Brachytherapy 13 (2014) 53e58
Salvage brachytherapy for recurrent prostate cancer Carlos Vargas1,*, Douglas Swartz2, Apoorva Vashi2, Marc Blasser4, Ali Kasraeian3, Jamie Cesaretti1, Kathleen Kiley1, Jason Koziol1, Mitchell Terk1 1
Florida Center for Prostate Care, Jacksonville, FL 2 McIver Urological Clinic, Jacksonville, FL 3 Kasraeian Urology, Jacksonville, FL 4 Urology Associates of Northeast Florida, Orange Park, FL
ABSTRACT
PURPOSE: To evaluate the role of salvage prostate brachytherapy for locally recurrent prostate cancer after external beam radiation alone. METHODS AND MATERIALS: Sixty-nine consecutive patients treated with salvage brachytherapy after a local failure were analyzed. All patients were found to have pathologic proven recurrent prostate cancer at least 2 years after initial therapy and no regional or distant disease on imaging studies. Pd-103 was used with a prescribed pD90 of 100 Gy. In total, 89.9% of patients received androgen suppression (AS) as part of their salvage therapy. Patients whose prostate-specific antigen O5.0 ng/mL while on AS were considered to have castration resistant prostate cancer (CRPC). Patients on AS O6 months before salvage brachytherapy were considered to have delayed therapy. Patients retreated within 5 years after their initial treatment were considered to have early failures. RESULTS: Total median followup after salvage therapy was 5.0 years (0.6e13.7). From the date of salvage, 5-year biochemical control for low-risk patients was 85.6%, intermediate-risk patients 74.8%, and high-risk patients 66%. Five-year biochemical control was 73.8% for non-CRPC and 22% for CRPC cases (!0.001). Including and excluding CRPC cases, early treatment after failure vs. delayed treatment was significantly better ( p!0.05). Chronic adverse events were seen in few patients, with genitourinary Grade 3 toxicity of 8.7% and no genitourinary Grade 4 or gastrointestinal Grade 3 or higher toxicities. CONCLUSIONS: A subset of failures after definitive radiation is local in nature, and excellent control is possible with salvage brachytherapy. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Salvage therapy; Brachytherapy; Local failure; Outcome; Castration resistant; Biochemical control; Biochemical failure; Androgen suppression; Radiation therapy
Introduction The management of patients with a rising prostatespecific antigen (PSA) after initial local management has been controversial. PSA failures may represent local or distant disease and androgen suppression (AS) is considered first line for its management (1). However, more recent studies have shown that after radical prostatectomy the predominant mode of failure is local, and localized radiation will dramatically change the natural history of the disease Received 11 April 2013; received in revised form 17 October 2013; accepted 25 October 2013. * Corresponding author. Florida Center for Prostate Care, Radiation Oncology, 710-1 Lomax Street, Jacksonville, FL 32204. Tel.: þ1-904-4832310; fax: þ1-904-483-2313. E-mail address: [email protected] (C. Vargas).
(2). Published data showed improved outcomes, with a decrease in both distant metastasis and local failure after local adjuvant radiation (3e6). Biochemical failures are the consequence of a localized or a distant prostate cancer failure. A proportion of biochemical failures may ultimately harbor residual localized cancer only. Furthermore, distant failures at least partially result from a second wave of metastatic disease from an initial local failure (7, 8). Therefore, isolated locally recurrent disease may benefit from local salvage therapy. Salvage therapy for a biochemical failure after radiation is rarely performed. Few publications have explored the role of salvage brachytherapy for this subset of patients (9, 10). This series is the largest experience for salvage brachytherapy for prostate cancer patients and one of the largest series for salvage therapy (11, 12). Our manuscript helps explore
1538-4721/$ - see front matter Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2013.10.012
54
C. Vargas et al. / Brachytherapy 13 (2014) 53e58
the possibility of successful local salvage therapy for locally recurrent prostate cancer after definitive external beam radiation.
Methods and materials Patient and treatment data were collected in our institutional review boardeapproved database. For this analysis, only patients treated for salvage for locally recurrent disease were selected (n 5 72). Patients lost to followup (n 5 3) were excluded. A total of 69 patients were available for review. All patients treated had received external beam radiation therapy alone to a median dose of 68.4 Gy (63e77.4 Gy). The majority of these patients were treated with threedimensional conformal radiation. However, eight cases were treated to doses of 77.4 Gy with intensity-modulated radiation therapy (IMRT) with or without image-guided radiation therapy (IGRT). We did not retreat patients treated previously with brachytherapy alone or combined with external beam. All patients required a positive prostate biopsy at least 2 years after the completion of external beam treatment. They were biopsied after a suspected local failure alone. This was defined by the American Society for Radiation Oncology definition or Phoenix definition. The median time to biopsy was 6.8 years (2.3e21 years). Digital rectal prostate findings remained the same with a persistent prostate abnormality in 27 of the 33 cases. Patients’ initial characteristic and characteristics at the time of failure are seen in Table 1. All patients were evaluated initially by a thorough history and physical examination (including digital rectal examination) followed by routine laboratory studies, including pelvic CT scans, bone scans, serum PSA levels, and Gleason score (GS). Prostate needle biopsies were done for all cases at least 2 years after the completion of definitive radiation. All patients were re-staged according to the American Joint Committee on Cancer staging system 7th edition. Patients retreated within 5 years of initial definitive therapy are considered to have an early failure. Patients receiving AS for more than 6 months before salvage therapy are classified as having delayed therapy. Patients whose PSA was 5.0 ng/mL or higher while on AS were analyzed independently and considered to have castration resistant prostate cancer (CRPC) for the purpose of the analysis of this article. CRPC defines a continuous spectrum of disease on medical or surgical castration. CRPC can include a rising PSA alone to clinically progressive disease; a PSA O5.0 ng/mL on AS defined a subset within the overall population.
Table 1 Patient’s characteristics Characteristics
Initial
Salvage
Age (y) Range T-stage (%) T1 T2 T3 PSA (ng/mL) (%) !10 10e20 O20 Gleason score (%) #6 7 8e10 Median PNI (%) Androgen suppression (%) Median (y) Range (y) FU (y) median Median (y) Range (y)
63.9 51e78
72.5 55e88
38.6 55.7 5.7
45.0 50.8 4.2
62.0 24.0 14.0
84.5 12.7 2.8
50.7 29.6 19.7 6
32.4 40.9 26.8 7 8.5 89 1.38 0.3e12.3
32.4
12.51 3.5e23.5
5.02 0.6e13.7
PSA 5 prostate-specific antigen; PNI 5 perineural invasion; FU 5 followup.
2 months before salvage radiation. Intraoperative and postoperative doses can be seen in Table 2. Data collection and review An ongoing prostate database has been available at our institution for the last 15 years; first salvage case was treated in January 1989 and the last case in September 2011. Information for salvage cases was prospectively collected in the database with additional fields added for these patients exclusively. Any adverse event (AE) found was recorded and defined in the database. For purpose of this review, the radiation oncology charts and urology charts were available for all cases and reviewed and compared with the information available in the database. Each chart was re-reviewed by the treating radiation oncologists, and special attention Table 2 Intraoperative and postoperative pd-103 brachytherapy doses Intraoperative doses IOP pD90 (Gy) IOP UV 150 (cc)
Minimum Maximum Median Minimum Maximum Median Minimum Maximum Median
Postoperative doses 79.95 133.83 108 0 0.42 0 0 0.07 0
POP pD90 (Gy) POP UV 150 (cc) POP RV 100 (cc)
Minimum Maximum Median Minimum Maximum Median Minimum Maximum Median
74.63 124.54 99.7 0 0.42 0 0 0.59 0
Treatment
IOP RV 100 (cc)
All patients were implanted using palladium-103 and interactive ultrasound-guided transperineal technique described previously (13). Prescribed prostate D90 was 100 Gy. AS for at least 6 months was recommended for all cases starting
IOP Pd 5 intraoperative prostate dose; POP pD 5 postoperative prostate dose; IOP UV 5 intraoperative urethra volume; POP UV 5 postoperative urethra volume; IOP RV 5 intraoperative rectum volume; POP RV 5 postoperative rectum volume.
C. Vargas et al. / Brachytherapy 13 (2014) 53e58
was paid to ensure that all known AEs were reported as well as failures. When additional information was needed, patients were contacted by phone by our research associates. Dates for all events were recorded based on the date of the finding either by PSA, imaging, or physical examination. Cause of death was available for all cases. Biochemical failure after salvage was based on current nadir plus 2 ng/mL definition, start of AS regardless of PSA, or a clinical failure. Distant metastases were based on imaging findings with or without biopsy. PSA value for grouping CRPC patients was selected based on K-clustering. KaplaneMaier curves and Cox univariate and multivariate analysis was used for all statistical calculations employing Systat Software Inc., Chicago, IL, and a two-sided p # 0.05 was considered significant.
Results Median followup from the time of initial radiation treatment was 12.5 years and from the time of salvage brachytherapy was 5.03 years. The median time between initial and salvage treatment was 7.5 years. Median time between initial treatment and salvage treatment for the first quartile was 3.03 years (2.3e4.25 years), second quartile was 5.03 years (4.48e6.7 years), third quartile was 7.76 years (6.9e8.52 years), fourth quartile was 9.95 (8.63e20.2 years). Patient characteristics are seen in Table 1. AS was recommended as neoadjuvant and adjuvant therapy and was used in 89% of cases. Median AS duration was 6 months (3 months to 12.3 years). At the time of salvage treatment, 28 patients were on AS for more than 6 months. Nine of the 28 patients on AS had a PSA $5.0 ng/mL on AS and were considered to have CRPC.
55
Table 3 Outcomes for all patients (n 5 69) and excluding Castration resistant patients (60) Characteristics
All cases
Excluding CRPC
PSA failures (%) Clinical failures (%) Deaths from prostate cancer (%) Deaths (%)
31.4 11.4 5.7 35.7
23.3 6.7 1.7 31.7
CRPC 5 castration resistant prostate cancer; PSA 5 prostate-specific antigen.
and overall survival was 64%. A total of 24 deaths were seen in the study population. Similar to the Center Disease Control data, overall cancer deaths were 52% of the total. Second malignancies accounted for 26% and prostate cancer for an additional 26%. Myocardial infarctions accounted for 33%, infections including pneumonia 8%, and cerebrovascular accidents accounted for the remainder 7% of the deaths. Analysis from the date of salvage radiation excluding CRPC patients A total of 60 patients were available for analysis excluding cases found to have CRPC. GS, PSA, or T-stage employed are based on information at the time of salvage therapy. Excellent BC rates were seen for the different risk groups. Five-year BC rates for patients with a GS of 6 was 80.1%, for a GS of 7 was 73.7%, and for GS 8e10 was 66% ( p 5 0.67). However, it is important to understand that GS assigned at the time of failure may partially represent post-radiation changes and not the true architecture of the tumor. Five-year BC rates for patients with for T1c-T2a was 77.6%, for T2b was 74.7%, and for T2c-T3 was 50%
Analysis from the date of salvage radiation Biochemical control (BC) rates were significantly different for patients considered to be castration resistant vs. non-castration resistant. Five-year BC was 73.8% for non-castration resistant patients and only 20% for castration resistant patients ( p !0.001) as seen in Table 3. Patients with a treatment delay had a significant lower BC than patients who were treated within 6 months of the start of AS. Five-year BC was 77.7% for patients treated without delay vs. 43.3% ( p 5 0.004) as seen in Fig. 1. If CRPC cases are excluded, the difference was smaller but remained significant and clinically relevant. Five-year BC was 77.8% for patients treated without delay vs. 58.9% ( p 5 0.05). Interestingly, there was no difference in outcome for patients who failed within 5 years of the initial treatment vs. more than 5 years ( p 5 0.7). This suggests that in our patient population, patients found to have an isolated pathologic failure early after treatment were as likely to have a true localized failure as patients failing a long time after initial treatment. At the median followup of 5 years, distant metastasis rate was 10%, prostate cancererelated deaths were 4.4%,
Fig. 1. Biochemical control for delayed vs. non-delayed salvage brachytherapy. Delayeddpatients who have started hormones for more than 6 months before radiation. Non-delayeddpatients who have started hormones within 6 months before radiation. PSA 5 prostate-specific antigen.
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C. Vargas et al. / Brachytherapy 13 (2014) 53e58
patients in total had Grade 3 GU AEs. Five had hematuria, and no transfusion was needed. Three of the five had radiation changes in the bladder and fulguration was done for two and hyperbaric oxygen for one. For the other two patients, necrotic tissue in the prostate was found and hyperbaric oxygen was used. One patient had acute retention that was managed with a supra-pubic tube and it resolved without further surgery. Grade 2 GU events were found in three patients. Two patients needed a temporary catheter for acute urinary retention that resolved spontaneously. One patient had hematuria that resolved with conservative management. A total of four Grade 2 patients mentioned rectal bleeding, and no transfusions were needed. Three of them had a colonoscopy that revealed mild radiation changes, and no active bleeding was found or cauterization was done. One patient described rectal bleeding and elected not to undergo a colonoscopy. They were managed conservatively and bleeding resolved. A total of four Grade 2 gastrointestinal AE events were reported. Fig. 2. Biochemical control for salvage brachytherapy by pre-salvage PSA. PSA 5 prostate-specific antigen.
( p 5 0.73). Although a large relative difference was seen in outcome for T2c-T3 patients, this was non-significant, given that few cases had T2c-T3 disease (n 5 6). Five-year BC for patients with a pre-salvage PSA !10 was 76% compared with 50.8% with a higher PSA ( p 5 0.029) as seen in Fig. 2. From the date of salvage, 5-year BC for low-risk patients was 85.6%, intermediate-risk patients 74.8%, and high-risk patients 66%. Initial patient characteristics had no relationship with final outcome by GS at diagnosis ( p 5 0.3), PSA at diagnosis ( p 5 0.87), or T-stage at diagnosis ( p 5 0.49). Analysis from the date of initial radiation excluding CRPC patients Analysis from the date of the initial external radiation therapy shows a different perspective for this patient population. We have to consider that BC was achieved by the salvage procedure done after the initial external beam. However, these numbers show how the cure rate curves are shifted to the right by the salvage intervention. Ten-year BC for this population is very encouraging and similar to typical 10-year outcomes after initial prostate cancer therapy. Ten-year BC rates for low-risk patients was 100%, for intermediate-risk patients 85.2%, and for high-risk patients 88.9% ( p 5 0.6) and was not significantly different by risk group. We have to understand that this is due to curve shift to the right, and long-term BCs were lower. Toxicity Overall toxicity was low with genitourinary (GU) toxicity Grade 3 of only 8.7%. No GU Grade 4 toxicity and no gastrointestinal Grade 3 or higher toxicity was encountered. Six
Discussion Prostate cancer clinically behaves as a predominantly localized disease (2). Even patients with high-risk prostate cancer can achieve excellent outcomes with aggressive local therapy (13e18). However, a small subset of patients will fail after surgery or radiation. Multiple publications have shown that after radical prostatectomy patients found to have high-risk features will benefit from localized radiation therapy (2, 5, 6, 19). Randomized trials have shown that local failure is the predominant form of failure after radical prostatectomy (2). Contrary to this established concept, patients with a rising PSA after radiation therapy and no evidence of distant failure are often treated with AS alone, without appropriate documentation of a local failure (1). However, multiple publications have shown that persistent localized disease is relatively common for the small subset of patients that present with a biochemical failure (20e22). Locally persistent disease on biopsy specimens after radiation therapy has been shown to be a strong predictor for failure after radiation therapy (20e22). Thus, patients with a biochemical failure may have a high risk of harboring persistent disease in the prostate that will ultimately lead to distant metastatic failure. Salvage radiation therapy after a biochemical failure for patients with proven localized disease only can achieve excellent control rates with a low toxicity. This publication is the largest series of salvage radiation for a localized failure after radiation. Toxicity in this series was low although it is a previously irradiated population. However, a selection bias may have been present because only patients without major complications after the first course of radiation were selected. Severe AEs after radiation are rare. It is well known that likely a genetic predisposition is responsible for some of these events (23). Thus, in effect, it is likely that patients without
C. Vargas et al. / Brachytherapy 13 (2014) 53e58
genetic mutations associated with lower radiation repair were selected. Furthermore, all patients treated with salvage brachytherapy underwent an intraoperatively planned seed implant technique. We have a large experience at our institution with this technique, having treated close to 4000 patients with our published results showing very low toxicity (13, 21). In this same note, the skill set and experience at our institution could have played a role. Technique may play also a role because the Mount Sinai publication employing a similar salvage technique had the same overall toxicity as our series (9). Patients with a rising and elevated PSA while on AS were not good candidates for salvage local therapy. Is very likely that distant disease is present by the time patients become castration resistant (24). Even in the absence of clinically apparent distant disease, microscopic foci are likely to be present (25). In our series, most castration resistant patients presented with distant clinical disease within the next few years following salvage therapy. Although the definition of CRPC in this study excluded patients with a lower rising PSA on medical castration, the higher threshold may define a population more likely to harbor metastatic disease even with negative scans. It was clearly seen that patients with a relatively high PSA on medical castration should not be offered salvage therapy. In retrospect, some patients in this study were treated before the term CRPC was commonly used. No difference in outcome was seen for patients treated within 5 years of the initial treatment or those treated after. This underscores that prostate cancer failure has an important local component and can remain localized for a relatively long time. However, after a biochemical progression is found, the possibility of local progression should be addressed and treated appropriately. Patients treated shortly after behaved better than patients whose treatment was delayed. The worse prognosis with delayed therapy in our population was partially due to the competing risk of castration resistant disease appearing. However, even accounting for it, delayed treatment had a detrimental effect. Our definition for delayed therapy was used as surrogate to define patients who were started on AS and later elected salvage therapy. This successfully showed a difference in outcome that was significant. Salvage therapy results were excellent. If 10-year outcomes are analyzed based on the date of initial treatment, patients whose disease remained localized will have similar outcomes as patients who did not fail. The excellent results of this study emphasize the importance of determining the site of failure and initiation of early salvage therapy when appropriate. Shortcomings are found in any retrospective publication. They include the relative long duration of the study and the potential differences in treatments for the patient population. Although inclusion criteria were uniform, it was not as strict as in prospective trial with more rigorous eligibility criteria. Another potential criticism of any salvage publication is that
57
it self-selects patients who are motivated and potentially overall healthier. However, other benefits can be seen from a heterogeneous population such as treatment effects and outcomes not published previously. It was apparent in this study that patients’ with a rising PSA on medical castration behave differently and likely present with subclinical metastatic disease. In a similar manner, delaying salvage therapy even while on AS may be deleterious to the outcome of the patient.
Conclusion Results with salvage brachytherapy are better than expected and similar to the general treated population. Toxicity was relatively low. References [1] Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238e244. [2] Swanson GP, Hussey MA, Tangen CM, et al. Predominant treatment failure in postprostatectomy patients is local: Analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007;25: 2225e2229. [3] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. J Urol 2009;181:956e962. [4] Van der Kwast TH, Bolla M, Van PH, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178e4186. [5] Vargas C, Kestin LL, Weed DW, et al. Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Radiat Oncol Biol Phys 2005;61:714e724. [6] Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009;27:2924e2930. [7] Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 1991;21:537e547. [8] Kuban DA, el-Mahdi AM, Schellhammer PF. Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma. Urology 1987;30:420e426. [9] Burri RJ, Stone NN, Unger P, et al. Long-term outcome and toxicity of salvage brachytherapy for local failure after initial radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010;77:1338e1344. [10] Grado GL, Collins JM, Kriegshauser JS, et al. Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 1999; 53:2e10. [11] Bianco FJ Jr, Scardino PT, Stephenson AJ, et al. Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:448e453. [12] Izawa JI, Madsen LT, Scott SM, et al. Salvage cryotherapy for recurrent prostate cancer after radiotherapy: Variables affecting patient outcome. J Clin Oncol 2002;20:2664e2671. [13] Vargas C, Swartz D, Vashi A, et al. Long-term outcomes and prognostic factors in patients treated with intraoperatively planned prostate brachytherapy. Brachytherapy 2013;12:120e125.
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[14] Viani GA, da Silva LG, Stefano EJ. High-dose conformal radiotherapy reduces prostate cancer-specific mortality: Results of a meta-analysis. Int J Radiat Oncol Biol Phys 2012;83:e619ee625. [15] Vargas CE, Martinez AA, Boike TP, et al. High-dose irradiation for prostate cancer via a high-dose-rate brachytherapy boost: Results of a phase I to II study. Int J Radiat Oncol Biol Phys 2006;66:416e423. [16] Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109(Suppl 1):22e29. [17] Walz J, Joniau S, Chun FK, et al. Pathological results and rates of treatment failure in high-risk prostate cancer patients after radical prostatectomy. BJU Int 2011;107:765e770. [18] Menon M, Bhandari M, Gupta N, et al. Biochemical recurrence following robot-assisted radical prostatectomy: Analysis of 1384 patients with a median 5-year follow-up. Eur Urol 2010;58:838e846. [19] Bolla M, Van PH, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: Long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380:1974e1976.
[20] Zelefsky MJ, Reuter VE, Fuks Z, et al. Influence of local tumor control on distant metastases and cancer related mortality after external beam radiotherapy for prostate cancer. J Urol 2008;179:1368e1373. [21] Stone NN, Stock RG, White I, et al. Patterns of local failure following prostate brachytherapy. J Urol 2007;177:1759e1763. [22] Kestin LL, Goldstein NS, Vicini FA, et al. Pathologic evidence of dose-response and dose-volume relationships for prostate cancer treated with combined external beam radiotherapy and highdose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54: 107e118. [23] Langsenlehner T, Renner W, Gerger A, et al. Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients. Radiother Oncol 2011;98:387e393. [24] Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005;23:8253e8261. [25] Smith MR, Saad F, Coleman R, et al. Denosumab and bonemetastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39e46.
Salvage brachytherapy for recurrent prostate cancer Carlos Vargas1,*, Douglas Swartz2, Apoorva Vashi2, Marc Blasser4, Ali Kasraeian3, Jamie Cesaretti1, Kathleen Kiley1, Jason Koziol1, Mitchell Terk1 1
Florida Center for Prostate Care, Jacksonville, FL 2 McIver Urological Clinic, Jacksonville, FL 3 Kasraeian Urology, Jacksonville, FL 4 Urology Associates of Northeast Florida, Orange Park, FL
ABSTRACT
PURPOSE: To evaluate the role of salvage prostate brachytherapy for locally recurrent prostate cancer after external beam radiation alone. METHODS AND MATERIALS: Sixty-nine consecutive patients treated with salvage brachytherapy after a local failure were analyzed. All patients were found to have pathologic proven recurrent prostate cancer at least 2 years after initial therapy and no regional or distant disease on imaging studies. Pd-103 was used with a prescribed pD90 of 100 Gy. In total, 89.9% of patients received androgen suppression (AS) as part of their salvage therapy. Patients whose prostate-specific antigen O5.0 ng/mL while on AS were considered to have castration resistant prostate cancer (CRPC). Patients on AS O6 months before salvage brachytherapy were considered to have delayed therapy. Patients retreated within 5 years after their initial treatment were considered to have early failures. RESULTS: Total median followup after salvage therapy was 5.0 years (0.6e13.7). From the date of salvage, 5-year biochemical control for low-risk patients was 85.6%, intermediate-risk patients 74.8%, and high-risk patients 66%. Five-year biochemical control was 73.8% for non-CRPC and 22% for CRPC cases (!0.001). Including and excluding CRPC cases, early treatment after failure vs. delayed treatment was significantly better ( p!0.05). Chronic adverse events were seen in few patients, with genitourinary Grade 3 toxicity of 8.7% and no genitourinary Grade 4 or gastrointestinal Grade 3 or higher toxicities. CONCLUSIONS: A subset of failures after definitive radiation is local in nature, and excellent control is possible with salvage brachytherapy. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Salvage therapy; Brachytherapy; Local failure; Outcome; Castration resistant; Biochemical control; Biochemical failure; Androgen suppression; Radiation therapy
Introduction The management of patients with a rising prostatespecific antigen (PSA) after initial local management has been controversial. PSA failures may represent local or distant disease and androgen suppression (AS) is considered first line for its management (1). However, more recent studies have shown that after radical prostatectomy the predominant mode of failure is local, and localized radiation will dramatically change the natural history of the disease Received 11 April 2013; received in revised form 17 October 2013; accepted 25 October 2013. * Corresponding author. Florida Center for Prostate Care, Radiation Oncology, 710-1 Lomax Street, Jacksonville, FL 32204. Tel.: þ1-904-4832310; fax: þ1-904-483-2313. E-mail address: [email protected] (C. Vargas).
(2). Published data showed improved outcomes, with a decrease in both distant metastasis and local failure after local adjuvant radiation (3e6). Biochemical failures are the consequence of a localized or a distant prostate cancer failure. A proportion of biochemical failures may ultimately harbor residual localized cancer only. Furthermore, distant failures at least partially result from a second wave of metastatic disease from an initial local failure (7, 8). Therefore, isolated locally recurrent disease may benefit from local salvage therapy. Salvage therapy for a biochemical failure after radiation is rarely performed. Few publications have explored the role of salvage brachytherapy for this subset of patients (9, 10). This series is the largest experience for salvage brachytherapy for prostate cancer patients and one of the largest series for salvage therapy (11, 12). Our manuscript helps explore
1538-4721/$ - see front matter Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2013.10.012
54
C. Vargas et al. / Brachytherapy 13 (2014) 53e58
the possibility of successful local salvage therapy for locally recurrent prostate cancer after definitive external beam radiation.
Methods and materials Patient and treatment data were collected in our institutional review boardeapproved database. For this analysis, only patients treated for salvage for locally recurrent disease were selected (n 5 72). Patients lost to followup (n 5 3) were excluded. A total of 69 patients were available for review. All patients treated had received external beam radiation therapy alone to a median dose of 68.4 Gy (63e77.4 Gy). The majority of these patients were treated with threedimensional conformal radiation. However, eight cases were treated to doses of 77.4 Gy with intensity-modulated radiation therapy (IMRT) with or without image-guided radiation therapy (IGRT). We did not retreat patients treated previously with brachytherapy alone or combined with external beam. All patients required a positive prostate biopsy at least 2 years after the completion of external beam treatment. They were biopsied after a suspected local failure alone. This was defined by the American Society for Radiation Oncology definition or Phoenix definition. The median time to biopsy was 6.8 years (2.3e21 years). Digital rectal prostate findings remained the same with a persistent prostate abnormality in 27 of the 33 cases. Patients’ initial characteristic and characteristics at the time of failure are seen in Table 1. All patients were evaluated initially by a thorough history and physical examination (including digital rectal examination) followed by routine laboratory studies, including pelvic CT scans, bone scans, serum PSA levels, and Gleason score (GS). Prostate needle biopsies were done for all cases at least 2 years after the completion of definitive radiation. All patients were re-staged according to the American Joint Committee on Cancer staging system 7th edition. Patients retreated within 5 years of initial definitive therapy are considered to have an early failure. Patients receiving AS for more than 6 months before salvage therapy are classified as having delayed therapy. Patients whose PSA was 5.0 ng/mL or higher while on AS were analyzed independently and considered to have castration resistant prostate cancer (CRPC) for the purpose of the analysis of this article. CRPC defines a continuous spectrum of disease on medical or surgical castration. CRPC can include a rising PSA alone to clinically progressive disease; a PSA O5.0 ng/mL on AS defined a subset within the overall population.
Table 1 Patient’s characteristics Characteristics
Initial
Salvage
Age (y) Range T-stage (%) T1 T2 T3 PSA (ng/mL) (%) !10 10e20 O20 Gleason score (%) #6 7 8e10 Median PNI (%) Androgen suppression (%) Median (y) Range (y) FU (y) median Median (y) Range (y)
63.9 51e78
72.5 55e88
38.6 55.7 5.7
45.0 50.8 4.2
62.0 24.0 14.0
84.5 12.7 2.8
50.7 29.6 19.7 6
32.4 40.9 26.8 7 8.5 89 1.38 0.3e12.3
32.4
12.51 3.5e23.5
5.02 0.6e13.7
PSA 5 prostate-specific antigen; PNI 5 perineural invasion; FU 5 followup.
2 months before salvage radiation. Intraoperative and postoperative doses can be seen in Table 2. Data collection and review An ongoing prostate database has been available at our institution for the last 15 years; first salvage case was treated in January 1989 and the last case in September 2011. Information for salvage cases was prospectively collected in the database with additional fields added for these patients exclusively. Any adverse event (AE) found was recorded and defined in the database. For purpose of this review, the radiation oncology charts and urology charts were available for all cases and reviewed and compared with the information available in the database. Each chart was re-reviewed by the treating radiation oncologists, and special attention Table 2 Intraoperative and postoperative pd-103 brachytherapy doses Intraoperative doses IOP pD90 (Gy) IOP UV 150 (cc)
Minimum Maximum Median Minimum Maximum Median Minimum Maximum Median
Postoperative doses 79.95 133.83 108 0 0.42 0 0 0.07 0
POP pD90 (Gy) POP UV 150 (cc) POP RV 100 (cc)
Minimum Maximum Median Minimum Maximum Median Minimum Maximum Median
74.63 124.54 99.7 0 0.42 0 0 0.59 0
Treatment
IOP RV 100 (cc)
All patients were implanted using palladium-103 and interactive ultrasound-guided transperineal technique described previously (13). Prescribed prostate D90 was 100 Gy. AS for at least 6 months was recommended for all cases starting
IOP Pd 5 intraoperative prostate dose; POP pD 5 postoperative prostate dose; IOP UV 5 intraoperative urethra volume; POP UV 5 postoperative urethra volume; IOP RV 5 intraoperative rectum volume; POP RV 5 postoperative rectum volume.
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was paid to ensure that all known AEs were reported as well as failures. When additional information was needed, patients were contacted by phone by our research associates. Dates for all events were recorded based on the date of the finding either by PSA, imaging, or physical examination. Cause of death was available for all cases. Biochemical failure after salvage was based on current nadir plus 2 ng/mL definition, start of AS regardless of PSA, or a clinical failure. Distant metastases were based on imaging findings with or without biopsy. PSA value for grouping CRPC patients was selected based on K-clustering. KaplaneMaier curves and Cox univariate and multivariate analysis was used for all statistical calculations employing Systat Software Inc., Chicago, IL, and a two-sided p # 0.05 was considered significant.
Results Median followup from the time of initial radiation treatment was 12.5 years and from the time of salvage brachytherapy was 5.03 years. The median time between initial and salvage treatment was 7.5 years. Median time between initial treatment and salvage treatment for the first quartile was 3.03 years (2.3e4.25 years), second quartile was 5.03 years (4.48e6.7 years), third quartile was 7.76 years (6.9e8.52 years), fourth quartile was 9.95 (8.63e20.2 years). Patient characteristics are seen in Table 1. AS was recommended as neoadjuvant and adjuvant therapy and was used in 89% of cases. Median AS duration was 6 months (3 months to 12.3 years). At the time of salvage treatment, 28 patients were on AS for more than 6 months. Nine of the 28 patients on AS had a PSA $5.0 ng/mL on AS and were considered to have CRPC.
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Table 3 Outcomes for all patients (n 5 69) and excluding Castration resistant patients (60) Characteristics
All cases
Excluding CRPC
PSA failures (%) Clinical failures (%) Deaths from prostate cancer (%) Deaths (%)
31.4 11.4 5.7 35.7
23.3 6.7 1.7 31.7
CRPC 5 castration resistant prostate cancer; PSA 5 prostate-specific antigen.
and overall survival was 64%. A total of 24 deaths were seen in the study population. Similar to the Center Disease Control data, overall cancer deaths were 52% of the total. Second malignancies accounted for 26% and prostate cancer for an additional 26%. Myocardial infarctions accounted for 33%, infections including pneumonia 8%, and cerebrovascular accidents accounted for the remainder 7% of the deaths. Analysis from the date of salvage radiation excluding CRPC patients A total of 60 patients were available for analysis excluding cases found to have CRPC. GS, PSA, or T-stage employed are based on information at the time of salvage therapy. Excellent BC rates were seen for the different risk groups. Five-year BC rates for patients with a GS of 6 was 80.1%, for a GS of 7 was 73.7%, and for GS 8e10 was 66% ( p 5 0.67). However, it is important to understand that GS assigned at the time of failure may partially represent post-radiation changes and not the true architecture of the tumor. Five-year BC rates for patients with for T1c-T2a was 77.6%, for T2b was 74.7%, and for T2c-T3 was 50%
Analysis from the date of salvage radiation Biochemical control (BC) rates were significantly different for patients considered to be castration resistant vs. non-castration resistant. Five-year BC was 73.8% for non-castration resistant patients and only 20% for castration resistant patients ( p !0.001) as seen in Table 3. Patients with a treatment delay had a significant lower BC than patients who were treated within 6 months of the start of AS. Five-year BC was 77.7% for patients treated without delay vs. 43.3% ( p 5 0.004) as seen in Fig. 1. If CRPC cases are excluded, the difference was smaller but remained significant and clinically relevant. Five-year BC was 77.8% for patients treated without delay vs. 58.9% ( p 5 0.05). Interestingly, there was no difference in outcome for patients who failed within 5 years of the initial treatment vs. more than 5 years ( p 5 0.7). This suggests that in our patient population, patients found to have an isolated pathologic failure early after treatment were as likely to have a true localized failure as patients failing a long time after initial treatment. At the median followup of 5 years, distant metastasis rate was 10%, prostate cancererelated deaths were 4.4%,
Fig. 1. Biochemical control for delayed vs. non-delayed salvage brachytherapy. Delayeddpatients who have started hormones for more than 6 months before radiation. Non-delayeddpatients who have started hormones within 6 months before radiation. PSA 5 prostate-specific antigen.
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patients in total had Grade 3 GU AEs. Five had hematuria, and no transfusion was needed. Three of the five had radiation changes in the bladder and fulguration was done for two and hyperbaric oxygen for one. For the other two patients, necrotic tissue in the prostate was found and hyperbaric oxygen was used. One patient had acute retention that was managed with a supra-pubic tube and it resolved without further surgery. Grade 2 GU events were found in three patients. Two patients needed a temporary catheter for acute urinary retention that resolved spontaneously. One patient had hematuria that resolved with conservative management. A total of four Grade 2 patients mentioned rectal bleeding, and no transfusions were needed. Three of them had a colonoscopy that revealed mild radiation changes, and no active bleeding was found or cauterization was done. One patient described rectal bleeding and elected not to undergo a colonoscopy. They were managed conservatively and bleeding resolved. A total of four Grade 2 gastrointestinal AE events were reported. Fig. 2. Biochemical control for salvage brachytherapy by pre-salvage PSA. PSA 5 prostate-specific antigen.
( p 5 0.73). Although a large relative difference was seen in outcome for T2c-T3 patients, this was non-significant, given that few cases had T2c-T3 disease (n 5 6). Five-year BC for patients with a pre-salvage PSA !10 was 76% compared with 50.8% with a higher PSA ( p 5 0.029) as seen in Fig. 2. From the date of salvage, 5-year BC for low-risk patients was 85.6%, intermediate-risk patients 74.8%, and high-risk patients 66%. Initial patient characteristics had no relationship with final outcome by GS at diagnosis ( p 5 0.3), PSA at diagnosis ( p 5 0.87), or T-stage at diagnosis ( p 5 0.49). Analysis from the date of initial radiation excluding CRPC patients Analysis from the date of the initial external radiation therapy shows a different perspective for this patient population. We have to consider that BC was achieved by the salvage procedure done after the initial external beam. However, these numbers show how the cure rate curves are shifted to the right by the salvage intervention. Ten-year BC for this population is very encouraging and similar to typical 10-year outcomes after initial prostate cancer therapy. Ten-year BC rates for low-risk patients was 100%, for intermediate-risk patients 85.2%, and for high-risk patients 88.9% ( p 5 0.6) and was not significantly different by risk group. We have to understand that this is due to curve shift to the right, and long-term BCs were lower. Toxicity Overall toxicity was low with genitourinary (GU) toxicity Grade 3 of only 8.7%. No GU Grade 4 toxicity and no gastrointestinal Grade 3 or higher toxicity was encountered. Six
Discussion Prostate cancer clinically behaves as a predominantly localized disease (2). Even patients with high-risk prostate cancer can achieve excellent outcomes with aggressive local therapy (13e18). However, a small subset of patients will fail after surgery or radiation. Multiple publications have shown that after radical prostatectomy patients found to have high-risk features will benefit from localized radiation therapy (2, 5, 6, 19). Randomized trials have shown that local failure is the predominant form of failure after radical prostatectomy (2). Contrary to this established concept, patients with a rising PSA after radiation therapy and no evidence of distant failure are often treated with AS alone, without appropriate documentation of a local failure (1). However, multiple publications have shown that persistent localized disease is relatively common for the small subset of patients that present with a biochemical failure (20e22). Locally persistent disease on biopsy specimens after radiation therapy has been shown to be a strong predictor for failure after radiation therapy (20e22). Thus, patients with a biochemical failure may have a high risk of harboring persistent disease in the prostate that will ultimately lead to distant metastatic failure. Salvage radiation therapy after a biochemical failure for patients with proven localized disease only can achieve excellent control rates with a low toxicity. This publication is the largest series of salvage radiation for a localized failure after radiation. Toxicity in this series was low although it is a previously irradiated population. However, a selection bias may have been present because only patients without major complications after the first course of radiation were selected. Severe AEs after radiation are rare. It is well known that likely a genetic predisposition is responsible for some of these events (23). Thus, in effect, it is likely that patients without
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genetic mutations associated with lower radiation repair were selected. Furthermore, all patients treated with salvage brachytherapy underwent an intraoperatively planned seed implant technique. We have a large experience at our institution with this technique, having treated close to 4000 patients with our published results showing very low toxicity (13, 21). In this same note, the skill set and experience at our institution could have played a role. Technique may play also a role because the Mount Sinai publication employing a similar salvage technique had the same overall toxicity as our series (9). Patients with a rising and elevated PSA while on AS were not good candidates for salvage local therapy. Is very likely that distant disease is present by the time patients become castration resistant (24). Even in the absence of clinically apparent distant disease, microscopic foci are likely to be present (25). In our series, most castration resistant patients presented with distant clinical disease within the next few years following salvage therapy. Although the definition of CRPC in this study excluded patients with a lower rising PSA on medical castration, the higher threshold may define a population more likely to harbor metastatic disease even with negative scans. It was clearly seen that patients with a relatively high PSA on medical castration should not be offered salvage therapy. In retrospect, some patients in this study were treated before the term CRPC was commonly used. No difference in outcome was seen for patients treated within 5 years of the initial treatment or those treated after. This underscores that prostate cancer failure has an important local component and can remain localized for a relatively long time. However, after a biochemical progression is found, the possibility of local progression should be addressed and treated appropriately. Patients treated shortly after behaved better than patients whose treatment was delayed. The worse prognosis with delayed therapy in our population was partially due to the competing risk of castration resistant disease appearing. However, even accounting for it, delayed treatment had a detrimental effect. Our definition for delayed therapy was used as surrogate to define patients who were started on AS and later elected salvage therapy. This successfully showed a difference in outcome that was significant. Salvage therapy results were excellent. If 10-year outcomes are analyzed based on the date of initial treatment, patients whose disease remained localized will have similar outcomes as patients who did not fail. The excellent results of this study emphasize the importance of determining the site of failure and initiation of early salvage therapy when appropriate. Shortcomings are found in any retrospective publication. They include the relative long duration of the study and the potential differences in treatments for the patient population. Although inclusion criteria were uniform, it was not as strict as in prospective trial with more rigorous eligibility criteria. Another potential criticism of any salvage publication is that
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it self-selects patients who are motivated and potentially overall healthier. However, other benefits can be seen from a heterogeneous population such as treatment effects and outcomes not published previously. It was apparent in this study that patients’ with a rising PSA on medical castration behave differently and likely present with subclinical metastatic disease. In a similar manner, delaying salvage therapy even while on AS may be deleterious to the outcome of the patient.
Conclusion Results with salvage brachytherapy are better than expected and similar to the general treated population. Toxicity was relatively low. References [1] Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238e244. [2] Swanson GP, Hussey MA, Tangen CM, et al. Predominant treatment failure in postprostatectomy patients is local: Analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007;25: 2225e2229. [3] Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. J Urol 2009;181:956e962. [4] Van der Kwast TH, Bolla M, Van PH, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178e4186. [5] Vargas C, Kestin LL, Weed DW, et al. Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Radiat Oncol Biol Phys 2005;61:714e724. [6] Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009;27:2924e2930. [7] Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 1991;21:537e547. [8] Kuban DA, el-Mahdi AM, Schellhammer PF. Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma. Urology 1987;30:420e426. [9] Burri RJ, Stone NN, Unger P, et al. Long-term outcome and toxicity of salvage brachytherapy for local failure after initial radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010;77:1338e1344. [10] Grado GL, Collins JM, Kriegshauser JS, et al. Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 1999; 53:2e10. [11] Bianco FJ Jr, Scardino PT, Stephenson AJ, et al. Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:448e453. [12] Izawa JI, Madsen LT, Scott SM, et al. Salvage cryotherapy for recurrent prostate cancer after radiotherapy: Variables affecting patient outcome. J Clin Oncol 2002;20:2664e2671. [13] Vargas C, Swartz D, Vashi A, et al. Long-term outcomes and prognostic factors in patients treated with intraoperatively planned prostate brachytherapy. Brachytherapy 2013;12:120e125.
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[14] Viani GA, da Silva LG, Stefano EJ. High-dose conformal radiotherapy reduces prostate cancer-specific mortality: Results of a meta-analysis. Int J Radiat Oncol Biol Phys 2012;83:e619ee625. [15] Vargas CE, Martinez AA, Boike TP, et al. High-dose irradiation for prostate cancer via a high-dose-rate brachytherapy boost: Results of a phase I to II study. Int J Radiat Oncol Biol Phys 2006;66:416e423. [16] Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109(Suppl 1):22e29. [17] Walz J, Joniau S, Chun FK, et al. Pathological results and rates of treatment failure in high-risk prostate cancer patients after radical prostatectomy. BJU Int 2011;107:765e770. [18] Menon M, Bhandari M, Gupta N, et al. Biochemical recurrence following robot-assisted radical prostatectomy: Analysis of 1384 patients with a median 5-year follow-up. Eur Urol 2010;58:838e846. [19] Bolla M, Van PH, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: Long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380:1974e1976.
[20] Zelefsky MJ, Reuter VE, Fuks Z, et al. Influence of local tumor control on distant metastases and cancer related mortality after external beam radiotherapy for prostate cancer. J Urol 2008;179:1368e1373. [21] Stone NN, Stock RG, White I, et al. Patterns of local failure following prostate brachytherapy. J Urol 2007;177:1759e1763. [22] Kestin LL, Goldstein NS, Vicini FA, et al. Pathologic evidence of dose-response and dose-volume relationships for prostate cancer treated with combined external beam radiotherapy and highdose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54: 107e118. [23] Langsenlehner T, Renner W, Gerger A, et al. Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients. Radiother Oncol 2011;98:387e393. [24] Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005;23:8253e8261. [25] Smith MR, Saad F, Coleman R, et al. Denosumab and bonemetastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39e46.
