitis, necrosis, and rectourethral fistula. The greatest risk appeared to be related to the use of very high activity sources (⬎0.5 mCi) and was probably related to technique and high-dose regions in the vicinity of sensitive structures.18 With the introduction of transperineal ultrasound-guided techniques and the customary use of lower activity 125I and 103Pd sources, the reported risks have diminished. Primary treatment with prostate brachytherapy commonly leads to acute urinary symptoms including frequency, urgency, dysuria, and so on. Some authors have reported an increase in the severity and duration of acute morbidity after salvage brachytherapy, although this has not been quantified.24 In patients having salvage brachytherapy urinary complications are demonstrably higher and have been reported with pelvic/penile pain in 6%, hematuria in 4%, and urinary incontinence in 14% to 24%.16,22 Rectal complications with proctitis may be seen in 4%. Bleeding or necrosis leading to the need for a colostomy is highly variable, ranging from 0%16 to 5%.23 The highest risk appears to be within a subgroup who were implanted after a failed retropubic implant and may not be representative of the average patient. Baseline urinary function should be assessed in patients being considered for salvage brachytherapy. Although prolonged urinary retention has not been reported in this population, it is a well-established risk in patients having brachytherapy for primary treatment. Terk et al25 reported an overall risk of prolonged retention in 6% of implants. They went on to document that patients with compromised baseline urinary func-
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tion, as measured by an elevated IPSS of 20 or greater, had a 29% risk of retention, whereas those with IPSS ⬍10 had a 2% risk. In the absence of specific data for patients having salvage brachytherapy, it is reasonable to use similar criteria and select favorable patients with an IPSS ⬍20 for treatment. In our own series, there was no significant rectal toxicity, but we determined an actuarial risk of urinary incontinence of 24% at 5 years. All incontinence developed between the first and third years. We have hypothesized that some of the incontinence was a result of a uniform sourceloading pattern used in all of our early patients. The value of improved dosimetry concepts is supported (but not proven) by the complete absence of any incontinence in the past 13 patients compared with higher risk in the original 17. It is interesting to compare these data to data from Kuban et al,6 which document a risk of major urinary complications in 18% of patients with untreated recurrent prostate cancer as a direct result of disease progression. It appears that both the acute and chronic morbidities are greater in salvage therapy than in primary treatment; however, in comparison to progressive untreated recurrence, the complications remain relatively modest. What Other Options Should Be Considered? Both observation and hormonal therapy were briefly addressed in the opening section. For the majority of recurrent prostate cancer patients, these must be considered the first choice for management. This would include all patients with a high probability of distant disease, limited life expectancy (relative to tumor growth), or very slowly growing cancers. In addition, men who are unable or unwilling to manage the expected morbidity from salvage treatments are best managed conservatively. Those being considered for aggressive salvage treatments should undergo repeat biopsy and be counseled to follow conservative management if local failure cannot be documented histologically. Patients who were candidates for radical prostatectomy at the time of the initial diagnosis and who are still young enough and healthy enough to consider definitive salvage treatment at the time of recurrence have also been considered candidates for salvage prostatectomy. In 1 survey of
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356 physicians, representing an approximately equal number of radiation oncologists and urologists, there was general agreement across specialty lines as to the appropriateness of salvage therapy in selected patients.26 Presented with a hypothetical 45- to 65-year-old patient with biopsy proven local recurrence and a PSA ⬍5 more than 2 years after external beam irradiation, 45% of clinicians recommended some form of definitive salvage treatment. More than half of the respondents preferred a salvage radical prostatectomy. Zinke et al27 reported a 55% clinical 5-year disease-free survival in similar patients before the introduction of PSA. Urinary incontinence rates of 32% were seen in their series. In an update of these Mayo Clinic surgical results,28 86 salvage prostatectomies were performed over 30 years and followed an average of 5.8 years. Fiveand 10-year cancer-specific survival of 85% and 54% were reported. Gleason score and DNA ploidy were suggested as independent prognostic predictors. In more recent series using PSA as an endpoint, disease-free survival of 44% to 80% have been reported with similar rates of complications.15,29-31 Bladder neck contractures were reported in 11% with only 10 of 43 patients remaining continent in 1 recent report.15 Cryotherapy has recently received a great deal of attention as primary and salvage treatment. Small numbers of patients have been reported after salvage cryotherapy, with several early series reporting positive biopsy rates of 25% to 35% at 1 year.32-34 Complications were significant with up to 60% incontinence and 9% rectal fistula risks. Using more current cryosurgery techniques,35 the biochemical control is reported as 66% at 12 months with similar positive biopsy rates. However, the incontinence risk is 9% with no fistulas reported, suggesting some benefit in complications from urethral warming but no significant improvement in cancer control.
Conclusions Selection criteria for patients considering salvage brachytherapy remain ambiguous. Many of the decisions hinge on an educated estimate of the relative risk of dying from recurrent prostate cancer versus intercurrent illness, the probability of remaining cancer free after salvage treatment, and the risk of complications. As such, it remains an art with many patients falling into a gray zone.
Table 1. Recommended Guidelines for Case Selection Exclusion Criteria
Inclusion Criteria
Negative or no prostate biopsy Recurrent Gleason 7–10 Distant disease
Positive prostate biopsy
Recurrent Gleason 2–6 Negative metastatic workup Life expectancy ⬍5 yr Life expectancy ⬎10 yr Disease free interval Disease free interval ⬍2 yr ⬎2 yr Short PSA doubling time Long PSA doubling time (⬍6 mo) (⬎9 mo) PSA ⬎10 PSA ⬍10
In an effort to “do no harm,” the decision to intervene ought to be made only after ruling out all possible reasons to exclude the patient from treatment. Certain selection and exclusion criteria can be extrapolated from available literature discussed in this article and are summarized in Table 1. Although they cannot be considered absolute, these guidelines should serve to identify patients most likely to require treatment and to benefit from that treatment. Historically, few patients have been considered appropriate candidates for any definitive salvage intervention after failing radiation treatment. With more young men receiving radiotherapy, this may change and salvage treatment might become more common in the coming years. Conversely, improvements in diagnostic studies and understanding of PSA kinetics might show that many of these patients harbor occult distant disease, rendering further local treatments futile. Selecting those men who will benefit most from brachytherapy will remain a significant but important challenge.
References 1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. Cancer J Clinicians 52:23-47, 2002 2. Moul JW: Treatment options for prostate cancer: Part 1—Stage, grade, PSA, and changes in the l990’s. Am J Managed Care 4:1031-1036, 1998 3. 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 prostrate carcinoma in the U.S. Cancer 86:1877-1882, 1999 4. Stephenson RA, Stanford JL: Population-based prostate cancer trends in the United States: Patters of change in the era of prostate-specific antigen. World J Urology 15: 331-335, l997
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5. The American Society for Therapeutic Radiology and Oncology (ASTRO) l997 Consensus Panel (Cox J, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF): Consensus statements on radiation therapy of prostate cancer: Guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. J Clin Oncol 17:1155-1163, 1999 6. Kuban DH, El-Mahdi AN, Schellhammer PF: Prognosis in patients with local recurrence after definitive irradiation for prostatic carcinoma. Cancer 63:2421-2425, 1989 7. Lee WR, Hanks GE, Hanlon A: Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: Clinical observations. J Clin Oncol l5:230-238, 1997 8. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 28l:1591-1597, 1999 9. Shipley WU, Thames HD, Sandler HM, et al: Radiation therapy for clinically localized prostate cancer: A multiinstitutional pooled analysis. JAMA 281:598-1604, l999 10. Stephenson RA: Population-based prostate cancer trends in the PSA-era: Data from the surveillance, epidemiology, and end results (SEER) program. Monogr Urol 19:1-19, l998 11. Schild SE, Buskirk SJ, Robinow JS, et al: The result of radiotherapy for isolated elevation of serum PSA levels following radical prostatectomy. Int J Radiat Oncol Biol Phys 23:141-145, 1992 12. Vicini FA, Ziaja EL, Kestin LL, et al: Treatment outcome with adjuvant and savage irradiation after radical prostatectomy for prostate cancer. Urology 54:111-117, 1999 13. Raymond JF, Vuong M, Russell KJ: Neutron beam radiotherapy for recurrent prostate cancer following radical prostatectomy. Int J Radiat Oncol Biol Phys 41:93-99, 1998 14. Wu JJ, King SC, Montana GS, et al: The efficacy of post-prostatectomy radiotherapy in patient with an isolate elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 32:317-323, 1995 15. Tefilli MV, Gheiler EL, Tuguert R, et al: Salvage surgery or salvage radiotherapy for locally recurrent prostate cancer. Urology 52:224-229, 1998 16. Beyer DC: Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology 54:880-883, 1999 17. Partin AW, Pearson JD, Landis PK, et al: Evaluation of serum prostate-specific antigen velocity after radical prostatectomy of distinguish local recurrence from distant metastases. Urology 43:649-659, 1994 18. Pollack A, Zagars GK, Kavadi VS: Prstate specific antigen doubling time and disease relapse after radiotherapy for prostate cancer. Cancer 74:670-678, 1994 19. Hanks GE, D’Amico A, Epstein BE, et al: Prostatic-specific antigen doubling times in patients with prostate cancer: A potentially useful reflection of tumor doubling time. Int J Radiat Oncol Biol Phys 27:125-127, 1993
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20. Goffinet DR, Martinez A, Freiha, F, et al: Iodine prostate implants for recurrent carcinomas after external beam irradiation: Preliminary results. Cancer 45:2717-2724, 1980 21. Wallner KE, Nori D, Morse MJ, et al: Iodine re-implantation for locally progressive prostatic carcinoma. J Urol 144:704-706, 1990 22. Loening SA, Turner JW: Use of percutaneous transperineal 198Au seeds to treat recurrent prostate adenocarcinoma after failure of definitive radiotherapy. Prostate 23:283-290, 1993 23. Grado GL, Collns JM, Kriegshauser JS, et al: Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 53:2-10, 1999 24. Battermann JJ: Feasibility of permanent implant for prostate cancer after previous radiotherapy in the true pelvis. Radiother Oncol 57:297-300, 2000 25. Sylvester J, Grimm P, Blasko J, et al: Transperineal permanent brachytherapy for local recurrence following external beam radiation for early-stage prostate cancer. J Brachyther Int 17:181-188, 2001 26. Terk MD, Stock RG, Stone NN: Indentification of patients at increased risk for prolonged urinary retention following radioactive see implantation of the prostate. J Urol 160:1379-1382, 1998 27. Zincke H: Radical prostatectomy and exenterative procedures for local failure after radiotherapy with curative intent: Comparison of outcomes. J Urol 147:894-899,1992 28. Cheng L, Sebo TJ, Slezak J, et al: Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy. Cancer 83:21642171, 1998 29. Ahlering TE, Lieskovsky G, Skinner DG: Salvage surgery plus androgen deprivation for radio-resistant prostatic adenocarcinoma. J Urol 147:900-902, 1992 30. Rogers E, Ohori M, Kassabian VS, et al: Salvage radical prostatectomy: Outcome measured by serum prostate specific antigen levels. J Urol 153:104-110, 1995 31. Lerner SE, Blute ML, Zincke H: Critical evaluation of salvage surgery for radio-recurrent/resistant prostate cancer. J Urol 154:1103-1109, l995 32. Miller RJ Jr, Cohen JK, Shuman B, et al: Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma. Cancer 77:1510-1514, 1996 33. Pisters LL, Von Eschenbach AC, Scott SM, et al: The efficacy and complications of salvage cryotherapy of the prostate. J Urol 157:921-925, 1997 34. Lee F, Bahn DK, McHugh TA, et al: Cryosurgery of prostate cancer. Use of adjuvant hormonal therapy and temperature monitoring—A one year follow-up. Anticancer Resource 17:1511-1515, 1997 35. De La Taille A, Hayek O, Benson MC, et al: Salvage cryotherapy for recurrent prostate cancer after radiation therapy: The Columbia experience. Urology 55:79-84, 2000
apy in approximately 50% of patients, although with careful case selection second relapse free survival rates of up to 83% may be achieved. A schema is presented, based on the available data, suggesting that it may be possible to identify those patients who are most likely to benefit from salvage treatment. These include men with the following: (1) histologically confirmed local recurrence, (2) no clinical or radiologic evidence of distant disease, (3) adequate urinary function (IPSS < 20), (4) age and overall health indicative of >5- to 10-year life expectancy, (5) prolonged disease-free interval (>2 years) from primary radiation therapy, (6) long prostate-specific antigen (PSA) doubling time (>6-9 months), (7) Gleason sum <6, and (7) PSA <10 ng/mL at the time of recurrence. © 2003 Elsevier Inc. All rights reserved.
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13,500 men may thus be faced with a recurrence after primary irradiation in the United States alone. Many of these patients have local recurrence as a component of their disease and might be considered for further treatment to the prostate. Although it has not been well documented, a significant percentage of these patients can be expected to have only a local recurrence with no distant disease. For many men, no further treatment is considered because of their advanced age or failing health. For others, the recurrent cancer might have a prolonged indolent course and not require intervention. Although the population of patients who may benefit from salvage therapy is thus reduced, it still represents a sizeable and growing group of men. This review is intended to help address this significant patient population, and in particular, to frame several important questions:
he management of prostate cancer is a subject of considerable debate among physicians. Treatment options including surgery, radiation, brachytherapy, watchful waiting, and hormonal ablation have proponents with good rationale and results published for each. Much less has been written regarding the care of patients who have failed initial treatment. In the United States alone, close to 190,000 patients are diagnosed each year with prostate cancer.1 In 1988, roughly half of all newly diagnosed prostate cancers were locally advanced or metastatic; however, close to 80% of men now present with clinically localized disease2 and are candidates for potentially curative therapy. Recent estimates from the National Cancer Data Base3 and the Surveillance, Epidemiology, and End Results program4 suggest that 30% of presenting patients are managed initially with external beam irradiation. Yet 10% of low-risk patients and as many as 50% of high-risk patients can be expected to suffer a failure of this primary treatment. Assuming an average case mix, up to
From the Arizona Oncology Services, Scottsdale, AZ. Address reprint requests to David C. Beyer, MD, FACR, 8994 East Desert Cove, Suite 100, Scottsdale, AZ 85260. E-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1302-0009$30.00/0 doi:10.1053/srao.2003.50015
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1. Can we identify those patients who are most likely to benefit from salvage treatment? 2. Can we identify those patients who are most likely to respond to salvage treatment? 3. What is the expected morbidity of salvage brachytherapy? 4. What other options should be considered? An American Society of Therapeutic Radiology and Oncology Consensus Panel acknowledged in 1997 that some component of local failure is common in irradiated patients with a rising
Seminars in Radiation Oncology, Vol 13, No 2 (April), 2003: pp 158-165
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prostate-specific antigen (PSA)5 and suggested a limited role for routine rebiopsy in patients experiencing a biochemical recurrence. Conservative therapy, with observation or hormonal intervention, is usually the treatment of choice for this population, and histologic confirmation offers little benefit. However, for the occasional patient being considered for any potentially aggressive local therapy, biopsy confirmation of prostatic recurrence is mandatory as a minimum requirement for local intervention. As with men evaluated for primary treatment, the age and overall health of the patient is the first and foremost factor in identifying appropriate candidates for salvage therapy. This requires an estimation of the individual’s likely mortality from other causes and the anticipated time to symptomatic progression of the cancer or death if left untreated. Unfortunately, neither will be known with any certainty, and as with primary treatment, one is unlikely to have much beyond “good clinical judgment” to guide this choice. With that being said, there are some data to serve as a guide. A few authors have written about the clinical course of recurrent disease after radiation therapy. In one report, Kuban et al6 showed that local recurrence diminishes the overall 5 year survival from 89% to 66%. Unfortunately, no PSA data were available during the years of this report, and their relevance in the PSA era is unclear. Lee et al7 reported a 5-year overall survival of 65% with a cause specific survival of 76% in 151 men after a PSA failure (defined as PSA ⬎1.5 with 2 consecutive rises). Local recurrence was documented in 26% with distant metastases in 47%. Pound et al8 reported on the natural history of recurrent disease after radical prostatectomy. After PSA failure, the median time to metastasis was 8 years, with death occurring an average of 5 years thereafter. The Gleason score, PSA doubling time, and interval between surgery and rising PSA were all significant factors predicting for a more aggressive disease course. Pound’s study represents a highly selected patient population and is perhaps not truly indicative of the average patient failing surgery or radiation therapy. The median age was not stated in the Pound series, but based on usual surgical criteria, might be expected to be at least a full decade younger than the average radiation therapy cohort. Until better data are available documenting the time
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to metastasis (or death) for radiation therapy populations, this might be considered a bestcase scenario, expecting the average patient to present with clinical progression less than 5 to 8 years after PSA failure. The risk of cancer progression must then be weighed against the individual patient’s life expectancy. Death from unrelated causes, including heart disease, other cancers, and a host of other illnesses, remains the leading causes of death in patients with prostate cancer. Age-specific actuarial life expectancy tables can be found for populations, although never for individuals. For older and sicker patients, intervention targeting locally recurrent prostate cancer will often be unnecessary. In clinical practice, however, one is often faced with relatively young and healthy patients who must be considered at risk for death or morbidity from recurrent prostate cancer. These patients would be candidates for intervention if the cancer would be expected to progress within their life expectancy. Historically, most radiation therapy practices have treated patients for primary prostate cancer who averaged over 70 years of age.9 Consequently, the typical patient showing a rising PSA several years after radiation might not have been a good candidate for aggressive second-line therapy. However, during the past decade, there has been a dramatic rise in the number of young prostate cancer patients (45-70 years of age),10 with almost a 2-fold increase in the number of younger men being treated with radiation therapy. Even if only a minority of the treated patients fail, many men will still be young enough to reasonably consider definitive salvage treatment. Local salvage treatment is not appropriate for patients with distant disease. Distant metastasis or complications of therapy will be the predominant cause of death. In these patients, local control is unlikely to affect survival. In the PSA era, however, most failures now present with only a rising PSA. Radionuclide bone scans, computed tomography scans, or magnetic resonance imaging studies may frequently miss subclinical deposits. There is, however, every reason to expect that the PSA may give some indication of the probability of occult distant metastases at the time of biochemical failure. In men irradiated for local recurrence after radical prostatectomy, both the absolute value of the PSA at the time of second-line therapy, and the interval from initial
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treatment to the biochemical failure predict for freedom from a second failure. Schild et al11 determined that grade, dose, and PSA ⬎1.1 ng/mL at the time of salvage irradiation independently identify patients at high risk of failing salvage therapy. Several other series confirm that delaying treatment after surgical failure for PSA levels ranging from 1.0 to 2.5 ng/mL will cause the 5-year biochemical no evidence of disease rates to fall by more than half compared with salvage started with lower PSA levels.12-14 Less information is available regarding the prognostic impact of the PSA level after radiation therapy. Given the nature of the treatments and differences in the definition of PSA failure between surgical and radiotherapy patients, one would reasonably expect that radiation patients would likely have a higher average PSA at the time of failure. Indeed, using the ASTRO definition of failure,5 which requires 3 rising intervals, few patients are likely to be identified as radiation failures while the PSA is still less than 2 ng/mL. Tefilli et al15 compared patients at a single institution having salvage radiotherapy after a radical prostatectomy with men having salvage prostatectomy after failed external beam and noted a significant difference in the serum PSA at the time second-line therapy was instituted. Patients having salvage radiation after surgery had a mean PSA of 1.1 ng/mL in contrast to 9.1 ng/mL for salvage after radiotherapy. Salvage treatment after radiation therapy was more likely to be delayed, averaging 15.6 months from the time of recurrence, compared with 4.9 months for patients receiving radiation after failing prostatectomy. There are limited data addressing the level of PSA at the time of salvage brachytherapy after external beam irradiation. One report suggests a PSA ⬎10 as indicative of a high risk of failure,16 although other levels were not addressed. It is not clear if this dramatic difference in the PSA cutpoint after surgery and radiation therapy is a reflection of a biologic difference between these 2 initial treatment modalities, a delay in recognition of recurrence, or simply a reflection of the paucity of studies looking at salvage brachytherapy. Most likely all 3 are true to some extent, although it seems reasonable to conclude that the risk of failing the second-line therapy does rise with PSA elevation.
The disease-free interval since initial treatment has also been suggested as an indicator of site of disease. After radical prostatectomy, patients who show signs of PSA failure within the first 24 months have a significantly increased risk of having distant metastases, whereas those with a later PSA failure are more likely to have only local failure.8 In addition, a PSA doubling time after initial therapy of less than 6 months has been suggested as a strong predictor of metastatic disease after prostatectomy.17 Similar results have been reported after radiation therapy. Pollack et al18 calculated the PSA doubling time in 119 men with a rising PSA after radiation therapy. Patients with a PSA doubling time of ⬍5 months had a 4-year freedom from metastasis of 69% compared with 100% in men with a PSA doubling time of ⬎12 months. This is consistent with other studies showing no clinical signs of progression seen at 28 months in patients with a PSA doubling time of more than 9 months.19 Thus, it appears that the patients most likely to benefit from additional local therapy after primary radiotherapy are those with the following: (1) pathologically documented local failure, (2) no clinical or radiologic evidence of distant metastases, (3) life expectancy ⬎5 to 10 years based on age and health, (4) disease-free interval ⬎2 years from primary radiation therapy, (5) PSA ⬍10 at the time of salvage, (6) long PSA doubling time (⬎6-9 months). Can We Identify Those Patients Who Are Most Likely to Respond to Salvage Treatment? The notion of using brachytherapy as a salvage treatment is not new. Shortly after the introduction of 125I as a clinically useful isotope for primary prostate cancer, Goffinet et al20 reported a small preliminary series of patients treated with retropubic implantation for recurrent disease. Implanting 14 to 23 mCi, they delivered 9,000 to 22,500 rads. Early results were encouraging with 11 of 14 patients locally controlled and 8 completely NED. This report is unfortunately limited by use of the now outdated retropubic technique, lack of PSA results, and short follow-up. Complications were modest, except in the group implanted with high activity (⬎0.5 mCi) sources. Wallner et al21 reported a unique series of 13 patients with locally recurrent disease after retropubic 125I implantation who underwent a sec-
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ond implant with a median matched peripheral dose of 170 Gy (calculated before the introduction of TG-43). A variety of techniques including retropubic implantation, open perineal placement, and fluoroscopic and computed tomography– guided brachytherapy were used. Five-year freedom from local progression of 51% was achieved, although 10 of 13 patients developed distant metastases with 59% survival at the 5-year mark. By today’s standards, these would have been considered to be fairly advanced cancers. PSA was not yet available, most patients had moderately or poorly differentiated cancers, and all had palpable tumors larger than 1.5 cm or extra prostatic extension. Looking primarily at biopsy results, Loening and Turner22 reported on 31 patients treated with transperineal ultrasound and fluoroscopy guided 198Au brachytherapy for salvage. Implants used a mean of 146 mCi and delivered a calculated dose of 20,000 rads. Seventeen of the patients had stage C or D disease at the time of radiotherapy, which consisted of an average of 6,000 rads. Follow-up was short, and no PSA information was presented. Twenty-one patients had follow-up biopsy 12 to 24 months after implantation. Forty percent of biopsies were negative, and 33% showed cancer with radiation effect. Three patients developed metastases, and the 5-year survival rate was 67% with only 2 cancer-related deaths. Taken together, it appears from these early series that several conclusions can be made. First, before the introduction of PSA, it was difficult to select patients with truly localized disease, and overall survival of just over 50% at 5 years could be expected. Local control was generally in excess of 50% with salvage brachytherapy, although it remains difficult to accurately assess. Complications were relatively modest, although frequent enough to discourage widespread adoption of these procedures. During the past decade, there has been a virtual revolution in prostate brachytherapy with the introduction of transperineal ultrasoundguided techniques, improved dosimetry, and general acceptance of the procedure for early cancer. During the same years, the introduction of routine PSA testing in screening, pretreatment selection, and posttreatment evaluation have brought about parallel changes in our understanding of the disease and in the stage of newly
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diagnosed cancers. A few studies have now been published addressing the use of salvage brachytherapy in this more modern era, taking advantage of these advances in implantation and PSA evaluation. Grado et al23 performed salvage brachytherapy in 46 patients who had recurrence 2 to 5 years after conventional external beam irradiation (median 66 Gy) and in 3 patients with recurrence after a 125I implant (dose not stated). They implanted a median of 31.76 mCi 125I or 126 mCi 103Pd to deliver a median matched peripheral dose of 160 Gy and 120 Gy, respectively. All implants were performed before the introduction of TG-43 and NIST-1999. Three- and 5-year biochemical disease-free survival rates of 48% and 34% were achieved using a definition of failure that required 2 rising PSA values. Patients who reached a PSA nadir of ⬍0.5 after salvage brachytherapy (47% in this report) fared dramatically better than those who failed to do so. At 5 years, the biochemical disease-free survival was 56% for those who achieved this nadir and 15% for those who failed to do so. This series presents a mixed cohort of adversely selected patients. Four men had also previously undergone radical prostatectomy and had grossly palpable recurrence. Eleven cancers were hormone refractory and 16 patients had previously undergone a transurethral resection of the prostate. It is highly unlikely that any patient with hormone refractory disease or a palpable mass after radical prostatectomy has a solitary local recurrence. Cure with salvage local therapy is not possible in these men. It is encouraging, however, to look at the subgroup who achieved a PSA nadir of ⬍0.5 after salvage. One might presume that these patients were less likely to have metastatic disease and they did show a 5-year PSA-free tumor control of 56%. Our own initial results for salvage brachytherapy were published for the first 17 consecutively treated patients.16 Doses of 120 Gy before TG-43 (or 110 Gy after TG-43) were used for 125I and 90 Gy for 103Pd before NIST-99 (or 100 Gy after NIST-99). Compared with Grado et al,23 we report that slightly better overall results were achieved with 53% biochemical disease-free survival and 93% prostate cancer-specific survival seen at 5 years. A Gleason sum ⱕ6 or PSA ⬍10 at the time of salvage predicted for low-risk patients and improved outcomes, although not at a statis-
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Figure 1. Actuarial biochemical disease-free survival is shown for salvage brachytherapy. (A) This shows the impact of serum PSA at the time of salvage for PSA ⬍10 ng/mL (dashed curve) versus PSA ⱖ10 ng/mL (solid). (B) This shows the effect of grade at the time of salvage for Gleason 2 to 6 (dashed) verus Gleason 7 to 10 (solid).
tically significant level. It is encouraging to note that 83% of these low-risk patients (N ⫽ 6) are still free of a second recurrence 5 years after salvage therapy. With additional treated patients and longer follow-up, a retrospective review of our results confirms many of these initial impressions. Currently, 30 patients have been followed up to 125 months (median, 46 months). The biochemical disease-free survival is shown in Figure 1 for the same risk groups, consisting of PSA ⬍10 versus PSA ⱖ10 (Fig 1A) and Gleason 2 to 6 versus Gleason 7 to 10 (Fig 1B). As in the initial analysis, a lower break point for PSA failed to discriminate any better than PSA greater than or less than 10, although the size of the cohort remains too small to make any statistically significant claims.
As might be expected with more than 5 years follow-up, late prostate cancer deaths have been seen. At 10 years, the prostate cancer specific survival rate is 60%. At the time of salvage, the Gleason score and PSA both predict for survival as can be seen in Figure 2. No cancer deaths have been seen in patients having a Gleason score of 6 or less at the time of salvage brachytherapy. In conclusion, it appears that salvage brachytherapy with 125I prescribed to 110 to 145 Gy (accounting for TG-43) is effective as a secondline treatment for selected patients failing initial radiation therapy. Incorporating the recommendations of NIST-99, 103Pd, doses of 100 to 115 Gy would be an alternative. Overall, approximately 50% of patients should be locally controlled clinically and remain bNED. As with primary treatment, the PSA and Gleason score at the time of
Figure 2. Prostate cancer specific survival is shown for salvage brachytherapy. (A) This shows the impact of serum PSA at the time of salvage for PSA ⬍10 ng/mL (dashed curve) versus PSA ⱖ10 ng/mL (solid). (B) This shows the effect of grade at the time of salvage for Gleason 2 to 6 (dashed) versus Gleason 7 to 10 (solid) and is statistically significant at P ⫽ .05.
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salvage can help select patients with better outcomes. Those most likely to respond are men with PSA ⬍10 and Gleason ⱕ6. What Is the Expected Morbidity of Salvage Brachytherapy? It is readily apparent from the preceding discussion that only a limited number of patients have been treated with salvage brachytherapy. All published series are retrospective in nature and no proper quality of life reports are available. All authors have addressed complications; however, only physician reported morbidity is noted and this might well underestimate the true risks. The earliest reports of brachytherapy for recurrent disease addressed the dangers of complications including urinary incontinence, proctitis, necrosis, and rectourethral fistula. The greatest risk appeared to be related to the use of very high activity sources (⬎0.5 mCi) and was probably related to technique and high-dose regions in the vicinity of sensitive structures.18 With the introduction of transperineal ultrasound-guided techniques and the customary use of lower activity 125I and 103Pd sources, the reported risks have diminished. Primary treatment with prostate brachytherapy commonly leads to acute urinary symptoms including frequency, urgency, dysuria, and so on. Some authors have reported an increase in the severity and duration of acute morbidity after salvage brachytherapy, although this has not been quantified.24 In patients having salvage brachytherapy urinary complications are demonstrably higher and have been reported with pelvic/penile pain in 6%, hematuria in 4%, and urinary incontinence in 14% to 24%.16,22 Rectal complications with proctitis may be seen in 4%. Bleeding or necrosis leading to the need for a colostomy is highly variable, ranging from 0%16 to 5%.23 The highest risk appears to be within a subgroup who were implanted after a failed retropubic implant and may not be representative of the average patient. Baseline urinary function should be assessed in patients being considered for salvage brachytherapy. Although prolonged urinary retention has not been reported in this population, it is a well-established risk in patients having brachytherapy for primary treatment. Terk et al25 reported an overall risk of prolonged retention in 6% of implants. They went on to document that patients with compromised baseline urinary func-
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tion, as measured by an elevated IPSS of 20 or greater, had a 29% risk of retention, whereas those with IPSS ⬍10 had a 2% risk. In the absence of specific data for patients having salvage brachytherapy, it is reasonable to use similar criteria and select favorable patients with an IPSS ⬍20 for treatment. In our own series, there was no significant rectal toxicity, but we determined an actuarial risk of urinary incontinence of 24% at 5 years. All incontinence developed between the first and third years. We have hypothesized that some of the incontinence was a result of a uniform sourceloading pattern used in all of our early patients. The value of improved dosimetry concepts is supported (but not proven) by the complete absence of any incontinence in the past 13 patients compared with higher risk in the original 17. It is interesting to compare these data to data from Kuban et al,6 which document a risk of major urinary complications in 18% of patients with untreated recurrent prostate cancer as a direct result of disease progression. It appears that both the acute and chronic morbidities are greater in salvage therapy than in primary treatment; however, in comparison to progressive untreated recurrence, the complications remain relatively modest. What Other Options Should Be Considered? Both observation and hormonal therapy were briefly addressed in the opening section. For the majority of recurrent prostate cancer patients, these must be considered the first choice for management. This would include all patients with a high probability of distant disease, limited life expectancy (relative to tumor growth), or very slowly growing cancers. In addition, men who are unable or unwilling to manage the expected morbidity from salvage treatments are best managed conservatively. Those being considered for aggressive salvage treatments should undergo repeat biopsy and be counseled to follow conservative management if local failure cannot be documented histologically. Patients who were candidates for radical prostatectomy at the time of the initial diagnosis and who are still young enough and healthy enough to consider definitive salvage treatment at the time of recurrence have also been considered candidates for salvage prostatectomy. In 1 survey of
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356 physicians, representing an approximately equal number of radiation oncologists and urologists, there was general agreement across specialty lines as to the appropriateness of salvage therapy in selected patients.26 Presented with a hypothetical 45- to 65-year-old patient with biopsy proven local recurrence and a PSA ⬍5 more than 2 years after external beam irradiation, 45% of clinicians recommended some form of definitive salvage treatment. More than half of the respondents preferred a salvage radical prostatectomy. Zinke et al27 reported a 55% clinical 5-year disease-free survival in similar patients before the introduction of PSA. Urinary incontinence rates of 32% were seen in their series. In an update of these Mayo Clinic surgical results,28 86 salvage prostatectomies were performed over 30 years and followed an average of 5.8 years. Fiveand 10-year cancer-specific survival of 85% and 54% were reported. Gleason score and DNA ploidy were suggested as independent prognostic predictors. In more recent series using PSA as an endpoint, disease-free survival of 44% to 80% have been reported with similar rates of complications.15,29-31 Bladder neck contractures were reported in 11% with only 10 of 43 patients remaining continent in 1 recent report.15 Cryotherapy has recently received a great deal of attention as primary and salvage treatment. Small numbers of patients have been reported after salvage cryotherapy, with several early series reporting positive biopsy rates of 25% to 35% at 1 year.32-34 Complications were significant with up to 60% incontinence and 9% rectal fistula risks. Using more current cryosurgery techniques,35 the biochemical control is reported as 66% at 12 months with similar positive biopsy rates. However, the incontinence risk is 9% with no fistulas reported, suggesting some benefit in complications from urethral warming but no significant improvement in cancer control.
Conclusions Selection criteria for patients considering salvage brachytherapy remain ambiguous. Many of the decisions hinge on an educated estimate of the relative risk of dying from recurrent prostate cancer versus intercurrent illness, the probability of remaining cancer free after salvage treatment, and the risk of complications. As such, it remains an art with many patients falling into a gray zone.
Table 1. Recommended Guidelines for Case Selection Exclusion Criteria
Inclusion Criteria
Negative or no prostate biopsy Recurrent Gleason 7–10 Distant disease
Positive prostate biopsy
Recurrent Gleason 2–6 Negative metastatic workup Life expectancy ⬍5 yr Life expectancy ⬎10 yr Disease free interval Disease free interval ⬍2 yr ⬎2 yr Short PSA doubling time Long PSA doubling time (⬍6 mo) (⬎9 mo) PSA ⬎10 PSA ⬍10
In an effort to “do no harm,” the decision to intervene ought to be made only after ruling out all possible reasons to exclude the patient from treatment. Certain selection and exclusion criteria can be extrapolated from available literature discussed in this article and are summarized in Table 1. Although they cannot be considered absolute, these guidelines should serve to identify patients most likely to require treatment and to benefit from that treatment. Historically, few patients have been considered appropriate candidates for any definitive salvage intervention after failing radiation treatment. With more young men receiving radiotherapy, this may change and salvage treatment might become more common in the coming years. Conversely, improvements in diagnostic studies and understanding of PSA kinetics might show that many of these patients harbor occult distant disease, rendering further local treatments futile. Selecting those men who will benefit most from brachytherapy will remain a significant but important challenge.
References 1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. Cancer J Clinicians 52:23-47, 2002 2. Moul JW: Treatment options for prostate cancer: Part 1—Stage, grade, PSA, and changes in the l990’s. Am J Managed Care 4:1031-1036, 1998 3. 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 prostrate carcinoma in the U.S. Cancer 86:1877-1882, 1999 4. Stephenson RA, Stanford JL: Population-based prostate cancer trends in the United States: Patters of change in the era of prostate-specific antigen. World J Urology 15: 331-335, l997
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5. The American Society for Therapeutic Radiology and Oncology (ASTRO) l997 Consensus Panel (Cox J, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF): Consensus statements on radiation therapy of prostate cancer: Guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. J Clin Oncol 17:1155-1163, 1999 6. Kuban DH, El-Mahdi AN, Schellhammer PF: Prognosis in patients with local recurrence after definitive irradiation for prostatic carcinoma. Cancer 63:2421-2425, 1989 7. Lee WR, Hanks GE, Hanlon A: Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: Clinical observations. J Clin Oncol l5:230-238, 1997 8. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 28l:1591-1597, 1999 9. Shipley WU, Thames HD, Sandler HM, et al: Radiation therapy for clinically localized prostate cancer: A multiinstitutional pooled analysis. JAMA 281:598-1604, l999 10. Stephenson RA: Population-based prostate cancer trends in the PSA-era: Data from the surveillance, epidemiology, and end results (SEER) program. Monogr Urol 19:1-19, l998 11. Schild SE, Buskirk SJ, Robinow JS, et al: The result of radiotherapy for isolated elevation of serum PSA levels following radical prostatectomy. Int J Radiat Oncol Biol Phys 23:141-145, 1992 12. Vicini FA, Ziaja EL, Kestin LL, et al: Treatment outcome with adjuvant and savage irradiation after radical prostatectomy for prostate cancer. Urology 54:111-117, 1999 13. Raymond JF, Vuong M, Russell KJ: Neutron beam radiotherapy for recurrent prostate cancer following radical prostatectomy. Int J Radiat Oncol Biol Phys 41:93-99, 1998 14. Wu JJ, King SC, Montana GS, et al: The efficacy of post-prostatectomy radiotherapy in patient with an isolate elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 32:317-323, 1995 15. Tefilli MV, Gheiler EL, Tuguert R, et al: Salvage surgery or salvage radiotherapy for locally recurrent prostate cancer. Urology 52:224-229, 1998 16. Beyer DC: Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology 54:880-883, 1999 17. Partin AW, Pearson JD, Landis PK, et al: Evaluation of serum prostate-specific antigen velocity after radical prostatectomy of distinguish local recurrence from distant metastases. Urology 43:649-659, 1994 18. Pollack A, Zagars GK, Kavadi VS: Prstate specific antigen doubling time and disease relapse after radiotherapy for prostate cancer. Cancer 74:670-678, 1994 19. Hanks GE, D’Amico A, Epstein BE, et al: Prostatic-specific antigen doubling times in patients with prostate cancer: A potentially useful reflection of tumor doubling time. Int J Radiat Oncol Biol Phys 27:125-127, 1993
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20. Goffinet DR, Martinez A, Freiha, F, et al: Iodine prostate implants for recurrent carcinomas after external beam irradiation: Preliminary results. Cancer 45:2717-2724, 1980 21. Wallner KE, Nori D, Morse MJ, et al: Iodine re-implantation for locally progressive prostatic carcinoma. J Urol 144:704-706, 1990 22. Loening SA, Turner JW: Use of percutaneous transperineal 198Au seeds to treat recurrent prostate adenocarcinoma after failure of definitive radiotherapy. Prostate 23:283-290, 1993 23. Grado GL, Collns JM, Kriegshauser JS, et al: Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 53:2-10, 1999 24. Battermann JJ: Feasibility of permanent implant for prostate cancer after previous radiotherapy in the true pelvis. Radiother Oncol 57:297-300, 2000 25. Sylvester J, Grimm P, Blasko J, et al: Transperineal permanent brachytherapy for local recurrence following external beam radiation for early-stage prostate cancer. J Brachyther Int 17:181-188, 2001 26. Terk MD, Stock RG, Stone NN: Indentification of patients at increased risk for prolonged urinary retention following radioactive see implantation of the prostate. J Urol 160:1379-1382, 1998 27. Zincke H: Radical prostatectomy and exenterative procedures for local failure after radiotherapy with curative intent: Comparison of outcomes. J Urol 147:894-899,1992 28. Cheng L, Sebo TJ, Slezak J, et al: Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy. Cancer 83:21642171, 1998 29. Ahlering TE, Lieskovsky G, Skinner DG: Salvage surgery plus androgen deprivation for radio-resistant prostatic adenocarcinoma. J Urol 147:900-902, 1992 30. Rogers E, Ohori M, Kassabian VS, et al: Salvage radical prostatectomy: Outcome measured by serum prostate specific antigen levels. J Urol 153:104-110, 1995 31. Lerner SE, Blute ML, Zincke H: Critical evaluation of salvage surgery for radio-recurrent/resistant prostate cancer. J Urol 154:1103-1109, l995 32. Miller RJ Jr, Cohen JK, Shuman B, et al: Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma. Cancer 77:1510-1514, 1996 33. Pisters LL, Von Eschenbach AC, Scott SM, et al: The efficacy and complications of salvage cryotherapy of the prostate. J Urol 157:921-925, 1997 34. Lee F, Bahn DK, McHugh TA, et al: Cryosurgery of prostate cancer. Use of adjuvant hormonal therapy and temperature monitoring—A one year follow-up. Anticancer Resource 17:1511-1515, 1997 35. De La Taille A, Hayek O, Benson MC, et al: Salvage cryotherapy for recurrent prostate cancer after radiation therapy: The Columbia experience. Urology 55:79-84, 2000