Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎
Original article
Underutilization of local salvage therapy after radiation therapy for prostate cancer1 Henry Tran, M.D.a, Jaime Kwoka, Tom Pickles, M.D.b, Scott Tyldesley, M.D.b, Peter C. Black, M.D.a,* a
b
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada Department of Radiation Oncology, Vancouver Cancer Center, BC Cancer Agency, Vancouver, Canada Received 14 August 2013; received in revised form 9 December 2013; accepted 30 December 2013
Abstract Objective: To evaluate the rates at which patients are offered and receive local salvage therapy (LST) after failure of primary radiotherapy for localized prostate cancer, as it is the only potentially curative treatment for localized recurrence but appears to be underutilized when compared with androgen-deprivation therapy (ADT) or observation. Materials and methods: Patients with localized prostate cancer who received primary radiotherapy with curative intent between 1999 and 2000 were identified in the British Columbia Tumour Registry. Exclusion criteria included patient age 472 years, prostate-specific antigen 440 ng/ml, and clinical stage T4 at diagnosis. Data on clinicopathologic features, primary therapy, prostate-specific antigen kinetics, and salvage therapy were collected retrospectively. Radiation failure was defined as biochemical recurrence according to the Phoenix criteria or by initiation of salvage therapy. Results: Of 1,782 patients treated in the study period, 1,067 met inclusion criteria. Of these, 257 failed radiation therapy. Radiation therapy failure was managed with observation (412 mo) in 126 patients and ADT in 119. Of the observed patients, 66 subsequently received ADT. Five patients (1.8%) received LST (3 radical prostatectomy and 2 brachytherapy). Conclusions: Only 2% of patients relapsing after radiation therapy for localized prostate cancer received LST. Although the benefits of LST are unproven, these findings reveal a possible underutilization of LST and indicate a need for enhanced collaboration between specialties to optimize care of this challenging cohort. r 2014 Elsevier Inc. All rights reserved. Keywords: Prostatic neoplasms; Radiotherapy; Brachytherapy; Salvage therapy; Cryotherapy; Salvage radical prostatectomy; Salvage brachytherapy
1. Introduction External beam radiation therapy (EBRT) and brachytherapy (BT) are commonly used treatment modalities for localized prostate cancer. Although highly efficacious, some patients do have disease recurrence, and management of these patients has traditionally been challenging. Several clinical questions arise in any patient, including whether a rise in prostate-specific antigen (PSA) is reflective of disease recurrence, whether treatment of the biochemical recurrence (BCR) is necessary, and whether the recurrence is localized to the prostate or metastatic. If one is convinced
1
Funding: UBC Summer Student Research Program.
Corresponding author. Tel.: þ1-604-875-4818; fax: þ1-604-875-5654. E-mail address: [email protected] (P.C. Black). *
1078-1439/$ – see front matter r 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2013.12.014
that the recurrence warrants therapy and is localized to the prostate, a number of local therapy options are available. Treatment options include salvage cryotherapy (SCT) [1,2], high-intensity focused ultrasound (HIFU) ablation [3], salvage BT (SBT) [4], and salvage radical prostatectomy (SRP) [2,5,6]. Further alternatives include observation for presumed indolent recurrence and androgen-deprivation therapy (ADT). Despite these many alternatives, our impression is that most patients are not offered local salvage therapy (LST) after failure of EBRT or BT. For example, the number of patients treated with SRP in Vancouver has been minimal (21 cases over 15 y) [6]. Observation and ADT appear to be the mainstays of therapy. LSTs, however, are the only potentially curative options. There is risk of underutilizing LST and missing opportunity for cure. SRP is the most established and definitive local salvage option, but it may be
2
H. Tran et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–6
avoided in many cases owing to technical difficulty and high risk of subsequent incontinence and impotence [5,7]. SCT, HIFU, and SBT are newer salvage options associated with less patient morbidity but also less certain efficacy [8]. Nevertheless, the likelihood of cure is difficult to predict in any individual patient for any given salvage therapy modality. In this study, we aimed to ascertain rates at which patients receive LST after failure of radiation therapy in British Columbia (B.C.).
2. Materials and methods All patients with localized prostate cancer (T1-3N0M0) who received primary radiation treatment (EBRT or BT) with curative intent in B.C. from January 1999 until December 2000 were identified from the prospectively maintained B.C. Cancer Agency database. These cases were linked to ADT records captured in a province-wide pharmacy database. The study was approved by the Research Ethics Board of University of British Columbia (protocol H12-01180). The medical records of the identified patients were retrospectively reviewed to acquire variables not included in the prospective database. Patients older than 72 years and those with high-risk disease defined by a PSA 440 ng/ml and clinical T4 disease at diagnosis were excluded. These arbitrary criteria were set based on the consensus of the authors that these patients were unlikely to be eligible for LST in the event of BCR. Gleason score was not used as exclusion criteria. Patients who had combined primary orchiectomy and radiotherapy were also excluded. Data regarding patient characteristics, clinical and pathologic cancer features (pretreatment PSA, clinical tumor stage, and Gleason score), primary radiotherapy modality (dose, fractions, start/end dates, and concomitant ADT), and subsequent PSA kinetics (PSA nadir and date/time to recurrence) were collected. A PSA nadir was not recorded for 26 patients who had no PSA follow-up within 3 years after primary EBRT or before secondary intervention. We determined from the patient charts which physician was performing the follow-up of the patient0 s prostate cancer at the time of radiation therapy failure. Failure of radiation therapy was defined as BCR meeting the Phoenix definition [9] or initiation of salvage therapy regardless of PSA kinetics. Relapsed patients were assigned to low-, intermediate-, or high-risk groups according to D0 Amico classification [10]. Patient characteristics, including age, Charlson score, PSA, digital rectal examination, biopsy, bone scan, and computed tomography scan results, at time of radiation failure were collected and analyzed for salvage eligibility. In an exploratory analysis, medical charts were reviewed to assess the salvage options offered to patients, recognizing that options may have been discussed but not documented. Reasons for not offering SRP specifically were also recorded. When no explicit reason was provided for patients
older than 75 years at time of radiation failure, we attributed this to age. Observation after BCR was defined as no secondary treatment within 1 year of BCR.
3. Results A total of 1,782 patients received curative radiotherapy for prostate cancer treatment between January 1999 and December 2000 in B.C. Of these patients, 715 were excluded: 624 for age 472 years at diagnosis, 63 for PSA 440 ng/ml, 19 for stage ZT4, and 9 had primary orchiectomy at time of primary radiotherapy. Of the remaining 1,067 patients included in the study, 796 patients (75%) received EBRT and 271 (25%) received BT (Fig.). Radiation failure was observed in 257 patients (24%) based on either BCR (85%) or initiation of secondary intervention for presumed relapse (15%). Only 19 of these patients (7%) had undergone BT, and the other 238 (93%) received EBRT. Of the 257 patients who failed primary radiotherapy, the median age at the time of first diagnosis was 67 years. The clinical tumor stage and Gleason scores are summarized in Table 1. The median time from primary therapy to radiation failure was 53 months. Table 2 provides a demographic and clinical breakdown of the study patients based on primary radiotherapy modality. At time of radiation failure, 126 patients (49%) were observed for 41 year without intervention. Of these, treatment beyond 1 year consisted of further observation in 61 and ADT in 65 patients. ADT was continuous in 15 (including 3 with bilateral orchiectomy), intermittent in 44, and not clearly defined in 6 patients. One patient receiving intermittent ADT eventually underwent secondary SBT 4 years after BCR. The median time to any intervention after BCR was 6 months. Another 119 patients (46%) received ADT within 1 year of radiation failure after radiotherapy. ADT was continuous in 46 (including 7 with bilateral orchiectomy), intermittent in 66, and not clearly defined in 7 patients. Of these patients, 3 were involved in a clinical trial comparing intermittent to continuous ADT [11]. Of note, 13 other patients were offered enrollment in this trial but declined or were found ineligible as per trial protocol. One patient was enrolled in a clinical trial with a vascular endothelial growth factor pathway inhibitor and subsequently received ADT. A total of 5 patients (1.9%) underwent LST. Two patients, including the one mentioned previously, received SBT and 3 patients received SRP. Two patients undergoing SRP also received ADT (Table 3). A discussion of LST was documented in the chart of 44 patients (17%), absent in 157 patients (61%), and could not be determined in 56 cases (22%). A discussion about SRP was specifically documented in 35 instances, whereas SBT, SCT, and HIFU were considered in 12, 15 and 5 instances, respectively (Table 4). The role of these latter interventions has evolved over the study period with varying
H. Tran et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–6
3
All patients who received curative radiotherapy for Prostate Ca between January 1999 - December 2000 n = 1782
Excluded Patients n=715
Included Patients n = 1067
Exclusion criteria: - Age > 72 - Pre-PSA > 40 - Tumor ≥ cT4 - Bilateral orchiectomy at time of primary radiotherapy No radiation failure n = 810 (75.9%)
Radiation Failure n = 257 (24.1%)
Fig. Breakdown of patients with prostate cancer in B.C. who received primary radiotherapy with curative intent between January 1999 and December 2000. Radiation failure was defined as biochemical recurrence according to the Phoenix criteria or initiation of salvage therapy at the discretion of the treating physician. Ca ¼ cancer. (Color version of figure is available online.)
accessibility. Following discussion, some patients were deemed ineligible for these LSTs. Of those deemed eligible for SRP, 7 patients were offered but declined it. 4. Discussion Our review of regional practice patterns reveals that LST is rarely performed in patients failing primary radiotherapy for localized prostate cancer. Despite favorable age, PSA,
Table 1 Baseline demographic and clinical characteristics of included patients (n ¼ 257) Characteristic
Median (range) or frequency (%)
Age at first diagnosis
67 y (47–72)
Clinical tumor stage T1 T2 T3 Tx
40 128 86 3
(15.6) (49.8) (33.5) (1.2)
Gleason score o7 7 47 Unassigned
98 115 43 1
(38.1) (44.8) (16.7) (0.4)
D0 Amico risk groups Low Intermediate High Unknown
36 65 152 4
(14.0) (25.3) (59.1) (1.6)
and tumor stage at time of first diagnosis in many of the cases in our cohort, 49% were managed after radiation failure with observation and another 46% with ADT alone.
Table 2 Patient characteristics based on type of primary radiotherapy modality (n ¼ 257) Patient and treatment factor
Median (range) or frequency (%)
EBRT, n ¼ 238 Concomitant ADT No concomitant ADT Dose, Gy Age at BCR, y Patients o65-y old at BCR Time to BCR, mo PSA at BCR, n ¼ 208 PSA nadir with ADT, n ¼ 162 PSA nadir without ADT, n ¼ 50 PSA nadir indeterminatea
179 (75.2) 59 (24.8) 68 (50–72) 73.5 (51–86) 23 (9.7) 53.5 (2–146) 3.3 (0.1–1,000) 0.04 (0.01–15.5) 1.1 (0.02–8.9) 26 (11)
Brachytherapy, n ¼ 19 Neoadjuvant ADT No neoadjuvant ADT Dose, Gy Age at BCR, y Time to BCR, mo PSA at BCR PSA nadir with neoadjuvant ADT PSA nadir without neoadjuvant ADT
13 (5.1) 6 (2.3) 144 70 (53–82) 62 (12–134) 2.8 (0.4–38) 0.02 (0.02–0.54) 0.415 (0.03–1.4)
RT ¼ radiation therapy. PSA nadir indeterminate if kinetics unavailable within 3 years after EBRT or before secondary intervention. This includes 3 patients who experienced metastatic progression shortly after RT. a
H. Tran et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–6
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Table 3 Salvage therapy after radiation therapy (n ¼ 257) Primary salvage Observation Observation
Secondary salvage None CADT IADT
Tertiary salvage
None Orchiectomy Brachytherapy
Orchiectomy Unspecified ADT ADT (within 1 y of BCR) CADT IADT Orchiectomy Unspecified ADT Clinical trial drug
126 61 12 42 1 1 3 6
(49.0) (23.7) (4.7) (16.3) (0.4) (0.4) (1.2) (2.3)
119 (46.3) 39 65 1 7 7
None Orchiectomy None None Observation
ADT
Salvage brachytherapy Salvage RP
Frequency (%)
(15.2) (25.3) (0.4) (2.7) (2.7)
1 (0.4) 1 (0.4)
ADT None
Unknown
2 (0.8) 1 (0.4) 7 (2.7)
CADT ¼ continuous androgen-deprivation therapy; IADT ¼ intermittent androgen-deprivation therapy; RP ¼ radical prostatectomy.
Only 5 of 257 patients (2%) received LST in the form of SRP or SBT. The patterns of care for salvage therapy after radiation therapy in our study are remarkably similar to those in the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database [12]. In CaPSURE, 587 of 935 men with localized prostate cancer who underwent radiotherapy between 1989 and 2004 developed recurrent disease. Of these, 73% went on to receive salvage therapy.
Table 4 Local salvage therapy discussion at time of radiation failure (n ¼ 257) Number of patients (frequency) Discussion of options for salvage therapy documented, but local salvage not considered Discussion of salvage therapy documented, including discussion of local salvage therapy No documentation available regarding discussion of salvage
157 (61.1)
Local salvage modality
Discussion documented 35 (13.6) 12 (4.7) 15 (5.8) 5 (2.0) 3 (1.2)
Radical prostatectomy Brachytherapy Cryotherapy High-intensity focused ultrasound Modality not specified
44 (17.1) 56 (21.8)
Salvage therapy consisted of ADT in 93.5% of patients, further EBRT in 1.9%, SCT in 3.0%, SRP in 0.9%, and SBT in 0.2% [12]. The principal difference between CaPSURE and B.C. data is the use of observation early in the management of many patients in B.C. In addition, SCT and HIFU are not available in B.C., requiring patients to travel out of province to receive therapy. Certain prognostic factors have been used as surrogates for prostate cancer–specific mortality in the post–radiation therapy setting. Such surrogates include PSA doubling time, time to PSA failure, PSA end (PSA concentration immediately after treatment), and PSA nadir [13]. LST is ideally offered to patients who would be likely to relapse and have only local disease. Using the aforementioned surrogates in addition to patient clinical parameters such as biopsy-proven local recurrence more than 1 year after radiation, and life expectancy greater than 10 years, we may be able to identify patients that would benefit most from LST [14]. Undoubtedly, LST after primary radiotherapy for prostate cancer faces several challenges, and many recurrences would be overtreated with LST, whereas others would likely be undertreated [8]. A subset of patients demonstrates slow PSA kinetics that is likely indicative of indolent disease, and observation is suitable for these patients. On the contrary, some patients fail radiation therapy because of metastatic disease, and such patients would not benefit from LST. Those with high-risk features before radiation, and a rapidly rising PSA soon after radiation therapy, are more likely to be in this latter group. Therefore LST is not advisable in a significant number of cases, and patient selection is a challenge in delivering LST; however, LST is likely beneficial in appropriately selected cases. Studies have shown that patients with a rising PSA, negative metastatic workup, and biopsy-proven local recurrence after EBRT have a rate of organ-confined disease of 20% to 40% [15–17]. It is likely, although not proven, that earlier intervention would lead to a lower rate of metastatic progression [18]. The other obstacle to LST is the fear of adverse effects associated with LST [19]. These effects are, however, not severe enough to withhold potentially curative therapy in most men with salvageable disease [19]. Especially with the advent of potentially less invasive procedures like SCT and SBT, LST can be delivered with acceptable toxicity [20,21]. One must also consider that the adverse effects of ADT are not negligible [22–24]. The morbidity of LST must be balanced with the potential for sparing toxicity from long-term ADT, including increased cardiovascular risk and skeletal-related events [25]. Furthermore, LST, if in fact curative, would spare toxicity related to symptomatic disease progression. The delivery of radiation therapy in B.C. and the subsequent management of radiation failure may not be generalizable to other settings. In B.C., all radiation is delivered at 6 centers linked through the B.C. Cancer Agency, and standardized protocols are followed at all centers. Patients are generally monitored for 1 to 2 years after treatment and then discharged back to the primary care
H. Tran et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–6
providers if the PSA kinetics are appropriate and no untoward toxicity has occurred. Patients are referred back to the Cancer Agency at the time of disease recurrence. Although one can pose the question whether this apparent lack of delivery of care is in fact detrimental to patients, the more pertinent question is how to determine which patients would benefit from LST and who should forego LST. There is likely a subset of patients who miss an opportunity for cure without LST. Radiation oncologists and urologists need to work together to optimize identification and care of these patients. We have considered both BT and EBRT together, but LST after BT requires specific consideration. In this situation, our experience indicates that disease recurrence or persistence in the prostate itself is rare, so that LST is less likely to be beneficial to the patient [26]. At the same time, there are fewer options for LST after BT, as there are significant concerns about delivering SBT, SCT, and HIFU owing to risk of further tissue damage and possible fistula formation. Furthermore, the high dose of radiation delivered to the prostate with BT makes SRP technically more difficult. There are few reports in the literature about SRP after BT [27], which reflects that it is suitable only for highly selected patients at tertiary care centers. Limitations of this study include its retrospective nature and inability to make determinations about treatment options with certainty in this manner. It is possible that some of the patients lost to follow-up underwent LST outside B. C., so that our estimation of LST rates could be artificially low. The selection criteria used to identify patients potentially eligible for LST were set arbitrarily and may be disputed. We initially started with narrower eligibility criteria, but determined that some of the small number of patients receiving LST would have been excluded, so we expanded the criteria accordingly. The radiation doses (mostly 70 Gy or less in 2 Gy fraction equivalence) and techniques (2½- or 3-dimensional conformal) used in 1999 and 2000 are no longer the same as those used today, so that radiation failures today may differ from this past era. If anything, we would expect the higher doses of radiation currently given to lead to higher cure rates; however, when local relapse does occur, this may be a further impediment to the consideration of LST. Regardless of these limitations, we believe that the conclusions of this study remain valid today. LSTs such as SCT, HIFU, SRP, and SBT are the only treatments available to patients who have failed primary radiotherapy that offer potential for cure. Although we recognize the significant obstacles in delivering LST, we believe it should at least be considered in many patients after relapse following radiotherapy. Through this review of regional practice patterns, we have identified that a very low proportion of patients in the study period received LST despite some patients appearing to be appropriate candidates. The data suggests a gap in delivery of optimal care that could be addressed by modifying practice patterns such
5
that every patient failing primary radiotherapy is considered for LST if he meets predetermined eligibility criteria. This would require better collaboration between urologists and radiation oncologists and between physicians in the community and at tertiary care centers.
References [1] Mouraviev V, Spiess PE, Jones JS. Salvage cryoablation for locally recurrent prostate cancer following primary radiotherapy. Eur Urol 2012;61:1204–11. [2] Pisters LL, Leibovici D, Blute M, et al. Locally recurrent prostate cancer after initial radiation therapy: a comparison of salvage radical prostatectomy versus cryotherapy. J Urol 2009;182:517–25:[discussion 25–7]. [3] Uddin Ahmed H, Cathcart P, Chalasani V, et al. Whole-gland salvage high-intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam radiation therapy. Cancer 2012;118:3071–8. [4] Gomez-Veiga F, Marino A, Alvarez L, et al. Brachytherapy for the treatment of recurrent prostate cancer after radiotherapy or radical prostatectomy. BJU Int 2012;109(Suppl. 1):17–21. [5] Chade DC, Eastham J, Graefen M, et al. Cancer control and functional outcomes of salvage radical prostatectomy for radiationrecurrent prostate cancer: a systematic review of the literature. Eur Urol 2012;61:961–71. [6] Corcoran NM, Godoy G, Studd RC, et al. Salvage prostatectomy post-definitive radiation therapy: the Vancouver experience. Can Urol Assoc J 2012;24:1–6. [7] Heidenreich A. Radical Salvage Prostatectomy for Radiorecurrent Prostate Cancer. Spain: European Society for Radiotherapy & Oncology; 2012. [8] Mottet N, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castrationresistant prostate cancer. Eur Urol 2011;59:572–83. [9] Roach M 3rd, Hanks G, Thames H Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965–74. [10] D0 Amico AV, Whittington R, Malkowicz SB, et al. The combination of preoperative prostate specific antigen and postoperative pathological findings to predict prostate specific antigen outcome in clinically localized prostate cancer. J Urol 1998;160:2096–101. [11] Crook JM, O0 Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367:895–903. [12] Agarwal PK, Sadetsky N, Konety BR, Resnick MI, Carroll PR, Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE): Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer 2008;112:307–14. [13] D0 Amico AV, Chen MH, Castro M, et al. Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials. Lancet Oncol 2012;13:189–95. [14] Parker CC, Dearnaley DP. The management of PSA failure after radical radiotherapy for localized prostate cancer. Radiother Oncol 1998;49:103–10. [15] Moul JW. Treatment of PSA only recurrence of prostate cancer after prior local therapy. Curr Pharm Des 2006;12:785–98. [16] Finley DS, Pouliot F, Miller DC, Belldegrun AS. Primary and salvage cryotherapy for prostate cancer. Urol Clin North Am 2010;37:67–82: [table of contents].
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[17] Cox JM, Busby JE. Salvage therapy for prostate cancer recurrence after radiation therapy. Curr Urol Rep 2009;10:199–205. [18] Lee WR, Hanks GE, Hanlon A. Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: clinical observations. J Clin Oncol 1997;15:230–8. [19] Stephenson AJ, Eastham JA. Role of salvage radical prostatectomy for recurrent prostate cancer after radiation therapy. J Clin Oncol 2005;23:8198–203. [20] Pisters LL, von Eschenbach AC, Scott SM, et al. The efficacy and complications of salvage cryotherapy of the prostate. J Urol 1997;157:921–5. [21] Pisters LL, Rewcastle JC, Donnelly BJ, Lugnani FM, Katz AE, Jones JS. Salvage prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180:559–63:[discussion 63–4]. [22] Nguyen PL, Chen MH, Beckman JA, et al. Influence of androgen deprivation therapy on all-cause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction. Int J Radiat Oncol Biol Phys 2012;82:1411–6.
[23] Faris JE, Smith MR. Metabolic sequelae associated with androgen deprivation therapy for prostate cancer. Curr Opin Endocrinol Diabetes Obes 2010;17:240–6. [24] Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2009;181:1998–2006:[discussion 7–8]. [25] Nanda A, Chen MH, Braccioforte MH, Moran BJ, D0 Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. J Am Med Assoc 2009;302:866–73. [26] Thompson A, Keyes M, Pickles T, et al. Evaluating the Phoenix definition of biochemical failure after (125) I prostate brachytherapy: can PSA kinetics distinguish PSA failures from PSA bounces? Int J Radiat Oncol Biol Phys 2010;78:415–21. [27] Heidenreich A, Richter S, Thuer D, Pfister D. Prognostic parameters, complications, and oncologic and functional outcome of salvage radical prostatectomy for locally recurrent prostate cancer after 21st-century radiotherapy. Eur Urol 2010;57:437–43.
Original article
Underutilization of local salvage therapy after radiation therapy for prostate cancer1 Henry Tran, M.D.a, Jaime Kwoka, Tom Pickles, M.D.b, Scott Tyldesley, M.D.b, Peter C. Black, M.D.a,* a
b
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada Department of Radiation Oncology, Vancouver Cancer Center, BC Cancer Agency, Vancouver, Canada Received 14 August 2013; received in revised form 9 December 2013; accepted 30 December 2013
Abstract Objective: To evaluate the rates at which patients are offered and receive local salvage therapy (LST) after failure of primary radiotherapy for localized prostate cancer, as it is the only potentially curative treatment for localized recurrence but appears to be underutilized when compared with androgen-deprivation therapy (ADT) or observation. Materials and methods: Patients with localized prostate cancer who received primary radiotherapy with curative intent between 1999 and 2000 were identified in the British Columbia Tumour Registry. Exclusion criteria included patient age 472 years, prostate-specific antigen 440 ng/ml, and clinical stage T4 at diagnosis. Data on clinicopathologic features, primary therapy, prostate-specific antigen kinetics, and salvage therapy were collected retrospectively. Radiation failure was defined as biochemical recurrence according to the Phoenix criteria or by initiation of salvage therapy. Results: Of 1,782 patients treated in the study period, 1,067 met inclusion criteria. Of these, 257 failed radiation therapy. Radiation therapy failure was managed with observation (412 mo) in 126 patients and ADT in 119. Of the observed patients, 66 subsequently received ADT. Five patients (1.8%) received LST (3 radical prostatectomy and 2 brachytherapy). Conclusions: Only 2% of patients relapsing after radiation therapy for localized prostate cancer received LST. Although the benefits of LST are unproven, these findings reveal a possible underutilization of LST and indicate a need for enhanced collaboration between specialties to optimize care of this challenging cohort. r 2014 Elsevier Inc. All rights reserved. Keywords: Prostatic neoplasms; Radiotherapy; Brachytherapy; Salvage therapy; Cryotherapy; Salvage radical prostatectomy; Salvage brachytherapy
1. Introduction External beam radiation therapy (EBRT) and brachytherapy (BT) are commonly used treatment modalities for localized prostate cancer. Although highly efficacious, some patients do have disease recurrence, and management of these patients has traditionally been challenging. Several clinical questions arise in any patient, including whether a rise in prostate-specific antigen (PSA) is reflective of disease recurrence, whether treatment of the biochemical recurrence (BCR) is necessary, and whether the recurrence is localized to the prostate or metastatic. If one is convinced
1
Funding: UBC Summer Student Research Program.
Corresponding author. Tel.: þ1-604-875-4818; fax: þ1-604-875-5654. E-mail address: [email protected] (P.C. Black). *
1078-1439/$ – see front matter r 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2013.12.014
that the recurrence warrants therapy and is localized to the prostate, a number of local therapy options are available. Treatment options include salvage cryotherapy (SCT) [1,2], high-intensity focused ultrasound (HIFU) ablation [3], salvage BT (SBT) [4], and salvage radical prostatectomy (SRP) [2,5,6]. Further alternatives include observation for presumed indolent recurrence and androgen-deprivation therapy (ADT). Despite these many alternatives, our impression is that most patients are not offered local salvage therapy (LST) after failure of EBRT or BT. For example, the number of patients treated with SRP in Vancouver has been minimal (21 cases over 15 y) [6]. Observation and ADT appear to be the mainstays of therapy. LSTs, however, are the only potentially curative options. There is risk of underutilizing LST and missing opportunity for cure. SRP is the most established and definitive local salvage option, but it may be
2
H. Tran et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–6
avoided in many cases owing to technical difficulty and high risk of subsequent incontinence and impotence [5,7]. SCT, HIFU, and SBT are newer salvage options associated with less patient morbidity but also less certain efficacy [8]. Nevertheless, the likelihood of cure is difficult to predict in any individual patient for any given salvage therapy modality. In this study, we aimed to ascertain rates at which patients receive LST after failure of radiation therapy in British Columbia (B.C.).
2. Materials and methods All patients with localized prostate cancer (T1-3N0M0) who received primary radiation treatment (EBRT or BT) with curative intent in B.C. from January 1999 until December 2000 were identified from the prospectively maintained B.C. Cancer Agency database. These cases were linked to ADT records captured in a province-wide pharmacy database. The study was approved by the Research Ethics Board of University of British Columbia (protocol H12-01180). The medical records of the identified patients were retrospectively reviewed to acquire variables not included in the prospective database. Patients older than 72 years and those with high-risk disease defined by a PSA 440 ng/ml and clinical T4 disease at diagnosis were excluded. These arbitrary criteria were set based on the consensus of the authors that these patients were unlikely to be eligible for LST in the event of BCR. Gleason score was not used as exclusion criteria. Patients who had combined primary orchiectomy and radiotherapy were also excluded. Data regarding patient characteristics, clinical and pathologic cancer features (pretreatment PSA, clinical tumor stage, and Gleason score), primary radiotherapy modality (dose, fractions, start/end dates, and concomitant ADT), and subsequent PSA kinetics (PSA nadir and date/time to recurrence) were collected. A PSA nadir was not recorded for 26 patients who had no PSA follow-up within 3 years after primary EBRT or before secondary intervention. We determined from the patient charts which physician was performing the follow-up of the patient0 s prostate cancer at the time of radiation therapy failure. Failure of radiation therapy was defined as BCR meeting the Phoenix definition [9] or initiation of salvage therapy regardless of PSA kinetics. Relapsed patients were assigned to low-, intermediate-, or high-risk groups according to D0 Amico classification [10]. Patient characteristics, including age, Charlson score, PSA, digital rectal examination, biopsy, bone scan, and computed tomography scan results, at time of radiation failure were collected and analyzed for salvage eligibility. In an exploratory analysis, medical charts were reviewed to assess the salvage options offered to patients, recognizing that options may have been discussed but not documented. Reasons for not offering SRP specifically were also recorded. When no explicit reason was provided for patients
older than 75 years at time of radiation failure, we attributed this to age. Observation after BCR was defined as no secondary treatment within 1 year of BCR.
3. Results A total of 1,782 patients received curative radiotherapy for prostate cancer treatment between January 1999 and December 2000 in B.C. Of these patients, 715 were excluded: 624 for age 472 years at diagnosis, 63 for PSA 440 ng/ml, 19 for stage ZT4, and 9 had primary orchiectomy at time of primary radiotherapy. Of the remaining 1,067 patients included in the study, 796 patients (75%) received EBRT and 271 (25%) received BT (Fig.). Radiation failure was observed in 257 patients (24%) based on either BCR (85%) or initiation of secondary intervention for presumed relapse (15%). Only 19 of these patients (7%) had undergone BT, and the other 238 (93%) received EBRT. Of the 257 patients who failed primary radiotherapy, the median age at the time of first diagnosis was 67 years. The clinical tumor stage and Gleason scores are summarized in Table 1. The median time from primary therapy to radiation failure was 53 months. Table 2 provides a demographic and clinical breakdown of the study patients based on primary radiotherapy modality. At time of radiation failure, 126 patients (49%) were observed for 41 year without intervention. Of these, treatment beyond 1 year consisted of further observation in 61 and ADT in 65 patients. ADT was continuous in 15 (including 3 with bilateral orchiectomy), intermittent in 44, and not clearly defined in 6 patients. One patient receiving intermittent ADT eventually underwent secondary SBT 4 years after BCR. The median time to any intervention after BCR was 6 months. Another 119 patients (46%) received ADT within 1 year of radiation failure after radiotherapy. ADT was continuous in 46 (including 7 with bilateral orchiectomy), intermittent in 66, and not clearly defined in 7 patients. Of these patients, 3 were involved in a clinical trial comparing intermittent to continuous ADT [11]. Of note, 13 other patients were offered enrollment in this trial but declined or were found ineligible as per trial protocol. One patient was enrolled in a clinical trial with a vascular endothelial growth factor pathway inhibitor and subsequently received ADT. A total of 5 patients (1.9%) underwent LST. Two patients, including the one mentioned previously, received SBT and 3 patients received SRP. Two patients undergoing SRP also received ADT (Table 3). A discussion of LST was documented in the chart of 44 patients (17%), absent in 157 patients (61%), and could not be determined in 56 cases (22%). A discussion about SRP was specifically documented in 35 instances, whereas SBT, SCT, and HIFU were considered in 12, 15 and 5 instances, respectively (Table 4). The role of these latter interventions has evolved over the study period with varying
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All patients who received curative radiotherapy for Prostate Ca between January 1999 - December 2000 n = 1782
Excluded Patients n=715
Included Patients n = 1067
Exclusion criteria: - Age > 72 - Pre-PSA > 40 - Tumor ≥ cT4 - Bilateral orchiectomy at time of primary radiotherapy No radiation failure n = 810 (75.9%)
Radiation Failure n = 257 (24.1%)
Fig. Breakdown of patients with prostate cancer in B.C. who received primary radiotherapy with curative intent between January 1999 and December 2000. Radiation failure was defined as biochemical recurrence according to the Phoenix criteria or initiation of salvage therapy at the discretion of the treating physician. Ca ¼ cancer. (Color version of figure is available online.)
accessibility. Following discussion, some patients were deemed ineligible for these LSTs. Of those deemed eligible for SRP, 7 patients were offered but declined it. 4. Discussion Our review of regional practice patterns reveals that LST is rarely performed in patients failing primary radiotherapy for localized prostate cancer. Despite favorable age, PSA,
Table 1 Baseline demographic and clinical characteristics of included patients (n ¼ 257) Characteristic
Median (range) or frequency (%)
Age at first diagnosis
67 y (47–72)
Clinical tumor stage T1 T2 T3 Tx
40 128 86 3
(15.6) (49.8) (33.5) (1.2)
Gleason score o7 7 47 Unassigned
98 115 43 1
(38.1) (44.8) (16.7) (0.4)
D0 Amico risk groups Low Intermediate High Unknown
36 65 152 4
(14.0) (25.3) (59.1) (1.6)
and tumor stage at time of first diagnosis in many of the cases in our cohort, 49% were managed after radiation failure with observation and another 46% with ADT alone.
Table 2 Patient characteristics based on type of primary radiotherapy modality (n ¼ 257) Patient and treatment factor
Median (range) or frequency (%)
EBRT, n ¼ 238 Concomitant ADT No concomitant ADT Dose, Gy Age at BCR, y Patients o65-y old at BCR Time to BCR, mo PSA at BCR, n ¼ 208 PSA nadir with ADT, n ¼ 162 PSA nadir without ADT, n ¼ 50 PSA nadir indeterminatea
179 (75.2) 59 (24.8) 68 (50–72) 73.5 (51–86) 23 (9.7) 53.5 (2–146) 3.3 (0.1–1,000) 0.04 (0.01–15.5) 1.1 (0.02–8.9) 26 (11)
Brachytherapy, n ¼ 19 Neoadjuvant ADT No neoadjuvant ADT Dose, Gy Age at BCR, y Time to BCR, mo PSA at BCR PSA nadir with neoadjuvant ADT PSA nadir without neoadjuvant ADT
13 (5.1) 6 (2.3) 144 70 (53–82) 62 (12–134) 2.8 (0.4–38) 0.02 (0.02–0.54) 0.415 (0.03–1.4)
RT ¼ radiation therapy. PSA nadir indeterminate if kinetics unavailable within 3 years after EBRT or before secondary intervention. This includes 3 patients who experienced metastatic progression shortly after RT. a
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Table 3 Salvage therapy after radiation therapy (n ¼ 257) Primary salvage Observation Observation
Secondary salvage None CADT IADT
Tertiary salvage
None Orchiectomy Brachytherapy
Orchiectomy Unspecified ADT ADT (within 1 y of BCR) CADT IADT Orchiectomy Unspecified ADT Clinical trial drug
126 61 12 42 1 1 3 6
(49.0) (23.7) (4.7) (16.3) (0.4) (0.4) (1.2) (2.3)
119 (46.3) 39 65 1 7 7
None Orchiectomy None None Observation
ADT
Salvage brachytherapy Salvage RP
Frequency (%)
(15.2) (25.3) (0.4) (2.7) (2.7)
1 (0.4) 1 (0.4)
ADT None
Unknown
2 (0.8) 1 (0.4) 7 (2.7)
CADT ¼ continuous androgen-deprivation therapy; IADT ¼ intermittent androgen-deprivation therapy; RP ¼ radical prostatectomy.
Only 5 of 257 patients (2%) received LST in the form of SRP or SBT. The patterns of care for salvage therapy after radiation therapy in our study are remarkably similar to those in the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database [12]. In CaPSURE, 587 of 935 men with localized prostate cancer who underwent radiotherapy between 1989 and 2004 developed recurrent disease. Of these, 73% went on to receive salvage therapy.
Table 4 Local salvage therapy discussion at time of radiation failure (n ¼ 257) Number of patients (frequency) Discussion of options for salvage therapy documented, but local salvage not considered Discussion of salvage therapy documented, including discussion of local salvage therapy No documentation available regarding discussion of salvage
157 (61.1)
Local salvage modality
Discussion documented 35 (13.6) 12 (4.7) 15 (5.8) 5 (2.0) 3 (1.2)
Radical prostatectomy Brachytherapy Cryotherapy High-intensity focused ultrasound Modality not specified
44 (17.1) 56 (21.8)
Salvage therapy consisted of ADT in 93.5% of patients, further EBRT in 1.9%, SCT in 3.0%, SRP in 0.9%, and SBT in 0.2% [12]. The principal difference between CaPSURE and B.C. data is the use of observation early in the management of many patients in B.C. In addition, SCT and HIFU are not available in B.C., requiring patients to travel out of province to receive therapy. Certain prognostic factors have been used as surrogates for prostate cancer–specific mortality in the post–radiation therapy setting. Such surrogates include PSA doubling time, time to PSA failure, PSA end (PSA concentration immediately after treatment), and PSA nadir [13]. LST is ideally offered to patients who would be likely to relapse and have only local disease. Using the aforementioned surrogates in addition to patient clinical parameters such as biopsy-proven local recurrence more than 1 year after radiation, and life expectancy greater than 10 years, we may be able to identify patients that would benefit most from LST [14]. Undoubtedly, LST after primary radiotherapy for prostate cancer faces several challenges, and many recurrences would be overtreated with LST, whereas others would likely be undertreated [8]. A subset of patients demonstrates slow PSA kinetics that is likely indicative of indolent disease, and observation is suitable for these patients. On the contrary, some patients fail radiation therapy because of metastatic disease, and such patients would not benefit from LST. Those with high-risk features before radiation, and a rapidly rising PSA soon after radiation therapy, are more likely to be in this latter group. Therefore LST is not advisable in a significant number of cases, and patient selection is a challenge in delivering LST; however, LST is likely beneficial in appropriately selected cases. Studies have shown that patients with a rising PSA, negative metastatic workup, and biopsy-proven local recurrence after EBRT have a rate of organ-confined disease of 20% to 40% [15–17]. It is likely, although not proven, that earlier intervention would lead to a lower rate of metastatic progression [18]. The other obstacle to LST is the fear of adverse effects associated with LST [19]. These effects are, however, not severe enough to withhold potentially curative therapy in most men with salvageable disease [19]. Especially with the advent of potentially less invasive procedures like SCT and SBT, LST can be delivered with acceptable toxicity [20,21]. One must also consider that the adverse effects of ADT are not negligible [22–24]. The morbidity of LST must be balanced with the potential for sparing toxicity from long-term ADT, including increased cardiovascular risk and skeletal-related events [25]. Furthermore, LST, if in fact curative, would spare toxicity related to symptomatic disease progression. The delivery of radiation therapy in B.C. and the subsequent management of radiation failure may not be generalizable to other settings. In B.C., all radiation is delivered at 6 centers linked through the B.C. Cancer Agency, and standardized protocols are followed at all centers. Patients are generally monitored for 1 to 2 years after treatment and then discharged back to the primary care
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providers if the PSA kinetics are appropriate and no untoward toxicity has occurred. Patients are referred back to the Cancer Agency at the time of disease recurrence. Although one can pose the question whether this apparent lack of delivery of care is in fact detrimental to patients, the more pertinent question is how to determine which patients would benefit from LST and who should forego LST. There is likely a subset of patients who miss an opportunity for cure without LST. Radiation oncologists and urologists need to work together to optimize identification and care of these patients. We have considered both BT and EBRT together, but LST after BT requires specific consideration. In this situation, our experience indicates that disease recurrence or persistence in the prostate itself is rare, so that LST is less likely to be beneficial to the patient [26]. At the same time, there are fewer options for LST after BT, as there are significant concerns about delivering SBT, SCT, and HIFU owing to risk of further tissue damage and possible fistula formation. Furthermore, the high dose of radiation delivered to the prostate with BT makes SRP technically more difficult. There are few reports in the literature about SRP after BT [27], which reflects that it is suitable only for highly selected patients at tertiary care centers. Limitations of this study include its retrospective nature and inability to make determinations about treatment options with certainty in this manner. It is possible that some of the patients lost to follow-up underwent LST outside B. C., so that our estimation of LST rates could be artificially low. The selection criteria used to identify patients potentially eligible for LST were set arbitrarily and may be disputed. We initially started with narrower eligibility criteria, but determined that some of the small number of patients receiving LST would have been excluded, so we expanded the criteria accordingly. The radiation doses (mostly 70 Gy or less in 2 Gy fraction equivalence) and techniques (2½- or 3-dimensional conformal) used in 1999 and 2000 are no longer the same as those used today, so that radiation failures today may differ from this past era. If anything, we would expect the higher doses of radiation currently given to lead to higher cure rates; however, when local relapse does occur, this may be a further impediment to the consideration of LST. Regardless of these limitations, we believe that the conclusions of this study remain valid today. LSTs such as SCT, HIFU, SRP, and SBT are the only treatments available to patients who have failed primary radiotherapy that offer potential for cure. Although we recognize the significant obstacles in delivering LST, we believe it should at least be considered in many patients after relapse following radiotherapy. Through this review of regional practice patterns, we have identified that a very low proportion of patients in the study period received LST despite some patients appearing to be appropriate candidates. The data suggests a gap in delivery of optimal care that could be addressed by modifying practice patterns such
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that every patient failing primary radiotherapy is considered for LST if he meets predetermined eligibility criteria. This would require better collaboration between urologists and radiation oncologists and between physicians in the community and at tertiary care centers.
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