Salvage therapy of intraprostatic

Critical Reviews in Oncology/Hematology 88 (2013) 550–563
Salvage therapy of intraprostatic failure after radical external-beam
radiotherapy for prostate cancer: A review
Filippo Alongi a , Berardino De Bari b,∗ , Franco Campostrini c , Stefano Arcangeli d ,
Deliu Victor Matei e , Egesta Lopci f , Giuseppe Petralia g , Massimo Bellomi g , Arturo Chiti f ,
Stefano Maria Magrini b , Marta Scorsetti a , Roberto Orecchia h , Barbara Alicja Jereczek-Fossa h
a
Radiotherapy and Radiosurgery, Humanitas Cancer Center, Istituto Clinico Humanitas, Milan, Rozzano, Italy
b Radiotherapy Department, Istituto del Radio di Brescia, University of Brescia, Italy
c Radiotherapy, Legnago Hospital, Legnago, Italy
d Radiotherapy, San Camillo Hospital, Rome, Italy
e Urology Department of the European Institute of Oncology, Milan, Italy
f Nuclear Medicine, Humanitas Cancer Center, Istituto Clinico Humanitas, Milan, Rozzano, Italy
g Radiology Department of the European Institute of Oncology and University of Milan, Milan, Italy
h Radiotherapy Department of the European Institute of Oncology and University of Milan, Milan, Italy
Accepted 17 July 2013
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Definition of recurrence after EBRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Imaging of intraprostatic relapse after EBRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Androgen deprivation therapy (ADT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Salvage prostatectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Cryotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. High-intensity focused ultrasound (HIFU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. External-beam radiation therapy (EBRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6. Brachytherapy (BRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Radical external-beam radiotherapy (EBRT) is a standard treatment for prostate cancer (PC) patients. Despite this, the rate of intraprostatic
relapses after primary EBRT is still not negligible. There is no consensus on the most appropriate management of these patients after EBRT
failure. Treatment strategies after PC relapse are strongly influenced by the effective site of the tumor recurrence, and thus the instrumental
evaluation with different imaging techniques becomes crucial. In cases of demonstrated intraprostatic failure, several systemic (androgen
deprivation therapy) or local (salvage prostatectomy, cryotherapy, high-intensity focused ultrasound, brachytherapy, stereotactic EBRT)
∗ Corresponding author at: AO Spedali Civili di Brescia – Istituto del Radio, P.le degli Spedali Civili, 1, 25123 Brescia, Italy. Tel.: +39 030 3995271;
fax: +39 030 396700.
E-mail addresses: [email protected], [email protected] (B. De Bari).
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.critrevonc.2013.07.009
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
551
treatment options could be proposed and are currently delivered by clinicians with a variety of results. In this review we analyze the correct
definition of intraprostatic relapse after radiotherapy, focusing on the recent developments in imaging to detect intraprostatic recurrence.
Furthermore, all available salvage treatment options after a radiation therapy local failure are presented and thoroughly discussed.
© 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Intraprostatic failure; EBRT; Salvage therapy; HIFU; Prostatectomy; Brachytherapy; Hormonal therapy; Cryotherapy
1. Introduction
For more than two decades external-beam radiation therapy (EBRT) has been considered standard practice for the
radical treatment of patients with localized prostate cancer
(PC). Consequently, this technique has evolved significantly.
Technological advances have been progressively introduced,
and treatments standards have evolved from two-dimensional
(2D) to three-dimensional conformal radiation therapy (3DCRT); more recently intensity-modulated radiation therapy
(IMRT) and image-guided radiation therapy (IGRT) have also
been introduced. In parallel with this technological evolution,
a progressive increase in prescribed and delivered radiation
doses to the prostate has been observed [1–3].
Modern EBRT as a primary treatment has been reported
to be well tolerated with minimal late severe toxicity. Clear
evidence of improved biochemical outcomes, using higher
radiation doses, has also been confirmed in large series
[1,2,4]. Despite these strategic efforts to optimize outcomes
of EBRT, the rate of biochemical failure (BF) after primary EBRT in PC is still not negligible. In a large series of
3839 PC patients, treated with EBRT in the prostate-specific
antigen (PSA) era, Kuban et al. [5] reported a biochemical
failure rate of 33%. In the literature, published rates of biochemical recurrence are in the range 22–69% after curative
RT ± androgen deprivation therapy (ADT) [6,7]. The management of PC relapse after EBRT is still undefined, and no
consensus regarding the most appropriate treatment option
has been established.
In this review, we analyze the correct definition of
intraprostatic relapse after EBRT, focusing on the recent
developments in imaging to detect prostatic recurrence.
Results in terms of clinical outcome and toxicity of all the
available salvage treatments for this type of local relapse are
reviewed.
2. Definition of recurrence after EBRT
The introduction of routine PSA dosage radically changed
clinical management of diagnosis and follow-up in PC
patients and allowed clinicians to diagnose BF earlier [7,8].
As a transient PSA rise after radical EBRT could also be
related to benign prostatic diseases, or could be associated
with EBRT itself (the “PSA bounce phenomenon” [9]), various criteria to define a BF after primary prostate EBRT
have been proposed. In 1996 the first Consensus Conference of the American Society of Therapeutic Radiology and
Oncology (ASTRO), that was held in S. Antonio, stated that
failure should be declared in the case of three consecutive
rises in the PSA after a nadir, or when any salvage treatment
because of a PSA rise is prescribed [10]. Nevertheless, these
criteria presented some limits, such as the absence of a cut-off
to consider as a BF a rise in PSA, and the poor performance
in patients submitted to combined radiation – ADT therapy.
Moreover, the duration of follow-up after EBRT can affect
the interpretation of long-term control rates, and then these
criteria could be related with some uncertainties to clinical
progression or survival [11,12].
Given these limits, ASTRO criteria were revised during a
second multidisciplinary Consensus Conference sponsored
by ASTRO and the Radiation Therapy Oncology Group
(RTOG) in Phoenix, Arizona [11]: a PSA rise of at least
2 ng/mL above the nadir was considered the standard definition for biochemical failure after EBRT ± ADT. The panel of
experts recommended that the failure date should be assessed
“at call” and not backdated, as in the previous consensus.
An adequate follow-up was also suggested and considered
crucial to avoid the artifacts resulting from short follow-up.
Moreover, a BF should be declared also in the case of positive
biopsies and/or prescription of salvage therapies (ADT, radical prostatectomy, brachytherapy, cryosurgery), even in the
absence of these new PSA failure criteria [12]. Despite some
limits (field of application strictly limited to EBRT ± ADT,
potential bias in favor of EBRT series when compared with
results of other treatment modalities), these new ASTRO
Phoenix criteria have been definitely acquired as the new
International standard.
To identify potential candidate patients for local retreatments, important information is the PSA doubling time
(PSA-DT) [12]. Local failure occurs more frequently with a
PSA-DT ≥ 6 months, while metastatic disease occurs more
frequently with a rapid rise in PSA (PSA-DT <6 months).
It should be strongly highlighted that the value of the
PSA-DT is not the only feature that could help clinicians
identify patients that are potentially candidates for a second local treatment. Even if the identification of the correct
selection criteria is still a subject for debate, it is crucial to
correctly identify patients who would really benefit from a
second local curative procedure, as only patients who do not
have ‘infraclinic’ distant failure could potentially be cured.
3. Imaging of intraprostatic relapse after EBRT
The availability of accurate diagnostic tools would
be very important because treatment strategies after PC
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F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
relapse are strongly influenced by the actual site of tumor
recurrence.
However, diagnosis of local recurrence after EBRT can
be rather challenging for conventional imaging modalities,
also because of the radiation-induced changes to the prostate
gland (parenchyma atrophy and fibrosis, and the reduction
of the vascular supply and of the glandular secretions).
Trans-rectal ultrasound (TRUS) is the most broadly available
instrument for the assessment of local relapse. Its sensitivity is low, circa 50%, which is similar to the sensitivity of
the digital rectal examination (DRE) [13,14]. Color Doppler,
or contrast-enhanced ultrasound (CEUS) with microbubble
contrast media, that can differentiate neovascularity-related
changes in the prostate structures, can potentially be exploited
for improving the sensitivity of TRUS [14]. Magnetic resonance imaging (MRI) is often used in the detection of
the primary tumor and extra-capsular extent [15]. However,
the influence of radiation-induced changes can also significantly affect MRI, because the contrast between recurrent
carcinoma and benign tissue is not always evident after radiotherapy [13,15]. Despite this limitation, the MRI technique
remains superior to DRE and TRUS. The introduction of
functional imaging techniques – such as dynamic contrastenhanced MRI (DCE-MRI), diffusion-weighted imaging
(DWI) and proton MR spectroscopy imaging (MRSI) –
improved accuracy in identifying locally recurrent carcinoma
from 68% to 90%, according to some clinical experiences
[13–17]. Table 1 summarizes indication of the European
Society of Urogenital Radiology (ESUR) about the different
MRI sequences [18].
Additional modalities that are still rather controversial
in their indication are represented by molecular imaging
techniques: i.e., positron emission tomography (PET) and/or
single photon emission computed tomography (SPECT).
SPECT is performed using 111 In-labeled capromab peptide (Prostascint, Cytogen Corporation, Princeton, NJ), the
labeled antibody to the prostate specific membrane antigen
(PSMA) [19]. The tracer, so far investigated in more than
2000 patients, has shown an interesting sensitivity (up to
92%) for the detection of local recurrence after radical prostatectomy [20]. However, the correlation between PSA value
and Prostascint detection of cancer recurrence after radiation therapy is weak, although still superior to that of DRE
and TRUS [20,21]. Also PET with radio-labeled choline
(11 C- and 18 F-choline) or acetate tracers (11 C-acetate) is
increasingly being applied in PC restaging after biochemical relapse [21]. The tumor cell retention of radio-labeled
acetate depends on fatty acid metabolism, which appears
to be predominant in PC cells, and from its incorporation
into phosphatidylcholine (because of up-regulation of choline
kinase) and neutral lipids [22,23]. Both radio-labeled choline
and acetate imaging demonstrated that the overall detection
rate in restaging prostate carcinoma is variable and depends
directly on PSA absolute value and PSA kinetics [24]. This
mechanism is not directly related to cell proliferation, but can
be influenced by tumor hypoxia [25,26]. In local recurrence,
however, the dependence on PSA value is negligible, and
PET can be considered more reliable since the biochemical
relapse after EBRT is associated with PSA values >2 ng/mL
[13], with a sensitivity ranging from 81% to 100% in identifying local relapses [27,28]. Potentially, PET could also be
of interest for target definition in salvage EBRT [29,30], but
it should still be considered as an experimental procedure.
Finally, despite the potential of MRI and of PET in these
clinical situations, it should be highlighted that recent guidelines of the European Association of Urology (EAU) and
of the National Institute for Health and Clinical Excellence
(NICE) in Britain do not recommend their routine prescription, limiting their use to well-defined clinical situations, but
do favor their further evaluation, possibly in the context of
clinical trials [31,32].
4. Treatment options
4.1. Androgen deprivation therapy (ADT)
Despite the conflicting data from non-randomized trials addressing the issue of the role of ADT in this clinical
scenario, it is considered the standard of care for patients
presenting with BF [33,34].
It remains controversial whether early-salvage ADT (i.e.,
at the time of BF) has better outcomes than either late-salvage
ADT (i.e., at the development of clinically evident distant metastases) or observation. Data from non-randomized
studies comparing early- versus late-salvage ADT after RT
are summarized in Table 2 [34–37]. These studies showed
improved overall survival (OS) with ADT according to PSA
level (<10 ng/mL, ≤15 ng/mL, or <20 ng/mL). This improvement is limited only to low PSA, M0 patients [34,35], and/or
to patients with longer PSA-DT (>7 months and >12 months)
[34,36]. Conversely, a retrospective cohort analysis of 248
men with BF after EBRT showed no advantage for ADT
(versus “watchful waiting”) in the subgroup of men with a
PSA-DT >12 months (P = 0.74), leading to the conclusions
that patients with signs of local recurrence only (low-risk
patients with late recurrence signs and a slow PSA rise) are
best managed by observation alone [38].
A recent secondary analysis of patients enrolled in the
ICORG 97-01 randomized trial (comparing 4 months versus
8 months of neoadjuvant ADT before RT for intermediateto high-risk PC) showed that early salvage ADT, based
on PSA ≤ 10 ng/mL and the absence of distant metastases,
improved OS [39]. Besides the limitations of the retrospective
analysis, these reports evidenced the positive impact on OS of
starting ADT at the earliest sign of recurrence. These advantages must be weighed against potential impact on quality of
life or on age-related health problems, especially for young
men and for long-term schedules [40,41]. Therefore, the optimal management and prescription of ADT in patients with
localized PC developing BF after a radical course of RT still
remains controversial, and some alternative schedules have
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
553
Table 1
Indications of the European Society of Urogenital Radiology (ESUR) for the different MRI sequences.
MRI sequences
Radiological aspect of cancer
Notes
T2-weighted images (T2WI)
Cancer appears as a round or
ill-defined, low-signal-intensity focus
in the peripheral zone
Dynamic contrast-enhanced (DCE)
Cancer appears as a round or
ill-defined, low-signal-intensity focus
in the peripheral zone, rapidly
enhancing after the administration of
gadolinium-based contrast medium
Diffusion-weighted imaging (DWI)
with apparent diffusion coefficient
(ADC)
Magnetic resonance spectroscopic
imaging (MRSI)
Cancer shows lower ADC values
compared to normal prostate tissue
• It provides the best depiction of the prostate’s zonal anatomy and
capsule. T2WI is used for prostate cancer detection, localization
and staging
• T2WI should always be performed with at least two functional
MRI techniques in order to provide better characterization of the
anatomy and of the pathological tissues
• Prostate intra-epithelial neoplasia, prostatitis, hemorrhage,
atrophy, scars and post-treatment changes can mimic cancer on
T2WI
• Biopsy-related hemorrhage can cause artifacts that mimic cancer
and limit lesion localization and staging. The interval between the
biopsy procedure and MRI should be at least 4–6 weeks
• Tumors located in the transition zone are more challenging to
detect (the signal intensity characteristics of this zone and cancer
usually overlap)
• It is the most common imaging method for evaluating tumor
vascularity
• Several studies have found that DCE-MRI is superior to T2WI for
prostate cancer localization
• If the prostate has high vascularity, then DCE-MR cannot be used
alone and should always be combined with T2WI and DWI
• Diffusion-weighted imaging is, however, affected by magnetic
susceptibility effects resulting in spatial distortion and signal loss
• Commercially available software packages allow overlying
spectral information on T2WIs
• The relevant metabolites are citrate (marker of benign tissue),
creatine (insignificant for diagnosis, but difficult to resolve from
choline), and choline (marker of malignant tissue)
Cancer shows lower levels of citrate
and higher levels of choline than
benign tissues
Adapted from Barentsz et al. [18].
been proposed [42]. In a recent non-inferiority study published by Crook et al., [43] continuous ADT was compared
with ADT provided in 8-month cycles, with non-treatment
periods determined according to the PSA level: the intermittent ADT was not inferior to the continuous schedule in terms
of overall survival, and it also showed better results in terms
of quality of life. Two randomized trials are currently ongoing, addressing the relevant issue of early ADT in patients
who relapse after initial curative RT.
In conclusion, according to the NICE Clinical Guideline
58 that is regulating the National Health Service in Britain,
ADT “. . .is not routinely recommended for men with prostate
Table 2
Studies comparing early- versus late-salvage androgen deprivation therapy (ADT) after radical radiotherapy (RT) with or without ADT for prostate cancer.
Ref
Study design
Population
Number of
patients
Median follow-up
(years)
Outcomes after salvage AD
34
Retrospective analysis
Clinically localized prostate cancer (all risk)
treated with RT alone
381
3.8–4.2
35
Secondary analysis of
RTOG 8610
247
9
36
Retrospective analysis
Bulky stage T2–T4 prostate cancer, N0/N1,
randomized to RT + 4 mo ADT versus RT
alone
Clinically localized prostate cancer (all risk)
treated with RT± ADT, includes
post-prostatectomy RT for rising PSA
124
6.2
37
Secondary analysis of
RTOG 8531
Unfavorable-prognosis prostate cancer (i.e.,
T3 or N1), includes post-prostatectomy pT3,
randomized to RT+ adjuvant life-long ADT
versus RT alone
243 (RT-alone
arm)
8.5
PCSS and OS improved with
early-salvage ADT (PSA < 10 ng/mL
BS-negative versus PSA >10 ng/mL
BS-negative versus BS-positive)
OS improved with early-salvage
ADT (M0 versus M1, and PSA level
<20 versus >20 ng/mL)
OS improved with early-salvage
ADT (PSA < 15 ng/mL versus
>15 ng/mL [HR 2.15] and PSADT
>7 versus <7 mo [HR 2.63])
OS improved with early-salvage
ADT (PSA <10 ng/mL versus
≥10 ng/mL [HR 1.5])
Ref, reference; ADT, androgen deprivation therapy; BS, bone scan; DSS, disease-specific survival; HR, hazard ratio; LF, local failure; M0, distant metastasis
absent; M1, distant metastasis present; N0, pelvic node negative; N1, pelvic node positive; OS, overall survival; PCSS, prostate cancer-specific survival; RTOG,
Radiation Therapy Oncology Group; PSADT, PSA doubling time.
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F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
Table 3
Outcomes and complication rates of salvage radical prostatectomy (SRP) series.
Ref.
No. pts
Median interval
between RT and SRP
Median follow-up
after SRP
OCD
(%)
BRFS
(%)
CSS
(%)
PSM
(%)
+LN
(%)
44
49
50
51
52
35
11
79
29
108
–
–
–
4.9 years
36 months
30
28
71
53
69
43
79
71
72
70
12
31
36
18
53
54
55
56
57
58
59
100
100
138
11
51
146
404
47 months
10 Years
–
36.9 months
–
4.6 years
41 months
12–120 months
53.5 months
50 months
5.1 months
(Minimum >10 years)
Period: 1966–1996
58 months
5 years
84
83
7.2 years
3.8 years
55
10
21
7
9
0
36
16
25
0
28
13
16
39
28
39
50
35
39
81
25
44
55
66
55
55
47
54
37
70
73
77
91
83
Rectal
injury
(%)
Anast.
stenosis
(%)
Urinary
incont.
(%)
9
0
6
6.9
6
11
0
12
22
21
46
64
39
67
51
1
30
32
10
22
44
30
OCD, organ-confined disease; BRFS, biochemical recurrence free survival; CSS, cancer-specific survival; PSM, positive surgical margins; LN, lymph nodes;
pts, patients.
cancer who have a biochemical relapse unless they have:
symptomatic local disease progression, any proven metastases, or a PSA doubling time of <3 months” [32]. The recent
update of the EAU Guidelines supports the use of ADT in
the treatment of post-EBRT biochemical failures in patients
with a “. . ..presumed systemic relapse. . .” [31].
Therefore, a comparison with other local salvage therapies, also in terms of health technology assessment, is needed
and would be an important challenge in the era of tailored
treatments.
Actually, NICE and EAU guidelines suggest the use of
radiotherapy for localized failure after prostatectomy and to
evaluate (in the context of clinical trials) local treatments after
radical radiotherapy failure [31,32].
4.2. Salvage prostatectomy
The improvements in surgical experience and the technical
advances, including robotic surgery, have ameliorated surgical performances for salvage radical prostatectomy (SRP)
over the last decade [31,44]. Even if SRP is not the only
surgical salvage approach (considering also pelvic exenteration, radical cystoprostatectomy or prostatectomy with
permanent umbilical cystostomy procedures) [45], laparoscopic and robotic approaches could potentially be favored
by a lower rate of serious side effects [46–48]. Correct
selection of patients reduces the need for more aggressive
surgical approaches, improves outcomes, and reduces toxicity rates. It relies upon three main elements: (a) positive
biopsy, (b) metastases exclusion, (c) the presence of favorable prognostic factors. The most appropriate candidate for
SRP is a non-metastatic patient with the disease, suitable
also for surgery when radiation therapy was planned, and
having a life expectancy which could allow him to benefit from intervention, with a PSA as low as possible (not
exceeding 10 ng/mL) and a Gleason score <7 (if a tumor
specimen is available and if it can be scored) [31]. Even with
the limits of the retrospective studies, recent series of SRP
suggest its superiority over other salvage treatment modalities such as cryotherapy, HIFU or brachytherapy in terms of
biochemical control. However, data are scarce and no conclusive statements can be made. Table 3 shows results of the
SRP series with at least 80 patients and/or 4 years of followup [44,49–59]: the 5-years BF free probability rates after SRP
ranged between 28% and 71%. Several BF definitions after
SRP have been applied – PSA > 0.1 ng/mL and rising [59],
PSA > 0.2 ng/mL [48,50,52–54], PSA > 0.4 ng/mL [60] – and
the median follow-up ranged from 45 to 120 months; this
might explain the wide variation in results, and it is limiting a
critical and comparative analysis. As the biochemical control
clearly worsens when the follow-up is longer (see results of
Pontes et al. [44] and Amling et al. [52], Table 3), early diagnosis of BF and aggressive treatment could produce better and
more durable results than the other salvage approaches [59].
Studies in Table 3 needed a biopsy to confirm the diagnosis
of relapse before SRP. Thus, the timing of biopsies became
a crucial point: if earlier diagnosis seems to be an important
prognostic factor, it could be also a potential but important
limit of the studies with shorter follow-up times and/or earlier
biopsies, as tumor clearance after radiotherapy may take up
to 30 months, with an overestimation of the post-EBRT local
relapse rates [61].
ADT (before and/or during primary EBRT or before SRP)
seems to offer no further oncological advantages, but disease
progression during ADT is a very unfavorable prognostic
factor.
As no data exist on the efficacy in terms of cancer-specific
survival [60,62] of pelvic lymph-node dissection (LND) associated with SRP, despite the possible role of LND to delay
further progression of clinically recurrent PC, no firm conclusion could be drawn and the procedure should be considered
only in highly selected patients.
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
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Table 4
Outcomes and complication rates of the larger salvage cryotherapy series.
Ref.
No. pts
Median follow-up
BRFS (%)
Definition of failure
Incontinence
Rectal toxicity (fistulas)
68
69
70
71
72
73
74
75
279
118
59
176
51
58
797
100
5 years
18.6 months
7 years
7.5 years
10.1 years
2 years
3.4 years
33.5 months
58.9
34
59
39% (at 8 and 10 years)
61
70
66
59 (at 3 years)
Three consecutive rises
PSA ≥ 0.5 ng/mL
PSA ≥ 0.5 ng/mL
PSA nadir + 2
PSA ≥ 0.5 ng/mL
PSA ≥ 0.5 ng/mL
PSA ≥ 0.5 ng/mL
Three consecutive rises
4.4%
6.7%
8%
–
–
–
–
13%
3.2%
3.3%
3.4%
–
–
–
–
1%
Ref, reference; pts, patients; BRFS, biochemical recurrence-free survival; PSA, prostate-specific antigen.
Table 5
Outcomes and complication rates of larger salvage high-intensity focused ultrasound (HIFU).
Ref.
No. pts
Median follow-up
(months)
BRFS (%)
Definition of failure
Incontinence
Bladder-neck stenosis/
Urethral stricture
Rectal toxicity
(fistulas)
82
83
84
85
31
167
71
290
7.5
18.1
14.8
48
50
17 (at 5 years)
61
Not reported
PSA < 0.2 ng/mL
PSA ≥ 1 ng/mL
PSA ≥ 0.5 ng/mL
Phoenix ASTRO consensus
definition and/or prescription of
hormonal therapy
7%
49.5%
7%
19.5%
36%
7.8%
17%
16%
6%
3%
6%
2%
Abbreviations: Ref, reference; pts, patients; FUP, follow-up; BRFS, Biochemical Recurrence Free Survival; PSA Failure, Cut off to assess PSA failure; GU,
genito-urinary
Looking at toxicities, erectile dysfunction and urinary incontinence ranged respectively between 80%
and 100% [47,48,63] and 32% and 67%, respectively
(Table 3). Some studies reported rates of 100% of urinary
incontinence [64].
Erectile dysfunction seems frequently not to be a major
problem in this setting, as it is often present before SRP
[63,65]. As shown by the Cancer of the Prostate Strategic
Urologic Research Endeavor (CAPSURE) Study, the 93.5%
of patients presenting a post-RT failure (including a relevant
number of them presenting a local relapse) received hormonal therapy, despite the resulting erectile dysfunction [8].
It should be noticed that, when compared to those initially
treated with surgery, these patients are older (27% aged >75
years), with more advanced disease, and that almost 40% of
them had already had hormonal treatments at presentation. In
this context, only 0.9% of them have been submitted to SRP,
and erectile dysfunction related to surgery does not seem to
be the most relevant issue. Looking at the bladder toxicity
after SRP, in particular urinary incontinence, it remains
high (despite the introduction of mini-invasive techniques),
ranging between 20 and 100% [47,48,64]. Strictures of
the anastomosis are not rare and, even if the studies did
not always report data about this possible side effect, rates
ranging between 11% and 30% have been published in the
literature (Table 3). Rectal injuries are less frequent, but not
negligible, with rates ranging between 1% and 10% (Table 3).
In conclusion, SRP could be considered as an option
in selected patients with local relapse. Its results should
be carefully evaluated, taking into account the potentially
severe side effects, and compared with the results of other
available treatments options (Tables 4–6).
4.3. Cryotherapy
Cryotherapy consists in the localized ablation of prostatic tissue by low temperature and thawing, which causes
direct injury to cells as well as secondary injury from
the inflammatory response of the body. Modern cryotherapy uses liquid nitrogen or argon gas circulating through
hollow needles to freeze the prostate and helium gas to
warm the urethra via the Joule–Thompson effect. Patients
who are presenting a prostate gland volume ≥60 mL and/or
have undergone a transurethral resection of prostate (TURP)
should be excluded because of the potential high risk of
urinary morbidity (incontinence and urethral strictures) [66].
The results obtained in 1600 patients treated with salvage
cryosurgery using various-generation cryotherapy devices
have been published (median follow-up: 18 months to 10
years), with biochemical control rates ranging between 34%
and 70% [67–74] (Table 4). However, the heterogeneity in the
criteria used to establish efficacy (PSA ≥ 0.3 ng/mL, nadir
plus 2 ng/mL, PSA ≥ 0.4 ng/mL, and PSA ≥ 0.5 ng/mL)
reflects the lack of agreement between cryosurgeons [67–74].
By assuming that the prostate gland is completely ablated and
no other metastatic foci are present in the body, undetectable
PSA could reasonably be considered the optimal endpoint for
cryotherapy and, obviously, some of the reported biochemical
response could be re-sized where properly redefined.
Thus, cryotherapy is a challenging option in patients showing a BF after RT, but the expected side effects on urethra,
rectum, penile bulb and erectile nerves could be considered prohibitive in some experiences, and seems also to be
related to the operator experience; Izawa et al. [75] showed
rates of urinary incontinence, obstructive symptoms, sexual
556
Table 6
Brachytherapy experiences of salvage intent after external-beam radiotherapy (EBRT).
No. pts
Type BRT
Dose BRT
Adjuvant ADT
(%)
Median follow-up
(months)
BRFS (years)
Definition of failure
Urinary
incontinence
GU 3–4
toxicity
GI 3–4
toxicity
Erectile
dysfunction
104
13
LDR
125 I:
NR
36
51% (5)
31%
NR
15%
NR
105
106
107
31
25
31
LDR
LDR
LDR
198 Au:
NR
0
97
23
47
30
67% (5)
70% (4)
87% (5)
0
0
0
NR
16%
NR
NR
24%
5%
NR
NR
NR
108
17
LDR
47
62
53% (5)
24%
24%
0
NR
109
17
LDR
71
44
57% (4)
6%
47%
6%
NR
110
31
LDR
100–200 Gy
125I: 135 Gy
103 Pd: 120 Gy
125 I: 144 Gy
103 Pd: 90 Gy
125 I: 120 Gy
103 Pd: 120–126 Gy
125 I: 103.5–112.5 Gy
125 I: 145 Gy
–
108
20% (5)
Metastases-free
survival
Overall survival
Phoenix criteria [11]
ASTRO
criteria [10]
ASTRO
criteria [10]
ASTRO
criteria [10]
Phoenix criteria [11]
NR
19% (late)
6% (late)
NR
111
37
LDR
84
86
54 (10)
Phoenix criteria [11]
NR
11%
NR
85%
112
49
LDR
NR
64
34% (5)
Two rises above nadir
6%
14% (TURP)
2%
NR
113
15
LDR
103 Pd or 125 I: 122 Gy
(median to 90% of the
volume)
103 Pd: 170 Gy
125 I: 160 Gy
(median)
103 Pd: 125 Gy
125 I: 144 Gy
0
23
71% (3)
Phoenix criteria [11]
0
0
0
13%
114
115
10
21
HDR
HDR
0
52
NR
19
NRa
89% (2)
ASTRO criteria [10]
ASTRO
criteria [10]
0
0
0
14%
0
0
NR
100%
(grade 2)
170 Gy (median)
11 Gy × 2 fr.
6Gy × 6 fractions
Ref, reference; GU, genitourinary; pts, patients; BRT, brachytherapy; ADT, androgen deprivation therapy; BRFS, biochemical recurrence-free survival; GI, gastrointestinal; ED, erectile dysfunction; LDR, low
dose rate; HDR, high dose rate; NR, not reported.
a In 7/11 cases: biochemical non-evidence of disease (bNED), in 3/11: PSA level continuously rose after salvage HDR-BT; 1/11: biochemical failure.
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
Ref.
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
impotence and severe perineal pain in 73%, 67%, 72% and
8%, respectively. Rates of rectal injuries (fistulas) ranging
between 1% and 3% have also been reported, especially in
the salvage setting (Table 4). The technology of cryoablation
devices has been improved, and the development of newgeneration real-time ultrasound probes as a guide for freezing
ablation allows safer and more precise treatments than in the
first experiences [76]. Methods to reduce the unacceptably
severe urinary toxicities (e.g., urethra-sparing techniques performed by urethral warming catheters and thermocouplers)
carry a not negligible risk of excluding cancer foci in the
prostate gland, particularly at the apex region, from ablative
freezing doses. Moreover, a single course of cryotherapy is
often not sufficient and multiple sessions are needed, causing a significant increase in morbidity, especially regarding
sexual dysfunctions (>90% of treated patients [77–79]).
In conclusion, at present there is no robust evidence in
favor of cryotherapy in the salvage setting after radiotherapy
failure.
4.4. High-intensity focused ultrasound (HIFU)
HIFU is a local treatment causing tissue ablation by
intense ultrasound waves with focused heating of the targeted
region. The HIFU technique in different tumor sites has been
the object of experimental studies for 50 years, principally
involving the liver. In the prostate, HIFU was originally proposed for benign diseases, but was then rapidly introduced as
a non-invasive option for PC patients with a definitive or salvage intent [80–84]. Different biochemical (decreasing PSA)
and pathological (high rate of negative biopsies or negative
specimen of SRP performed after HIFU) evidences of the
efficacy of HIFU have been already published [85,86].
HIFU shares with other salvage local therapies the limits of the heterogeneity in the definition of PSA failure in
the published studies; these limits are even more evident for
salvage HIFU series. Globally, data on about 200 patients
treated with HIFU as salvage treatment after EBRT are available (see Table 5). Crouzet et al. [84] in the largest published
experience of 290 patients, with the longest follow-up of 48
months – obtained 7-year cancer-specific and metastasis-free
survival rates of 80% and 79.6%, respectively.
In the salvage setting, HIFU led to local toxicities
much more frequently than when used as primary treatment
[82,87]. Urinary incontinence (7–50%), late urethral strictures (7.8–36%) and recto-urethral fistulas (2–6%) are the
principal side effects of salvage HIFU (Table 5). The rate
of recto-urethral fistula after salvage HIFU was shown to be
more common when EBRT was combined with brachytherapy [88,89]. In the series of Murat et al. [82], 11% of patients
required the implantation of an artificial urinary sphincter,
confirming the high rate of urinary side effects with the risk
of re-intervention already shown by Zacharakis et al. [87].
Some authors recommend a bladder-neck incision before salvage HIFU in order to minimize acute urinary retention and
bladder outlet obstruction [82,89,90].
557
It is worth noting that the assessment of toxicity is not
consistently reported in the HIFU series, and various criteria
are applied, so the real rates of late injury might be underevaluated.
In conclusion, the evidence for salvage HIFU (and
cryotherapy) in treating BF after RT remains limited.
In fact, the NICE Guidelines statement is that “. . .Highintensity focused ultrasound and cryotherapy are not
recommended for men with locally advanced prostate cancer
other than in the context of controlled clinical trials comparing their use with established interventions”; however, the
same Guidelines recommend “clinical trials into comparative clinical and cost effectiveness of local salvage treatments
such as cryotherapy and HIFU” [32].
4.5. External-beam radiation therapy (EBRT)
Studies on re-irradiation have been published for various
tumors sites [91–93], but they have rarely been reported for
intraprostatic recurrent PC, with principal series concerning
the role of BRT (see Section 4.6).
Apart from the availability of other salvage treatments,
several clinical, technical and anatomical reasons could
explain this lack of data. Among them: elderly age of the
majority of patients, frequent metastatic evolution, clinically
evident or subclinical normal tissue damage due to the high
doses of EBRT already delivered (at least 70 Gy).
However, the use of EBRT in this context has been theoretically considered and documented in a very limited group
of patients. High doses of EBRT are needed to treat PC,
as the presence of a dose–response effect has been well
established [94]. Theoretically, re-irradiation up to significant doses could be effective in at least some patients with
late intraprostatic recurrences. “Small field” RT to limited
volume relapsing PC could reduce the tumor clonogen number and, as a consequence, prolong the progression-free
interval. The concept of spatial cooperation between radiation and systemic therapy might also be attractive in this
kind of clinical scenario [91]. The indication for such a
local approach should in principle be based on the interval between primary RT and diagnosis of recurrent disease
(early recurrence indicating low radiosensitivity), absence
of radiation injury from the primary treatment, patient’s
preferences, comorbidities and general conditions. EBRT reirradiation may be realized with different technical solutions,
including IMRT (nowadays largely available) and stereotactic body irradiation (SBRT), that can be realized with different
machines, such as CyberKnife© units, modern Linac-based
systems (True Beam© , RapidArc© , V-MAT© , Axesse© ),
Helical Tomotherapy© or VERO© [91,95,96].
SBRT is particularly interesting, as it allows the reduction
of the safety margins around the target (thus minimizing the
exposure of the previously irradiated surrounding normal tissues) and hypofractionation, which is very often used when
stereotactic techniques are employed, and that could be of
558
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
particular value for PC considering its low alpha/beta ratio
[97].
Recently, a couple of reports on stereotactic prostate reirradiation have been published [98,99]. Vavassori et al. [98]
reported the preliminary results on six patients treated with
CyberKnife SBRT (30 Gy in 5 fractions over 5 consecutive
days). Jereczek-Fossa et al. [99] updated this study: nine
more patients were considered, and overall 15 patients with
biopsy-proven isolated intraprostatic recurrence were treated
with the same CyberKnife SBRT schedule; 6/15 also received
systemic therapy. Complete biochemical response was registered in six out of nine patients treated with SBRT only
(no systemic therapy), confirming the potential radiosensitivity of intraprostatic recurrence. The pattern of failure was
predominantly out-field (four out of five events). Actuarial
3-year progression-free survival was 22%. Interestingly, no
acute or late rectal toxicity was registered. Urinary toxicity included five acute events (only one grade 3) and three
late events (only one grade 3). The authors concluded that
Cyber Knife re-irradiation using 30 Gy/5 fractions is a feasible approach to isolated intraprostatic recurrence, offering
excellent in-field tumor control and a low toxicity profile.
Similarly, no late toxicity was registered in another study,
after 9 months follow-up in two PC patients re-treated with
helical tomotherapy, with a biochemical response observed
in one of these patients [100].
Partial re-irradiation has also been proposed with the
advance in molecular imaging and radiation treatment planning and delivery [101]. This concept, based on the limited
multifocality of recurrent PC, could be of particular interest as it potentially allows better sparing of the surrounding
healthy tissues [101,102].
Effective local therapy might reduce the burden of the
systemic therapies usually given to patients with recurrent
PC.
In conclusion, EBRT re-irradiation is not a standard and
has rarely been used as salvage treatment for locally relapsing
prostate cancer (1.9% of the 438 patients initially treated with
radiotherapy considered by the CAPSURE study [8]). This
option should be considered only in very selected cases. The
prospective collection of data on these treatments is strongly
advised, even if a formal perspective trial is difficult to imagine because of the small number of potential candidates.
4.6. Brachytherapy (BRT)
Even if BRT is a well-established treatment option for
low-risk and, in selected cases, intermediate-risk PC patients
[33], only a few experiences have been published about its
use for the treatment of post-RT intraprostatic relapse. The
first studies were published in the 1990s [103,104], but only
recently has BRT been progressively and more extensively
employed in this particular clinical setting. The dose delivered – either with 125 I or 103 Pd – varied between 108–170 Gy
and 90–170 Gy, respectively, and the type of source did not
appear to be related to the outcome, even though a direct
comparison between the two sources in the salvage setting has
never been performed. Table 6 shows clinical outcomes and
toxicity of salvage BRT [103–114]. However, some biases
could surely affect the results and the possibility of making
conclusions about efficacy and safety of salvage BRT, also
because of the different definitions of BF used in the published studies, and the use of neoadjuvant and/or adjuvant
hormonal therapies that is not always clearly reported. In general, despite these limitations, published 5-year biochemical
disease-free survival (bDFS) rates range from 20% to 87%.
The number of patients enrolled in the studies is often limited
(13–49), with only five studies presenting results from >30
patients, and only three of these five reports presenting mature
results with a median follow-up >60 months [109–111]. In
these three studies, a total of 117 patients were enrolled,
accounting for 40% of the patients treated by salvage BRT.
After a median follow-up of 64–108 months, the reported 5year bDFS ranges from 20% to 64%. Burri et al. [110] also
reported data about the 10-year bDFS, with an interesting rate
of 53% (median follow-up: 86 months). It should be noted
that in their study, 84% of patients also received ADT at the
time of salvage BRT.
Usually, BRT has been delivered using LDR techniques,
but two studies have been published (in 2007 and 2012) about
the use of HDR–BRT [113,114]. Jo et al. [113] treated 11
patients with 2 fractions of 11 Gy: they reported 7/11 cases of
biochemical non-evidence of disease (bNED), 3/11 patients
presenting PSA level continuously rising, and 1/11 patients
showing a biochemical failure. These authors reported no
G3–G4 toxicities, but they did not give information about
the length of the follow-up time. Lee et al. reported their
experience with 21 patients treated with 6 fractions of 6 Gy:
the bDFS rate was 89%, but the median follow-up was only
19 months and the data on the bDFS were calculated at 2
years. Moreover, 52% of patients received adjuvant ADT
[114]. Toxicity was acceptable, with no rectal toxicity, 14%
rate of G3–G4 urinary toxicity, and 100% rate of G2 erectile
dysfunction.
Table 6 shows a summary of the complications reported
in the studies. Even if the gastrointestinal or genitourinary
complications were the most common types, not all the studies give information about safety. The incidence of G3–G4
genitourinary and gastrointestinal complications ranges from
0% to 47% and from 2.7% to 24%, respectively. Erectile dysfunction rates were high with salvage BRT in two studies at
85% [110] and 100% [115], but much lower in another recent
study, at 13% only [114]. In general, data about sexual dysfunction is very rarely reported in the available studies, and it
is impossible to reach a definitive conclusion about this issue.
5. Conclusions
The rate of Bf after curative EBRT for PC is not negligible
and should be defined following the consensus definition of nadir + 2 ng/mL (ASTRO “Phoenix” definition). The
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
prescription of several MRI sequences and of TC–PET with
radiolabeled choline is increasingly frequent in these clinical
situations, but no single diagnostic modality could be considered as a standard to detect early local recurrence after
EBRT. Moreover, prospective data collection is needed to
clarify their efficacy in distinguishing between local and distant relapse.
Furthermore, in most patients systemic progression
occurs despite local salvage therapy, probably because of
micrometastatic disease outside the prostate and pelvis that is
missed by the available diagnostic tools. Thus, to date, androgen deprivation is the most common management option
in the salvage setting after curative RT, but its deleterious
side effects, especially for long-term schedules, should be
carefully considered.
If successful, local therapy could minimize the burden
of the systemic therapies usually prescribed to patients with
recurrent PC. No data exist on the best schedule and timing
for associating a systemic therapy with the local treatments.
Several reports on the results of local approaches for
intraprostatic failure after EBRT (prostatectomy, HIFU,
cryotherapy, re-irradiation) have been published. Considerable limitations can be found in these reports: retrospective
nature, small number of cases, heterogeneous criteria for toxicity and tumor outcome reporting, and no information on
follow-up and/or on some relevant endpoints (for some of
these reports). Moreover, no standard doses or protocols are
available, and only some patients receive combined therapies
(e.g. local treatment and ADT). At present no firm recommendations can therefore be made. Meanwhile, perspective
collection of outcome data on the few selected patients treated
with local treatment modalities is strongly suggested.
Ideally, salvage therapy must be tailored to the initial
tumor features, PSA kinetics and patient conditions and preferences.
Most probably, SRP can represent a viable option in the
case of fit, motivated patients with biopsy-proven intraprostatic failure of low- to intermediate-risk cancer with no
evidence of extraprostatic disease and acceptance of erectile dysfunction. However, most of the patients treated with
primary EBRT have been previously excluded and/or are not
suitable for surgery because of age or clinical reasons; previous irradiation could affect the feasibility and safety of SRP,
which is often offered only by high-volume urology centers. Early diagnosis and appropriate selection of the patients
remain the key factors to obtain better outcomes and lower
intraoperative complications, bleeding or rectal injuries.
Alternative local salvage therapies are currently reserved
for highly selected patients, but their efficacy and safety
should be carefully evaluated and no conclusive statements
may yet be made.
The distinction between isolated local and distant
metastatic failure is crucial: future developments in imaging
modalities, in conjunction with PSA kinetics, will possibly
allow a better selection of patients based on the type and the
behavior of the intraprostatic relapse.
559
Conflict of interest
None declared.
Funding
None to be declared.
Reviewer
Helen Boyle, MD, Centre Léon Bérard, 28 Rue Laennec,
F-69008 Lyon, France
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Biographies
Alongi Filippo, MD: radiation oncologist and clinical investigator. He has published more than 50 articles
(indexed/peer-reviewed journals) and several book chapters.
Main topics of his activity are: SBRT, hypofractionation,
IGRT, molecular imaging in radiation oncology, and prostate
cancer. Since 2012, he has been the national coordinator
of the young group of AIRO (Italian Society of Radiation
Oncology) and he is a member of the board of AIRO prostate
working group.
De Bari Berardino, MD: radiation oncologist and clinical investigator. He has published more than 30 articles
(indexed/peer-reviewed journals) and one book chapter. Main
topics of his activity are: prostate cancer, GI cancer, neurooncology and IGRT. He is an ESTRO (European Society of
Radiation Oncology) fellow and coordinator of the ESTRO
contouring workshops in the context of the FALCON project,
including also prostate cancer. He speaks regularly at international conferences and teaching events. Dr De Bari is a
member of the board of the AIRO prostate working group.
F. Alongi et al. / Critical Reviews in Oncology/Hematology 88 (2013) 550–563
Campostrini Franco, MD: radiation oncologist and clinical investigator. He has published more than 20 articles
(indexed/peer-reviewed journals). Main topics of his activity are: prostate cancer and head and neck cancers. He is
director of the Department of Radiotherapy of the Legnago,
he is a member of the board of AIRO prostate working group.
Arcangeli Stefano, MD: radiation oncologist and clinical researcher. He has published more than 30 articles
(indexed/peer-reviewed journals) and several book chapters. Main topics of his activity are: radiation oncology and
prostate cancer, SBRT.
Deliu Victor Matei, MD: urologist, Senior Deputy Director of the Division of Urology of the Europeran Institute of
Oncology (Milan, Italy). His main research interests include
robotic surgery for prostate cancer. He is author of more than
20 full papers and speaks regularly at international conferences and teaching events.
Lopci Egesta, MD: medical doctor and clinical investigator in nuclear medicine. She has published more than 20
articles (indexed/peer reviewed journals). Main topics of her
activity are: molecular imaging in radiation oncology, choline
PET in prostate cancer.
Petralia Giuseppe, MD: radiologist and assistant of the
Department of Radiology of the European Institute of Oncology (Milan, Italy). Main research interests include MRI of
prostate cancer. He is an author of about 50 full papers and
speaks regularly at international conferences and teaching
events.
Bellomi Massimo, MD: radiologist and professor of the
University of Milan (Milan, Italy). He is Head of the Radiology Department of the European Institute of Oncology
(Milan, Italy). His main research interests include imaging
of pelvic malignancies. He is an author of about 150 full
papers and speaks regularly at international conferences and
teaching events.
Chiti Arturo, MD: medical doctor and clinical investigator in nuclear medicine. He is Director of Nuclear
Medicine Department of Istituto Clinico Humanitas (Milan,
Italy). He has published more than 70 articles (indexed/
563
peer-reviewed journals) and several book chapters. Main
topics of his activity are: molecular imaging in radiation
oncology, head and neck and prostate cancer. From 2012
he has been president of EANM (European Association of
Nuclear Medicine).
Magrini Stefano Maria, MD: radiation oncologist and professor of the University of Brescia (Brescia, Italy) and Head
of the Department of Radiotherapy of the Spedali Civili of
Brescia (Brescia, Italy). His main research interests include
prostate cancer, brain tumors and head and neck cancers,
combined modality treatments, and new radiotherapy techniques. He has been a member of the ESTRO board and of
several ESTRO committees, and has been a member of the
AIRO board and coordinator of the AIRO prostate cancer
working group. He has published more than 250 full papers
and speaks regularly at international conferences and teaching events.
Scorsetti Marta, MD: radiation oncologist and clinical
investigator. Director of Radiation Therapy Department of
Istituto Clinico Humanitas in Milan (Milan, Italy). She has
published more than 60 articles (indexed/peer-reviewed journals) and several book chapters. Main topics of her activity
are: SBRT, hypofractionation, IGRT, radiosurgery, lung and
prostate cancer.
Orecchia Roberto, MD: radiation oncologist and professor of the University of Milan (Milan, Italy) and Head of
the Division of Radiotherapy of the European Institute of
Oncology (Milan, Italy). His main research interests include
breast and prostate cancer. He has published almost 250 full
papers and speaks regularly at international conferences and
teaching events.
Jereczek-Fossa Barbara Alicja, MD and PhD: radiation
oncologist and assistant professor of the University of Milan
(Milan, Italy) and Senior Deputy Director of the Division of
Radiotherapy of the European Institute of Oncology (Milan,
Italy). Her main research interests include prostate cancer,
combined modality treatments and high precision radiotherapy. She is an author of about 100 full papers and book
chapters and speaks regularly at international conferences
and teaching events.