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Med Radiol Diagn Imaging (2016)DOI 10.1007/174_2016_56, © Springer International Publishing Switzerland
Prostate Cancer
Max Peters, Metha Maenhout, Steven Frank, and Marco van Vulpen
Abstract
Salvage radiotherapy for locally recurrent prostate cancer after primary radiation is gen-erally performed using brachytherapy. Only a limited amount of small studies has been per-formed so far. In these studies the rate of severe toxicity, requiring operative reinterven-tion, was high and cancer control outcome was disappointing. Furthermore, it is unclear whether salvage treatment will improve dis-ease-specific or overall survival. For these rea-sons, salvage brachytherapy is not popular and usually only performed in large tertiary cen-ters. Salvage can currently be considered in patients with a pathology-proven local recur-rence with an interval of at least 2–3 years after primary treatment, together with a lim-ited and nonaggressive tumor presentation at time of salvage. Currently, experienced groups recommend at least equal doses used in pri-mary treatment, together with targeting the entire prostate. Diagnostic developments in magnetic resonance imaging (MRI) and posi-tron emission tomography (PET) and biopsy techniques such as transperineal and MRI-targeted biopsies provide the possibility to localize the macroscopic recurrent tumor in the prostate. This enables a shift to focal sal-vage techniques which can be expected to reduce severe toxicity rates while maintaining cancer control.
M. Peters (*) • M. Maenhout • S. Frank M. van Vulpen Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlandse-mail: [email protected]; [email protected]; [email protected]; [email protected]
Contents
1 Introduction ...................................................... 000
2 Detecting a Patient with a Local Recurrence Only .............................................. 000
3 General Results of Prostate Cancer Salvage ................................................. 000
4 Re-irradiation of Prostate Cancer .................. 000
5 Focal Salvage, the Near Future ....................... 000
References ............................................................... 000
1 Introduction
Re-irradiation in prostate cancer after primary curative radiotherapy or prostatectomy is gener-ally called a salvage treatment and will further be referred to as salvage in this entire chapter. In addition, salvage here refers to the post- radiotherapy setting only. Salvage radiotherapy post prostatectomy falls outside the scope of this chapter.
The treatment of patients suffering from radio- recurrent prostate cancer is a significant clinical problem worldwide (Ward et al. 2008). It has been calculated that in the United States approxi-mately 31,680 men per year will be at risk for failure after primary radiotherapy (Ward et al. 2008). Owing to the rising incidence of prostate cancer and the increasing use of radiotherapy, this number is likely to increase in the future (Dutch cancer society 2010). Other sources suggest that up to 60 % of patients undergoing radiotherapy as a primary treatment option may experience a recurrence within 10 years after treatment (Brachman et al. 2000; Agarwal et al. 2008; Zelefsky et al. 2007; Heidenreich et al. 2008). Even in the era of dose escalation (≥78 Gy) for primary prostate cancer, biochemical recur-rences occur in approximately 10 % of low-risk, 23 % of intermediate-risk, and 44 % of high-risk patients after 8 years (Zumsteg et al. 2015). Even though, following primary treatment, it is dif-ficult to differentiate between locally recurrent disease and distant metastases when the prostate-specific antigen (PSA) level increases, many of these patients will harbor organ-confined disease (Pound et al. 2001). Some expect even over two-thirds of patients to have locally recurrent disease (Menard et al. 2015; Cellini et al. 2002; Pucar et al. 2008; Arrayeh et al. 2012). Others state most men with a rising PSA after treatment will harbor micrometastatic disease and only a minor-ity would have a true local recurrence only and could potentially benefit from a salvage treat-ment (Ward et al. 2005; Nguyen et al. 2007a, b; Huang et al. 2007; Leibovici et al. 2012).
For patients diagnosed with recurrent pros-tate cancer after primary radiotherapy, different salvage treatment methods with a curative intend
exist: salvage radical prostatectomy, salvage brachytherapy, salvage external beam radiother-apy, salvage high-intensity focused ultrasound (HIFU), and salvage cryosurgery (Nguyen et al. 2007a, b; Moman et al. 2009; Alongi et al. 2013; Peters et al. 2013). These procedures are associ-ated with high failure and high severe toxicity rates and are therefore unpopular (Moman et al. 2009; Peters et al. 2013). This probably explains the absence of large prospective trials in the lit-erature. Most data are derived from retrospec-tive evaluation of a limited number of patients, which are often heterogeneous before salvage treatment regarding prognostic characteris-tics. The only palliative treatment alternative is hormonal therapy or androgen deprivation therapy (ADT), which is associated with often significant cardiovascular, metabolic, and even mental side effects (Heidenreich et al. 2014; Nguyen et al. 2015). In the case of a biochemi-cal recurrence after radiotherapy for prostate cancer, hormonal therapy is the worldwide most applied treatment, with approximately 98 % of patients being treated in this manner (Moman et al. 2009; Tran et al. 2014).
The high failure rates after prostate cancer sal-vage are probably related to inaccurate patient selection, as many of these patients will have early distant metastases (Haider et al. 2008; Nguyen et al. 2007a, b). The high severe toxicity rate might be related to the fact that current sal-vage treatments are directed at the entire prostatic volume. This is required because of a lack of accurate localization possibilities and blind sys-tematic biopsies to detect a local recurrence. Currently, new MRI and PET-imaging modalities are adopted, which provide more accurate local-ization information (Barentsz et al. 2012; Umbehr et al. 2013; Fütterer et al 2015; Hamoen et al. 2015; Evangelista et al. 2013; de Rooij et al. 2015). In addition, template prostate mapping biopsies and MRI-targeted biopsies provide addi-tional information regarding location and the presence of clinically significant disease (Siddiqui et al. 2015; Valerio et al. 2015; Moore et al. 2013). These modalities will be used in the near future for focal salvage treatment planning of prostate cancer recurrences (Moman et al.
M. Peters et al.
2010; Peters et al. 2014), which can be expected to have limited severe toxicity rates.
This chapter will first discuss the possibilities and difficulties with regard to detecting a local recurrence and will provide current internationally used selection criteria to identify patients for sal-vage. Next, the results of prostate cancer salvage will be discussed when comparing different sal-vage methods. Further, technical details of current radiotherapy salvage techniques will be described, followed by new developments, most importantly focal salvage.
2 Detecting a Patient with a Local Recurrence Only
As prostate cancer salvage has a high risk of treatment failure, it is essential to perform proper patient selection before treatment. Only patients with a true local recurrence will be able to benefit from any salvage treatment. Each detection tool has several specific pitfalls in prostate cancer recurrence assessment, and these will be dis-cussed below. This will result in a list of interna-tionally accepted patient selection criteria for prostate cancer salvage.
PSA is currently used for follow-up of pros-tate cancer treatment. The independent prognos-tic value of PSA pre-primary treatment has been well established. Pre-salvage, the PSA value also seems to be a prognostic factor in many studies using varying modalities (Chade et al. 2012; Wenske et al. 2013; Murat et al. 2009). However, the definition of a normal PSA value after pri-mary treatment remains problematic and differs between different primary treatment modalities. The lowest PSA value after treatment is called the nadir value. Different from the situation after radical prostatectomy, patients following radio-therapy will still have a prostate gland and there-fore are not expected to achieve an undetectable nadir. Still, post-radiation PSA values are lower compared to the pretreatment values as irradiated prostates show atrophy and a reduction of size and gland tissue (Grignon and Hammond 1995). There are potentially three sources of PSA which contribute to the nadir: (1) remaining normal
prostate gland tissue, (2) remaining local prostate cancer cells, and (3) subclinical metastases. Of course, serum PSA measurements cannot differ-entiate between any of these three PSA sources. Therefore, changes in PSA over time are evalu-ated. The longer the time to nadir, the more likely it is that remaining benign prostate tissue is the source of the residual PSA (Huang et al. 2011). Furthermore, PSA from benign residual prostate tissue will not show a clear rise. Early distant metastases will also produce PSA and will even-tually “overgrow” the PSA decline after the local treatment, mostly in the first few years after treat-ment. Also, these patients usually will have a higher nadir PSA (Zietman et al. 1996). A slow PSA rise many years after treatment will proba-bly be due to a local recurrence as these prostate cancer cells first would have to recover the dam-age from the prostate cancer treatment (Zumsteg et al. 2015). A PSA rise after treatment can fur-ther be attributed to PSA from cancer cells or a PSA bounce. This last phenomenon is a tempo-rary rise of PSA followed by a PSA decline back to nadir levels and is not associated with cancer progression. Bounces may occur in up to 40 % of patients (Akyol et al. 2005; Roach et al. 2006). To date, no conclusive evidence-based explana-tion for the bouncing behavior of PSA exists. Precipitating factors such as ejaculation or instru-mentation are known to cause some PSA fluctua-tion (Das et al. 2002). Also the physiological variability of PSA assays in healthy test subjects was found to be considerable (Prestigiacomo and Stamey 1996). Lastly, PSA bounces after therapy have been associated with an increase in bio-chemical recurrence- free, prostate cancer-spe-cific, and overall survival after brachytherapy using multivariable analyses (Hinnen et al. 2012). It is hypothesized that a delayed wave of cell destruction due to radiation effects is responsible for the bounce phenomenon and therefore possi-bly leads to an increase in survival. A small frac-tion of bounces may be caused by these factors; however, they fail to provide a complete explana-tion. In clinical practice a PSA rise, therefore, needs differentiation between PSA bounce and cancer progression. For this reason different guidelines have been developed of which the
Prostate Cancer
most commonly used are the ASTRO definition (Cox et al. 1997) and the Phoenix definition (Roach et al. 2006). The ASTRO definition required three rises of more than 50 % with at least an interval of 3 months and the moment of failure is subsequently backdated to midway between the nadir and the first rise. However, this definition seemed to have a high false-positive rate of approximately 20 % after the use of adju-vant hormonal treatment (Roach et al. 2006). Therefore, currently, the Phoenix definition is the internationally accepted approach. A biochemi-cal relapse is considered any PSA rise of 2 ng/ml above nadir. This definition does not suffer in terms of accuracy with ADT use (Buyyounouski et al. 2005). In clinical practice, outcome is worse if the PSA level at the time of salvage is higher than 10 ng/ml (Izawa et al. 2002; de la Taille et al. 2000; Wenske et al. 2013; Chade et al. 2012), the PSA doubling time should be ideally more than 12 months (Zelefsky et al. 2005; Nguyen et al. 2007a, b), and the interval to PSA
failure should be at least 3 years (Nguyen et al. 2007a, b). Of course, these tumor characteristics will somehow reflect the amount of tumor and the tumor aggressiveness and thus the risk of already having metastases (Freedland et al. 2005).
Of course, each local recurrence should be pathology proven. Usually this is performed by systematic transrectal ultrasound (TRUS)-guided biopsies (Fig. 1). Crook et al. (1995) routinely performed prostate biopsies post treatment and found that 19 % of patients with an initially nega-tive biopsy later had a positive biopsy for cancer. Systematic biopsy schedules have a high chance of spatially missing tumor (sampling error), espe-cially as local radio-recurrent tumor is hardly vis-ible on TRUS (Crook et al. 1993). As the chance of a successful local salvage treatment will depend on the amount of tumor in the prostate at the time of salvage, it is obvious that currently used systematic biopsy schedules will detect most recurring tumor in a rather advanced state. Newer biopsy techniques have a higher accuracy
Fig. 1 Example of an internationally used systematic biopsy scheme which can be used to prove a local recurrence. The number of cores depicted here is 10
M. Peters et al.
in detecting localized recurrences and further-more in assessing clinically significant disease. Transperineal template prostate mapping (TTPM) biopsies are taken with a brachytherapy grid, usually with 5 mm spacing. With TTPM, a large part of the prostate is sampled, usually subdi-vided in 24 Barzell zones (Barzell and Whitmore 2003). This technique leads to the detection of approximately 30 % more clinically significant tumors over systematic transrectal biopsies alone (Onik et al. 2009; Sivaraman et al. 2015). This is mainly due to the higher amount of cores taken but also because the anterior part of the prostate is sampled, which is undersampled with transrec-tal biopsies. A limitation of TTPM is the detec-tion of more clinically insignificant tumors. However, these lesions are often eligible for active surveillance, which shows excellent results regarding (cancer-specific) survival (Klotz et al. 2010, 2015). In addition, MRI-guided biopsies to a suspicious lesion can lead to an increase in detecting clinically significant disease while not increasing or even decreasing the detection rate of insignificant lesions (Siddiqui et al. 2015; Moore et al. 2013).
Next, the evaluation of the biopsies is difficult. In early reports, little was known about the rate of histological clearance of irradiated tumor, and fail-ures were determined on biopsies even 6 months after radiotherapy (Scardino 1983). More recent analyses have shown that early biopsies have a high chance of being false positive. Radiation causes postmitotic cell death. Therefore, fatally damaged cells may even survive a limited number of cell divisions before dying off (Mostofi et al. 1992). As there is no visible difference between these dying cells and viable tumor cells, it is impossible for a pathologist to predict whether visible tumor cells are really clonogenic and need treatment (Crook et al. 1997). Approximately 30 % of biopsies posi-tive in the first year after radiation treatment will be negative for tumor in 24–30 months (Crook et al. 1995, 2000). Crook et al. (1995) therefore determined that the optimal time to biopsy would be 30–36 months post radiotherapy. Of course, even 36 months after treatment biopsies may be false positive, although chances are reduced at that moment. As postradiation pathology is difficult to
interpret, experienced uropathologists are required to evaluate these biopsies. An extra difficulty is the interpretation of biopsies. The currently used Gleason system is based on the glandular pattern of the tumor seen at relatively low magnification. As an irradiated prostate will show a significantly changed anatomy, especially on glandular level, Gleason score seems less useful after radiation treatment. Still, to evaluate the possibilities for salvage, it will be required to have some informa-tion on the potential aggressiveness of the visible tumor cells. Pathologists will need to be cautious here as one of the problems with evaluating car-cinomas that have been treated with radiotherapy is that the grade often appears higher (Bostwick et al. 1982). Although post-RT prostate biopsies are burdened with problems of timing, interpre-tation, and sampling error, they are required as evidence before radical local salvage for radiation failure is considered.
Imaging to visualize the local recurrence is regularly performed using TRUS. Unfortunately, sensitivity is very poor for the primary setting (Crook et al. 1993; Onur et al. 2004). In radio- recurrent disease, accuracy may even be further decreased due to fibrosis of the prostatic tissue. Therefore, current clinical practice lacks a proper imaging tool to detect a local recurrence. Promising local imaging techniques still under development are dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F or 11C-choline positron emission tomogra-phy (PET) (Rouviere et al. 2004; Haider et al. 2008; Moman et al. 2010; Wang et al. 2009; Breeuwsma et al. 2010; Barentsz et al. 2012; de Rooij et al. 2015; Umbehr et al. 2013). More recent developments have provided prostate- specific membrane antigen (PSMA) PET-CT using various tracers (Jadvar 2015; Rybalov et al. 2014). However larger series evaluating these techniques and assessment with the pathology reference standard is needed. Recent diagnostic meta-analyses have shown that the use of MRI (using the prostate imaging report-ing and data system (PI-RADS)) can help in assessing localized disease, capsular extension, and the exclusion of clinically significant dis-ease with a negative predictive value up to 95 %
Prostate Cancer
(Hamoen et al. 2015; Fütterer et al. 2015; de Rooij et al. 2015).
Imaging to exclude possible distant metasta-ses should be performed when evaluating the possibilities for salvage. But as a bone scan, pel-vic computed tomography (CT), and MRI need a significant tumor load to show metastases (Hovels et al. 2008; Abuzallouf et al. 2004), it is unlikely they will detect small metastases present in patients being selected for salvage treatment, e.g., with a PSA less than 10 ng/ml (Zagars and Pollack 1997; Nguyen et al. 2007a, b). Next, a pelvic lymph node dissection may be performed to exclude metastases. As a limited pelvic node dissection of the obturator fossa will only detect approximately 30 % of lymph node metastases, the value of a lymph node dissection is ques-tioned (Heesakkers et al. 2008). For early metas-tases detection in the future, the role of choline PET with various tracers (Breeuwsma et al. 2010) and magnetic nanoparticles in MRI (Barentsz et al. 2007) needs to be further evaluated. PET-CT imaging seems to be able to provide more accu-rate assessment of metastatic disease and assess-ment of prostate-confined recurrences. Recent overviews have shown promising results regard-ing lymph node involvement, prostate-confined recurrences, and distant metastatic disease (pooled sensitivity and specificity of 85.6 and 92.6 % for all three sites) (Evangelista et al. 2013). However, the spread across series is still large and standardization is necessary to achieve this high diagnostic accuracy in every center.
Of course, clinical patient characteristics before primary treatment and salvage are of importance when evaluating the possibility of successful salvage. Patients with a high initial chance of developing distant metastases are unlikely to have a local recurrence only (Nguyen et al. 2007a, b). An initial high Gleason score, high T-stage, high PSA value, and high PSA kinetics (before primary treatment) are possibly also risk factors post treatment to evaluate the likelihood of effective salvage. Therefore, sal-vage especially is advocated in primary low-risk clinical features (Nguyen et al. 2007a, b). However, evidence in this area from multivari-able models is generally lacking and pre-salvage
characteristics seem to have the highest predic-tive ability for cancer control outcomes (Chade et al. 2011, 2012; Wenske et al. 2013; Murat et al. 2009). From these larger salvage series, it seems pre- salvage PSA, PSADT, and pre-salvage Gleason score are most often associated with cancer control outcomes.
Next, the chance of having toxicity from a local salvage treatment will be increased if a patient had severe toxicity during or after pri-mary radiation treatment. Also, other additional treatments may attribute to the possible toxicity from salvage, like a transurethral resection (TURP), high-intensity focussed ultrasound (HIFU) treatment, or ADT use. These treatments will produce extra scar tissue and, therefore, will reduce the repair capacity of normal tissue in case of re-irradiation of the prostate. So far, how-ever, no current salvage re-irradiation literature exists, which models these characteristics in a multivariable manner to the probability of devel-oping toxicity.
Based on the above, a list of preliminary selec-tion criteria for local salvage can be completed. Still, it is of major importance to use such a list reasonably, as many clinical aspects, like age, medical history, and performance score contrib-ute in the decision for a local salvage treatment. The list below partially uses the criteria as described in the currently active radiation therapy oncology group (RTOG) trial 0526 (principle investigator: J. Crook, MD). These selection cri-teria were also mostly verified in a recent interna-tional collaboration on selection for salvage treatment (van den Bos et al. 2015).
• Biopsy-proven local recurrence at least 3 years after primary radiation treatment
• Posttreatment PSA <10 ng/ml, PSA doubling time (PSADT) >12 months
• Bone scan and CT abdomen or lymph node dissection without evidence of metastases
• Primary tumor characteristics preferably low to intermediate risk
• Acceptable toxicity of primary radiation treatment
• No other prostate treatments performed (like TURP, HIFU, etc.)
M. Peters et al.
• Additional to RTOG: verification of tumor localization with multiparametric MRI (con-sisting at least of a 1.5 Tesla T2-weighted, dynamic contrast-enhanced, and diffusion-weighted imaging sequence). Exclusion of metastatic disease using PET-CT (18F or 11C choline PET or Ga-68-PSMA)
3 General Results of Prostate Cancer Salvage
Different salvage treatment modalities are cur-rently clinically practiced. Radical prostatec-tomy, external beam radiotherapy, cryosurgery, additional I125/Pd103 or Ir192 brachytherapy, and HIFU are used (Pisters et al. 2000; Lee et al. 2008; Grado et al. 1999; Murat et al. 2009; van der Poel et al. 2007; Nguyen et al. 2007a, b; Chade et al. 2011, 2012, Paparel et al. 2009 Wenske et al. 2013, Williams et al. 2011, Spiess et al. 2010, Chen et al. 2013, Peters et al. 2013, Burri et al. 2010; Henríquez et al. 2014; Yamada et al. 2014). Literature is scarce and shows dis-cordant results in terms of treatment effect and toxicity. Furthermore, few large series have been published; most studies are retrospective and contain less than 100 patients. No head-to-head comparisons have been performed. As a consequence, current treatment decisions often depend on patients’ and doctors’/institutional preferences. An overview of the literature is pre-sented below.
Salvage radical prostatectomy has been described in several articles and has been per-formed in these series since the 1960s. Five-year biochemical no evidence of disease (bNED) ranges from 50 to 60 % (Nguyen et al. 2007a, b, Chade et al. 2012). In most series pre-salvage PSA was <10 ng/ml. Only a few rather large series have been described. Chade et al. (2011) described the largest salvage radical prostatec-tomy series with 404 radio-recurrent prostate cancer patients, treated since 1985. Ward et al. (2005) described the results of 199 patients, treated since 1967. In addition, Paparel et al. (2009) described 146 patients from a single institution. Finally, Stephenson et al. (2004)
described results of 100 patients (Stephenson et al. 2004). The other published studies con-tain between 6 and 51 patients (Sanderson et al. 2006; van der Poel et al. 2007; Vaidya and Soloway 2000). The definition of bNED after prostatectomy was most commonly defined as a rise in PSA of >0.2 ng/ml. It was concluded that patients with a pre-salvage PSA of <10 ng/ml did significantly better compared to patients with a PSA >10 ng/ml (Ward et al. 2005; Bianco et al. 2005). In addition, a lower pre-salvage Gleason score was shown to improve biochemi-cal disease- free survival and reduced the devel-opment of metastases in multivariable analysis (Chade et al. 2011). Multivariable analysis was not performed for mortality in this largest series. However, these factors were associated with prostate cancer- specific survival after mul-tivariable analysis in the series of Paparel et al. (2009). Neoadjuvant hormonal therapy did not seem to improve outcome (Ward et al. 2005; van der Poel et al. 2007). Also a cystoprosta-tectomy did not seem to improve oncologic out-come compared to a radical prostatectomy alone (Ward et al. 2005). Although preoperative mor-bidity, lasting from the previous radiotherapy treatment, was low, urinary incontinence had a weighted average of 41 %, bladder neck stric-tures of 24 %, and rectal injury of approximately 5 % (Nguyen et al. 2007a, b).
Salvage cryotherapy studies have been described with patients treated since the 1990s (Nguyen et al. 2007a, b). Five larger series have been published. The largest series describes 797 patients from 6 tertiary centers, of the basis of which a pretreatment nomogram to predict bio-chemical recurrence was created (Spiess et al. 2010). Wenske et al. (2013) described 328 patients after either primary EBRT (n = 259), pri-mary I-125 brachytherapy (n = 49), or primary cryotherapy (n = 20). Furthermore, Williams et al. described 187 patients, Izawa et al. (2002) showed outcomes of 131 patients, and Chin et al. (2001) described results of 125 patients. Other studies contained 59 patients or less (Bahn et al. 2003). Most series used a double freeze-thaw therapy (Izawa et al. 2002; Chin et al. 2001; Bahn et al. 2003, Williams et al. 2011). Unfortunately,
Prostate Cancer
the series published on salvage cryotherapy used different definitions for a relapse after salvage, which hampers a decent comparison. In addition, there were also large differences in prognostic characteristics between cohorts. From their over-view Nguyen et al. (2007a, b) concluded that out-come of salvage cryotherapy is comparable with the outcome reported from the prostatectomy data above. This is confirmed in the larger series, although the spread across series remains signifi-cant. Toxicity again is severe, with a weighted average of urinary incontinence of 36 %, urinary sloughing 11 %, bladder neck stricture or reten-tion 36 %, perineal pain 44 %, and fistulas approximately 3 % (Nguyen et al. 2007a, b).
Salvage brachytherapy series also describe patients treated since the 1990s (Nguyen et al. 2007a, b). Compared to the salvage prostatectomy and salvage cryotherapy series, far less and smaller brachytherapy series have been published. The largest I-125 salvage brachytherapy study contained 49 patients (Grado et al. 1999). Recently, Chen et al. (2013) reported on their HDR-salvage brachytherapy patients (n = 52), and the results of a somewhat larger combined I-125 salvage brachytherapy (n = 37) and HDR-salvage brachytherapy (n = 19) cohort have been pub-lished (Henríquez et al. 2014). In addition, a phase II study of salvage HDR brachytherapy (n = 42) has recently been reported (Yamada et al. 2014). Other series reported 31 patients or less (Nguyen et al. 2007b; Wallner et al. 1990; Beyer 1999; Lee et al. 2008; Battermann 2000; Moman et al. 2010). Again, varying definitions of PSA relapse after treatment hamper comparison between the differ-ent series. Still, midterm outcomes can be consid-ered comparable to salvage prostatectomy and salvage cryotherapy series (Nguyen et al. 2007a, b). However, multivariable analyses do not pro-vide uniform parameters associated with bio-chemical failure or survival due to insufficient sample size and sometimes methodological limi-tations. Weighted incontinence rate was 6 % and other grade 3–4 toxicities were weighted 6 % for the gastrointestinal (GI) tract and 17 % for the genitourinary (GU) tract. Fistulas averaged 3 % (Nguyen et al. 2007a, b). Table 1 shows an over-view of published salvage brachytherapy series.
Data on other modalities for local salvage are very limited. One study on HIFU has a mean follow-up of 15 months and showed an inconti-nence rate of 7 %, bladder neck stenosis 17 %, and fistulas 6 % (Gelet et al. 2004). A more recent and larger series in 290 patients has shown a 5-year biochemical recurrence-free rate in 43, 22, and 17 % in D’Amico low-, intermediate-, and high-risk patients, respectively. Grade 3 urinary incontinence occurred in approximately 10 % of patients; 46 % of patients had a bladder outlet obstruction for which intervention was needed, of which four patients (1.3 %) required urinary diversion. Rectourethral fistulas occurred in 2 % and pubic osteitis in 2.7 % (Crouzet et al. 2012).
Ferromagnetic thermal ablation has been described in 14 patients (Master et al. 2004) and external beam radiotherapy (30.6–50 Gy) com-bined with external hyperthermia (5–8 treat-ments) in three patients (Kalapurakal et al. 2001). Of course, further more extensive studies are required to be able to judge these new develop-ments regarding tumor control and toxicity.
In the studies above outcome is mainly described as bNED. Still, survival data are required to judge whether salvage is worthwhile performing. Salvage is often performed in an older patient population. Because of the compet-ing risks in these patients, the potential survival benefit is therefore not automatically derived from the benefit in bNED. However, ADT use can be postponed or prevented with postponing the moment of biochemical failure, thereby reducing side effects from this palliative strategy and possibly increasing cost-effectiveness. Therefore, a generally accepted primary goal of a salvage approach can be to postpone hormonal therapy. This leads to a discussion whether also patients with oligo-metastases in slowly pro-gressing disease might benefit from a local sal-vage treatment.
The high severe toxicity rates of the varying salvage modalities make salvage unpopular and this probably causes the absence of large ran-domized studies. Still, these are required to eval-uate whether salvage has a future. A randomized study would preferably consist of comparing hor-monal treatment alone to one type of salvage and
M. Peters et al.
Tab
le 1
O
verv
iew
of
clin
ical
out
com
e an
d se
vere
toxi
city
of
publ
ishe
d se
ries
on
salv
age
brac
hyth
erap
y
Ref
eren
ceiP
SA (
ng/m
l)N
HD
R/s
eeds
HT
(%
)FU
(m
onth
s)bN
ED
, Kap
lan-
Mei
er
estim
ates
% G
I ≥ g
rade
3%
GU
≥ g
rade
3
Yam
ada
et a
l. (2
014)
Med
ian
3.5
42H
DR
+ (
43)
Med
ian
3669
% (
5-ye
ar)
08
Hen
ríqu
ez (
2014
)M
edia
n 3.
756
HD
R (
n =
19)
, se
eds
(n =
37)
+ (
27)
Med
ian
4877
% (
5-ye
ar)a,
b4
23
Che
n et
al.
(201
3)M
edia
n 9.
352
HD
R+
(46
)M
edia
n 60
51 %
(5-
year
)a0
2
Bur
ri e
t al.
(201
0)M
edia
n 5.
637
Seed
s+
(84
)M
edia
n 86
54 %
(10
-yea
r)3
8
Mom
an e
t al.
(201
0)M
ean
11.4
31Se
eds
+ (
16)
Mea
n 11
020
% (
5-ye
ar)a
06
Lee
et a
l. (2
008)
Med
ian
3.8
21Se
eds
NA
Med
ian
3638
% (
5-ye
ar)b
00
Ngu
yen
et a
l. (2
007a
, b)
Med
ian
7.5
25Se
eds
−M
edia
n 47
70 %
(4-
year
)a24
16
Lee
et a
l. (2
007)
Med
ian
5.9
21H
DR
+ (
52)
Med
ian
1989
% (
2-ye
ar)b
014
Won
g et
al.
(200
6)M
edia
n 4.
717
Seed
s+
(88
)M
edia
n 44
75 %
(4-
year
)b6
47
Lo
et a
l. (2
005)
NA
30Se
eds
−M
edia
n 59
57 %
(5-
year
)b3
10
Kou
trou
velis
et a
l. (2
003)
NA
31Se
eds
+M
edia
n 30
87 %
(3-
year
)b5
13
Gra
do e
t al.
(199
9)M
edia
n 5.
649
Seed
s+
(16
)M
edia
n 64
34 %
(5-
year
)c4
20
Bey
er (
1999
)M
edia
n 2.
217
Seed
s+
(47
)M
edia
n 62
53 %
(5-
year
)b0
24
Loe
ning
and
Tur
ner
(199
3)N
A31
Seed
s−
Med
ian
2367
% (
2-ye
ar)c
00
Dif
fere
nt P
SA f
ailu
re d
efini
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Prostate Cancer
would have to prove a gain in survival. Next to toxicity scoring, quality of life will be essential to monitor (Nguyen et al. 2009) to judge the actual influence of severe toxicities and compare the difference between ADT use and salvage therapy.
4 Re-irradiation of Prostate Cancer
Post-radiotherapy local salvage is historically per-formed by brachytherapy (LDR, PDR, or HDR) or EBRT (Kimura et al. 2010). There is a prefer-ence for brachytherapy, as it can be expected that the surrounding area which receives a relatively high dose will be larger after EBRT, and there-fore EBRT can be expected to cause more severe toxicity. This explains why there is hardly any lit-erature on EBRT for recurrent local disease after primary radiotherapy. In a national disease regis-try, the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), 935 men were described who received a salvage treatment after primary EBRT. Of these men only eight received salvage by EBRT (Agarwal et al. 2008). In their article, Agarwal et al. (2008) did not notice any survival benefit for any particular combination of primary and salvage therapy. The inability to pro-tect the bladder and the anterior rectal wall without blocking a part of the prostate/tumor was largely caused by the limitations of the EBRT technique. Current EBRT techniques have improved enor-mously, e.g., by daily position verification tech-niques (van der Heide et al. 2007) and by the introduction of intensity-modulated radiotherapy (IMRT). Passive-scattering proton therapy has recently been associated with a potential increase in GI toxicity in a large propensity score-matched analysis (Sheets et al. 2012). Advanced forms of proton therapy delivery with intensity-mod-ulated proton therapy (IMPT) may provide bet-ter salvage outcome and toxicity data, but IMPT will need IGRT and daily position verification. Although most articles and textbooks discourage the use of EBRT for salvage after primary radio-therapy, these new techniques indeed might lead to comparable results as described above. But as the current standard salvage techniques already
show hardly acceptable severe toxicity rates, the further evaluation of EBRT for this purpose seems not the way forward.
In salvage brachytherapy permanent seeds are commonly used. Both I125 and Pd103 have been described (Wallner et al. 1990; Beyer 1999; Grado et al. 1999; Koutrouvelis et al. 2003; Lee et al. 2008; Battermann 2000; Nguyen et al. 2007b; Moman et al. 2010). More recently, HDR brachytherapy is being adopted in the salvage setting (Chen et al. 2013; Henríquez et al. 2014; Yamada et al. 2014). Again, comparison in out-come is hampered by differences in study popu-lations, treatment methods, and the definition of failure (Nguyen et al. 2007a, b). In patients who meet the criteria described in part 2, it can be expected to achieve a 5-year bNED rate of approximately 50–70 % (Table 1). Five-year overall survival rates ranging from 80 to 90 % have been described (Beyer 1999; Lee et al. 2008). Still, the severe toxicity rate is high, up to approximately 10–30 % for GU and GI combined (Moman et al. 2010; Nguyen et al. 2007b, Peters et al. 2013). Currently, an RTOG trial (no. 0526) is ongoing for the prospective evaluation of brachytherapy after EBRT. The results of this trial can be expected to give more insight in the toxicity risk profiles of patients receiving salvage brachytherapy. This can improve patient selec-tion and may augment the benefit/risk ratio (Nguyen et al. 2007a, b; Moman et al. 2010).
As all studies showed a rather large proportion of patients with severe toxicity, specific dose con-straints for salvage are essential. Many different doses have been applied, but most groups used regular doses, which are also applied for a pri-mary treatment, e.g., 120–145 Gy in I125 implants and 100–120 Gy in Pd103. Recent research has suggested dose constraints for whole-gland salvage I-125 brachytherapy for the urethra, bladder, and rectal wall (Peters et al. 2015, 2016). These constraints are, however, based on 28 salvage patients without the use of multivariable modeling, taking into account other important prognostic characteristics related to toxicity. In essence, these dose constraints there-fore represent a univariable association between dosimetry and late severe GU and GI toxicity for
M. Peters et al.
salvage patients. However, it was shown that these restrictions were all set lower than in the primary brachytherapy setting, indicating increased sensitivity of these structures after a primary course of radiation.
From the salvage prostatectomy data, a learn-ing curve has been described (Ward et al. 2005), with less severe toxicity over time. This also seems likely for permanent seed salvage. The technical performance of LDR salvage treatment after primary radiotherapy should, therefore, probably be performed in agreement with current brachytherapy guidelines (Kovacs et al. 2005). Still, technical difficulties remain, e.g., how to perform post-salvage dosimetry after a primary seed implant.
Most experience in salvage re-irradiation has been developed in permanent seed (LDR) brachytherapy (Battermann 2000), but HDR might also be of use for salvage. Currently only scarce literature exists on this topic (Table 1). The problem with HDR is that primary treatment often is performed in several fractions and that catheters retract during treatment, and therefore, it seems prone to more severe toxicity and a poorer outcome. Still, current clinical practice is actively working toward a single-fraction pri-mary HDR treatment. Furthermore, current brachytherapy groups have developed on-line MRI guidance techniques. With these techniques a single-fraction HDR treatment for salvage can be developed. Current results of HDR brachy-therapy in terms of cancer control and late toxic-ity are promising and seem to be favorable compared to previous LDR brachytherapy (Table 1) (Morton et al. 2013).
5 Focal Salvage, the Near Future
Several studies have shown that for salvage after primary radiotherapy, the rate of treatment- related toxicity is high (Nguyen et al. 2007a, b; Moman et al. 2010, Peters et al. 2013). Multiple factors will contribute to the fact that toxicity rates after salvage are greater compared to primary treat-ment, e.g., the cumulated radiotherapy dose and
the patient’s age and comorbidities. Most likely, the area of normal tissue which receives a signifi-cant radiation dose is too large. This probably is caused by the fact that local salvage always is per-formed on the entire prostate, as the spatial accu-racy of current biopsy and imaging is poor (Moman et al. 2010). If the location of the local recurrence could be determined with better accu-racy, treatment of the macroscopic tumor alone would result in reduced normal tissue exposure. This could be expected to reduce the rate of severe toxicity (Moman et al. 2010).
Evidence is emerging that local recurrences are located predominantly at the primary lesion site (GTV) (Cellini et al. 2002; Pucar et al. 2008; Arrayeh et al. 2012; Menard et al. 2015). Apparently, the surviving macroscopic tumor received an insufficient radiation dose from the primary treatment. Minor secondary tumor lesions (CTV) probably will have received suffi-cient doses. This corresponds with the remarks above that the radiation dose should not be low-ered, and this adds to the argument of reducing the target volume to the macroscopic lesion alone (Moman et al. 2010). This can be called focal sal-vage (Moman et al. 2010; Peters et al. 2014).
There are several new imaging techniques, which may contribute to a spatially accurate detection of a local recurrence in the prostate. 18F-fluorocholine PET-guided target volume delineation for partial prostate re-irradiation in locally recurrent prostate cancer has already been described (Wang et al. 2009). However, PET seems to have a larger role in excluding lymph node and distant metastases (Umbehr et al. 2013; Evangelista et al. 2013). As resolu-tion of MRI is better, more groups use advanced functional MRI techniques to localize the recur-rence in the prostate (Ahmed et al. 2012; Peters et al. 2014; Menard et al. 2015). Dynamic contrast- enhanced (DCE)-MRI shows blood per-fusion. After radiation treatment a large part of the prostate will be fibrotic and a normal T2- weighted image cannot differentiate between fibrosis and tumor. DCE-MRI will be able to visualize a high blood perfusion, caused by neo-vascularization of the recurring tumor, in a fibrotic prostate bed. A sensitivity of 70–74 %
Prostate Cancer
and a specificity of 73–85 % have been described (Rouviere et al. 2004; Haider et al. 2008). Recent diagnostic meta-analyses have shown mp-MRI (DCE-MRI in combination with diffusion- weighted imaging and/or MR spectroscopy) to be of importance in several aspects of prostate can-cer staging, and a negative predictive value of 95 % for clinically significant disease can be achieved with standardized assessment (using PIRADS). However, these studies pertain to the
primary setting (Hamoen et al. 2015; Fütterer et al. 2015; de Rooij et al. 2015; Barentsz et al. 2012). An example of the combination of T2- weighted, DCE-MRI, and DWI-MRI for salvage planning is depicted in Fig. 2. The intraoperative MRI-based catheter reconstruction is depicted in Fig. 3. Finally, Fig. 4 shows the same MRI sequences and planning for a patient who under-went focal salvage HDR after radiotherapy fail-ure. Lastly, each suspicious lesion on MRI should
a b c
Fig. 2 Multiparametric MRI used for tumor delineation. (a) Transversal T2-weighted image, (b) transversal ADC, (c) transversal K-trans
a b
Fig. 3 Catheter visualization on MRI. (a) Sagittal SPIR image, (b) transversal SPAIR image
M. Peters et al.
always be confirmed by biopsies, preferably MRI guided (Siddiqui et al. 2015; Moore et al. 2013).
Eggener et al. (2007) already proposed a set of criteria for primary focal therapy using multiple clinical, biopsy, and imaging characteristics that results in the exclusion of high-risk patients. Moman et al. (2010) did the same for focal sal-vage in a planning study. Ideally, multivariable prediction models are needed to provide the opti-mal set of selection criteria for both whole-gland and focal salvage. Larger series in the future are needed to attain this goal.
Focal salvage has been performed using sev-eral modalities, most importantly cryotherapy (Eisenberg and Shinohara 2008; de Castro Abreu et al. 2013; Bomers et al. 2013; Li et al. 2015), HIFU (Ahmed et al. 2012; Baco et al. 2014), and I125 brachytherapy (Peters et al. 2014; Hsu et al. 2013). In these cohorts toxicity indeed seemed reduced, while cancer control seemed to be main-tained. One-, 2-, 3-, and 5-year BDFS ranges were 83–100 %, 49–100 %, 50–91 %, and 46.5–54.4 %, respectively, for these focal salvage modalities, which seems comparable to whole- gland salvage cancer control outcomes. Toxicity was mostly self-limiting or handled by medication in these series. Salvage brachytherapy showed a biochemical recurrence-free rate of approximately 60 % after 3 years with only one grade three urethral stricture in a combined set of 42 patients (Peters et al. 2014; Hsu et al. 2013; Sasaki et al. 2013). Currently, the FORECAST trial is under way for focal salvage
cryotherapy and HIFU, and results can be expected in the next few years (Kanthabalan et al. 2015).
These focal salvage strategies also started a discussion on cure versus chronic disease. As doubling time of prostate cancer generally is very slow and patients evaluated for salvage only have low- to intermediate-risk features and probably an advanced age, it remains questionable whether salvage will be able to improve survival. Most of these patients would probably not die from their prostate cancer. If acceptable toxicity rates could be achieved with focal salvage, re-treatment would be possible if, during follow-up, another area of locally recurrent disease would be diag-nosed. In this way, ADT could be postponed or even prevented in a subset of patients. This could turn recurrent prostate cancer into a more chronic disease and have a positive effect on the quality of life of recurrent prostate cancer patients.
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