Salvage therapy of small volume prostate cancer nodal failures: A

Critical Reviews in Oncology/Hematology 90 (2014) 24–35
Salvage therapy of small volume prostate cancer nodal failures: A review
of the literature
Berardino De Bari a , Filippo Alongi b,∗ , Michela Buglione a , Franco Campostrini c ,
Alberto Briganti d , Genoveffa Berardi e , Giuseppe Petralia f , Massimo Bellomi f , Arturo Chiti g ,
Andrei Fodor e , Nazareno Suardi d , Cesare Cozzarini e , Di Muzio Nadia e , Marta Scorsetti b ,
Roberto Orecchia h , Francesco Montorsi d , Filippo Bertoni i , Stefano Maria Magrini a ,
Barbara Alicja Jereczek-Fossa h
b
a Radiotherapy Department, Istituto del Radio di Brescia, University of Brescia, Brescia, Italy
Radiotherapy and Radiosurgery, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Milan, Italy
c Radiotherapy Department, Legnago Hospital, Legnago, Italy
d Department of Urology, Vita-Salute University San Raffaele, Milan, Italy
e Radiation Therapy, San Raffaele Scientific Institute, Milan, Italy
f Department of Radiology, European Institute of Oncology, Milan, Italy
g Nuclear Medicine, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Milan, Italy
h Department of Radiotherapy, European Institute of Oncology, Milan Italy and University of Milan, Italy
i Department of Radiation Therapy, Modena Hospital, Modena, Italy
Accepted 13 November 2013
Contents
1.
2.
3.
4.
5.
6.
7.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
“Oligometastases” and “oligo-recurrence” in prostate cancer patients: in search of a definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Imaging of lymph-nodes by CT and MRI in patients with relapse of prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Androgen deprivation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
External beam radiotherapy and stereotactic body radiotherapy for lymph node recurrence from prostate cancer . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Fundings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
New imaging modalities may be useful to identify prostate cancer patients with small volume, limited nodal relapse (“oligo-recurrent”)
potentially amenable to local treatments (radiotherapy, surgery) with the aim of long-term control of the disease, even in a condition traditionally
∗ Corresponding author at: Radiotherapy and Radiosurgery, Humanitas Cancer Center, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan,
Italy. Tel.: +39 0282247454; fax: +39 0282248509.
E-mail addresses: [email protected], [email protected] (F. Alongi).
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.critrevonc.2013.11.003
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
25
considered prognostically unfavorable. This report reviews the new diagnostic tools and the main published data about the role of surgery and
radiation therapy in this particular subgroup of patients.
© 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nodal relapse; Prostate cancer; PET prostate; SBRT; Radiotherapy; Surgery; ADT prostate; Salvage lymph node dissection; Oligo-recurrent disease
1. Introduction
In patients with rising PSA values after primary treatment
of prostate cancer the new imaging modalities allow the identification of patients with an apparently limited burden of
local and/or metastatic recurrent disease. In the last decade,
the new clinical entities termed “oligometastases” and “oligorecurrences” have been proposed for this clinical condition
and are now largely accepted amongst oncologists [1].
Although systemic therapy is the main therapeutic
approach in advanced cancer, investigations suggest that
local approaches (surgery, radiotherapy) can offer durable
progression-free-survival in these selected groups of patients
(“chronic curable cancer”) [1,2]. Traditionally, lymph node
recurrent prostate cancer after the primary loco-regional
treatment has been considered as an unfavorable situation,
and palliative systemic hormonal therapy (Androgen Deprivation Therapy, ADT) remains the golden standard in this
population of patients [3,4]. Despite that, once started, ADT
should often be continued for a long period (usually until
progression, when other hormonal manipulations and/or
chemotherapy may be considered) and is related with significant side effects and deterioration of the patients quality of
life [5]. Therefore, because of the long natural history of the
prostate cancer, local therapies are considered with increasing interest, because of their potential efficacy for long term
disease control or, even, cure.
The aim of the present review is to provide a correct definition of oligo-recurrent disease, with a focus on recent
advances in imaging procedures for the detection of nodal
recurrences. Furthermore, all available salvage treatments for
nodal prostate cancer relapses are presented and thoroughly
discussed.
2. “Oligometastases” and “oligo-recurrence” in
prostate cancer patients: in search of a definition
Modern surgical approaches and the advances in radiotherapy treatment planning and dose delivery allow radiation
oncologists (and surgeons) to offer potentially curative treatments also to patients that traditionally candidates only to
palliative systemic therapies, possibly at a reasonable price
in terms of toxicity.
Even if the terms “oligometastases” and “oligorecurrence” could be considered as synonyms, they do not
represent the same clinical situation, since the status of
the primary tumor is not the same. Indeed, oligometastatic
patients are those presenting 1–5 metastatic sites and also
an active primary lesion, while in the oligo-recurrent status,
the primary tumor is cured [6]. On the other hand, if several reports agree on the idea that an oligo-recurrent disease
should not present more than 5 lesions, at our knowledge
there are no clear indications about the size of these lesions.
Usually, trials and studies on oligo-recurrent disease consider
a diameter of 5 cm the upper limit to treat an oligo-recurrent
disease with ablative doses of RT.
Considering the crucial prognostic role of the local control on the primary tumor [6], it could be easily argued
that, in theory, an oligo-recurrent disease is more easily
amenable to local therapies applied with curative intent than
an oligometastasic one.
Last but not least, the possibility to achieve durable tumor
control in clinically evident metastatic sites could be relevant
also for long term control of the primary tumor or of other
sites of micrometastases, following the “seed and soil” and
the “multiple steps cancer progression” theories [7,8], and
represents one of the most important reasons supporting the
role of focused surgical and/or radiation therapies also in
potentially multi-micrometastatic patients.
3. Imaging of lymph-nodes by CT and MRI in
patients with relapse of prostate cancer
According to many authors, conventional CT and MRI
are approximately equivalent in detecting nodal metastases
(LNMs). [9]. As it is shown in Table 1, all nodes exceeding a minimal threshold of 6–15 mm could be considered
potentially involved [9–11]. It should be noted that the threshold of 6–7 mm that is used in some studies is extremely low,
explaining its high sensibility, but also probably influencing
the accuracy of the results. Despite that, pathologic reports
on specimens of nodal dissections for prostate cancer showed
that metastatic deposits could be found in about 25% of normal sized LNs [10,12]. Furthermore, it is well known that also
benign conditions could be responsible of enlarged LNs.
Tables 1 and 2 summarize the most relevant prospective
trials exploring the efficacy of conventional CT scan [12–17]
and MRI [12,17–25] to identify prostate cancer nodal metastases, using a reliable pelvic nodal dissection (PLND) or
accurate biopsies as reference tests. The sensitivity values
represent the great limit of both the techniques: with values
ranging between 25% and 78% for the CT scan and between
0% and 86% for the standard MRI, respectively, with a large
number of LNMs undetected. Saokar et al. compared the
sensitivity of CT and MRI [26]. They concluded that MRI
26
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
Table 1
Performances of the magnetic resonance imaging (MRI) in detecting nodal metastases.
Authors (year of publication)
References
Number of
patients
Inferior
threshold
(mm)
LNM %
Sensitivity %
Specificity %
Accuracy %
Heesakkers et al. (2008)
Lecouvet et al. (2012)
Bezzi et al. (1988)
Rifkin et al. (1990)
Jager et al. (1996)
Perrotti et al. (1996)
Harisinghani et al. (2003)
12
17
18
19
20
21
22
375
100
51
185
63
56
80
8–10
10
10
10
8.
10
10
16
NA
25
12.5
14
9
NA
23
24
25
411
29
36
8
6
4
5.5
NA
47
97
95 (R3) 96 (R4)
95
95
98
90
79 (standard MRI)
96 (USPIO-MRI)
98
85
97.6
NA
NA
88
NA
89
86
NA
Wang et al. (2006)
Eiber et al. (2010)
Budiharto et al. (2011)
34
77 (R3) 82 (R4)
69
4
60
0
45 (standard MRI)
100 (USPIO-MRI)
27
86a
18.8
NA
86
NA
Note: Inferior threshold: Figure above which a lymph node is considered pathological; % LNM: Percentage of patients with positive lymph nodes histopathologically controlled; USPIO contrast agent: UltraSmall Particles of Iron Oxide (no longer commercially available).
a Correlation with histopathology in only 10 patients; NA: Not available; R1 and R2: Two different readers.
was significantly more accurate than CT in identifying lymph
nodes in the range 1–5 mm.
MRI potential has been increased by the introduction of
a new contrast medium and functional sequences. The Diffusion Weighted MRI (DWI–MRI) is a functional technique,
based on the reduction of water protons mobility in hypercellular cancer tissues, giving a higher signal compared to
the surrounding unaffected healthy tissue [10,11]. Studies
performed with DWI–MRI are limited and not yet conclusive (Table 2). Eiber et al. [24] performed a comparison
between DWI–MRI and standard T2W MRI, concluding that
the functional sequences of DWI-MRI were significantly
more accurate than size-based criteria to detect LNMs (Table
II). Moreover, Mir et al. showed that the fusion of DWIMRI with standard T2W images improves the identification
of pelvic LNs in comparison to T2W alone [27], but these
results were not confirmed by Budiharto et al. in a prospective histopathology-based evaluation of 11 C-choline PET-CT
and DWI-MRI for the detection of LNMs [25]. Despite its
obvious interest, DWI-MRI is still under evaluation.
As described by the leading study of Harisinghani [22],
confirmed by several other Authors, MR Lymphoangiography (MRL) showed very promising results with sensitivity
and specificity rates of 82–100% and 93–96%, that are
superior to both standard MRI [22] and modern CT [12].
However, MRL with USPIO (UltraSmall Particles of Iron
Oxide, Ferumoxtran-10) has been substantially abandoned
since marketing authorization for contrast medium is lacking.
A recent meta-analysis about the diagnostic performance
of 18F-choline and 11C-choline PET or PET-CT in the
nodal staging of prostate cancer showed a pooled sensitivity of 49.2% (95% confidence interval [CI], 39.9–58.4) and
a pooled specificity of 95% (95% CI, 92–97.1) [28].
The definition of a PSA cut-off value to refer prostate
cancer patients with biochemical failure to [11C]Choline
PET/CT scanning would be helpful for the clinical management of these patients. Unfortunately, there is currently
no consensus on such a cut-off value. Using ROC analysis in a large sample, Giovacchini et al. found that positive
and negative [11C]Choline PET/CT scans could be best
Table 2
Performances of the conventional CT scan in detecting nodal metastases.
Authors (year of publication)
References Number of patients Inferior threshold (mm) LNM % Sensitivity %
Specificity %
Accuracy %
Heesakkers et al. (2008)
Golimbu et al. (1981)
Flanigan et al. (1985)
Van Poppel et al. (1994)
Rorvik et al. (1998)
Lecouvet et al. (2012)
12
13
14
15
16
17
375
46
53
285
64
100
8–10
10
15
6
10
10
16
37
26.5
16
15
NA
NA
70
91
96.5
NA
NA
Perrotti et al. (1996)
Harisinghani et al. (2003)
21
22
56
80
10
10
9
NA
Wang et al. (2006)
Eiber et al. (2010)
Budiharto T et al. (2011)
23
24
25
411
29
36
8
6
4
5.5
NA
47
97
93
100
100
98
95 (R3)
96 (R4)
90
79 (standard MRI)
96 (USPIO-MRI)
98
85
97.6
34
30
50
78
25
77 (R3)
82 (R4)
0
45 (standard MRI)
100 (USPIO-MRI)
27
86a
18.8
86
NA
NA
86
NA
Note: Inferior threshold: Figure above which a lymph node is considered pathological; % LNM.: Percentage of patients with positive lymph nodes histopathologically controlled; USPIO contrast agent: UltraSmall Particles of Iron Oxide (no longer commercially available.
a Correlation with histopathology in only 10 patients; NA: Not available; R3 and R4: Two different readers.
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
discriminated using a PSA cut-off value of 1.4 ng/ml, with
a sensitivity of 73% and a specificity of 72% while only 24%
of patients with a PSA value below 1.4 ng/ml can have positive PET/CT findings [29]. Krause et al. reported a detection
rate by [11C]Choline PET/CT of 36% with PSA levels lower
than 1 ng/ml [30], while Vees et al. reported a detection rate
of about 50% with a similar range [31]. In a recent study by
Picchio et al., a potential role of PET, particularly in patients
at high risk of relapse with a fast PSA kinetics, was shown
even in presence of low PSA values [32].
The discrepancies reported by authors from different
Institutions can be attributed to differences in clinical and
pathological characteristics of the samples, and statistical
uncertainty derived from small sample sizes.
Also for these reasons, the EAU Guidelines clearly discourage the routinely use of [11C]-choline PET/CT for the
early diagnosis of nodal relapses from prostate cancer.
These guidelines underline that the detection rate of
[11C]Choline PET/CT appears to depend strongly on PSA
levels at the time of diagnosis, pathologic stage at time of
initial diagnosis, previous biochemical failure, and older age
as recently demonstrated in a cohort of 358 patients with PSA
relapse following radical prostatectomy and a mean PSA level
of 3.97–6.94 ng/ml at the time of evaluation [29]. Furthermore, the probability of false-positive results in up to 20% of
patients has to be considered when interpreting PET results
[4].Summary:
- Conventional contrast enhanced CT and MRI still remain
the standard for lymph node relapse detection;
- In this setting, DWI–MRI is interesting, but data about its
usefulness are not conclusive yet;
- Despite its diffusion in the clinical practice, [11C]Choline
PET/CT, remains object of investigation due to the uncertainness regarding PSA value related to its accuracy.
4. Androgen deprivation therapy
ADT, as systemic therapy, is suggested as an appropriate
treatment option for advanced and metastatic disease and it
has been largely adopted, despite the fact that conflicting data
from non randomized trials are available and that the scientific
support for this approach is weak.
Nevertheless, in the case of proven metastatic disease,
although not curative, ADT as monotherapy remains the upfront standard treatment. ADT is frequently able to provide
very good short-term symptom and biochemical control,
before the emergence of castration-resistant clones, when
second-line hormonal therapy, novel agents, and chemotherapy with docetaxel are instead suggested [4].
In the pre-PSA era, ADT has primarily been used in
metastatic disease, especially for symptomatic patients. In
the post-PSA era, ADT has progressively been administered also to metastatic prostate cancer patients with longer
life expectancies to maintain biochemical control, often in
27
absence of symptoms or in adjuvant setting after radical treatment, particularly when high risk factors of systemic disease
are present [34].
However, the optimal timing to administer ADT in patients
with a biochemical failure after radical prostatectomy or a
radical course of RT remains controversial. After failure,
ADT has been shown to be inadequate to extinguish the
entire cancer population, and benefits of the ADT should
be evaluated also considering its potential deleterious side
effects, especially for long term schedules [35–39]. Indeed,
some of these side effects can negatively affect the quality of life, especially in young men, while others may
contribute to an increased risk for health age-related problems. In this scenario, ADT in salvage setting could be
also delayed until symptoms appearance, or when a measurable lesion, as well as nodal relapses, is clearly detected at
imaging.
In this context, even in the absence of well-structured studies, various experiences (mainly in the adjuvant postsurgical
setting)showed the possibility to achieve a long term cancer control in selected patients with a minimal lymph node
involvement, with the addition of hormonal therapy [40–42],
with results which did not differ from those of patients without lymph node metastases [43,44]. Radiotherapy associated
to ADT has also been shown in retrospective studies to obtain
long term disease control and survival in patients with nodal
disease at presentation [45].
The evidence about ADT for the treatment of clinically
evident isolated nodal relapses of prostate cancer after primary treatment is instead really scarce. This is somewhat
paradoxical, since, to date, the standard treatment for this
condition is ADT itself.
On the whole, most information on the use of ADT for
nodal involvement in prostate cancer refers to patients given
ADT integrated with primary treatment (surgery or radiotherapy) for locally advanced disease and therefore to the
adjuvant setting.
There are still no clear evidences of overall and/or clinical
disease free survival difference when ADT is immediately
added, with the exception of few retrospective data [46] and
of a single prospective trial [47], showing a positive significant impact of immediate ADT on overall, disease-specific,
and progression-free survival compared to the observation
arm, where ADT was deferred until disease progression after
the local treatment. However, this positive impact of immediate ADT has not been confirmed in other large retrospective
studies addressing this issue [48].
The role of ADT, delivered concomitantly to local therapies (such as RT) in the treatment of node positive patients,
was studied in the RTOG 85-31 randomized trial, where early
androgen suppression plus RT versus RT and delayed HT
were prospectively compared [49]. This study represents the
only level 1 evidence trial addressing this issue and showed
a positive statistical impact of the RT in this clinical setting,
but it included only a relatively small number of patients
surgically staged.
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Table 3
Studies including patients with lymph node recurrent prostate cancer treated with either open or laparoscopic salvage lymph node dissection.
Authors (year of publication)
References
Number of
patients
Mean PSA at
salvage lymph
node dissection
Mean number of
lymph nodes removed
(Range and site)
Early
post-operative
PSA < 0.2 ng/ml
Complication rates
(grade II-IV)
Rinnab et al. (2008)
54
15
2.56
NA
8%
Paralytic ileus 1/15
Temporary
hydronephrosis 1/15
Lymphocele requiring
drainage 1/15
Winter et al. (2010)
Martini et al. (2012)
55
56
11
8
3.02
1.82
40%
50%
NA
Schilling et al. (2008)
57
10
1a vs 15.1b
NA
Any
Rigatti et al. (2011)
58
72
3.73
NA
11.6 (1–24, pelvic
nodes)
18 (1–22, directed
regional
lymphadenectomy,
based on 11C-choline
PET/CT results, not
described otherwise)
30.6
(4–87, pelvic nodes in
72/72 patients and
retroperitoneal nodes
in 56/72 patients)
56.9%
Lyphocele requiring
drainage 10/72
Deep venous
thrombosis 2/72
Pulmonary embolism
1/72
Wound dehiscence
3/72
Ureteral injury 1/72
Ileus 14/72
Surgical
reintervention 2/72
NA, not available.
a Mean PSA in men with negative choline PET-CT scan.
b Mean PSA in men with positive choline PET-CT scan.
Briganti et al. retrospectively analyzed data of 703 nodes
positive patients treated after surgery with adjuvant HT plus
RT and of patients treated with adjuvant HT alone [46]. After
a median follow-up of 100 months, adjuvant RT plus hormone therapy significantly improved outcome of pT2-4 pN1
patients, who had a 2.5-fold higher chance of being free from
cancer mortality, with significantly higher cancer specific and
overall survivals rates.
The dilemma regarding the selection criteria to identify the
N+ patients which should receive ADT plus local treatments
and the correct timing in delivering them is a major issue.
Indeed, not all node-positive patients seem to have the same
progression and death risk. [50,51]. In various experiences,
tumor stage, preoperative PSA level, Gleason score before
and after RP, pathological tumor stage and DNA-ploidy of a
tumor have been indicated as important prognostic factors to
guide treatment decision [52]. Roach and coworkers showed
that the indications to ADT seem to be stronger when the
N+ status is associated with higher Gleason score and more
advanced T category [53].
Summary
- ADT remains the standard of care;
- high level evidences about ADT in this clinical scenario
are lacking;
- perspective, well structured trials are needed to assess the
optimal timing and schedule of delivery;
5. Role of surgery
To date, there are only a few investigational studies reporting the outcomes of patients treated after primary therapy
with salvage lymph node dissection (sLND) [54–58] for biochemical recurrence (BCR) associated with evidence of nodal
uptake at CT-PET (Table 3). None of these studies compared
the oncologic outcome of the surgical approach to the one
associated with standard treatments, such as ADT.
Moreover, a distinction should be made in the different
types of sLND, as in the different published series different
surgical procedures have been proposed [54–60].
The introduction of sophisticated imaging modalities,
such as [11C]Choline PET/CT scan, has contributed to the
selection of candidates for sLND. However, it should be kept
in mind that any available imaging modality might significantly underestimate the presence of nodal metastases at
recurrence. Therefore, a substantial number of these patients
might be affected by more disseminated disease, even in the
presence of solitary or limited nodal uptake at [11C]Choline
PET/CT [60,61]. This limitation, together with poor patient
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
selection, might represent the main reason for the limited
durable cancer response of sLND that has been reported in
some series. However, it has been hypothesized that sLND
might also aim at reducing tumor burden in the possible
context of cytoreductive therapy, as proposed for other solid
tumors [62]. Even though sLND might not be associated with
a durable response over time, tumor load might be decreased
and further cancer progression might possibly be delayed.
Delaying further cancer progression with surgery might represent a significant endpoint for some men with clinically
recurrent prostate cancer who have been previously submitted
to several therapies, since few treatment options are available
for them. In addition to decreasing tumor volume, it might
be speculated that this new surgical option might also aim at
postponing the delivery of ADT in a proportion of selected
patients, therefore reducing the exposure to such systemic
therapies that are not devoid of significant side effects [63].
This should, however, be balanced with the potential side
effects of sLND.
Rinnab et al. evaluated, in 15 patients with [11C]Choline
PET/CT positive nodes patients, the oncologic outcome
after surgery. Authors concluded that, despite the potential
of the [11C]Choline PET/CT in detection of lymph node
metastases when rising PSA occurs, the benefit that can be
achieved through [11C]Choline PET/CT and subsequent salvage lymph node dissection is rather small [54].
Recently, Rigatti et al. published the largest prospective
series with 72 patients treated with pelvic/retroperitoneal
sLND [58]. The authors found that PSA at surgery (<4 ng/ml),
time to biochemical relapse (<24 months) and negative
lymph nodes at previous RP were independent predictors
of PSA response to surgery. The 5-year BCR free survival, clinical recurrence and cancer specific survival rates
were 19%, 34% and 75%, respectively. At multivariable
analyses, only PSA >4 ng/ml and the presence of retroperitoneal uptake at the pre-salvage LND [11C]Choline PET/CT
represented independent preoperative predictors of clinical recurrence. Similarly, the presence of pathologic nodes
in the retroperitoneum, higher number of positive lymph
nodes and the evidence of a biochemical response (PSA
<0.2 ng/ml) assessed 40 days after sLND represented postoperative independent predictors of clinical recurrence after
salvage surgery.
These data seem to show that [11C]Choline PET/CT and
sLND might be considered for highly selected patients with
biochemical relapse of prostate cancer associated with evidence of nodal recurrence. However, only a minority of
patients submitted to salvage surgery showed a durable PSA
remission, while in the majority of the cases PSA increased
after an initial response post surgery. A possible explanation
for this might reside on the insufficient selection of the patient
cohort included, which might have contributed to dilute the
effect of salvage surgery. However, although larger studies are
needed to better identify the best candidates for this surgical
approach, these preliminary data are hypothesis generating:
sLDN seems to achieve the highest success rates in selected
29
patients with limited pelvic nodal recurrence after primary
treatment. Moreover, even if in a significant proportion of
patients authors failed in showing a durable cancer control, it
might be argued that in patients with complete or partial initial PSA response after surgery, the delay of salvage medical
therapy (i.e. hormonal blockade) might represent a benefit
related to this surgical approach [58].
The role of adjuvant RT after salvage surgery for a nodal
relapse remains to be investigated. Jilg et al. reported data
about 47 patients operated for a nodal relapse of a previously
treated prostate cancer, with 27/47 patients irradiated after
salvage surgery. Authors confirm the positive predictive value
of the Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b
(OR 5.91, p = 0.042) and of the N0 status at primary therapy
(OR 8.01, p = 0.011) and the negative predictive value of clinical progression of the preoperative Gleason 8–10 (HR 3.5,
p = 0.039) of the presence of retroperitoneal positive lymph
nodes (HR 3.76, p = 0.021) and of an incomplete biochemical
response (HR 4.0, p = 0.031), but adjuvant RT did not show
to have a significant impact on the outcome of the patients
[64].
Any salvage “targeted” nodal therapy given in prostate
cancer should take into account a potential significant underestimation of nodal recurrence even at [11C]Choline PET/CT
[54–58,61]. This is due to the relatively limited spatial resolution of any imaging technique, which might be thus
associated with a certain risk of missing micro-metastatic
disease. For this reason, another drawback of the surgical
treatment resides in the fact that removing only the nodes that
resulted positive at imaging might lead to frequent long-term
failure rates, but more extensive surgical procedures implies
obviously an increased surgical risk.
Summary:
- sLND should be still considered experimental, given the
lack of prospective, comparative studies [4];
- the available literature seems to support the surgical
approach only in very selected cases of nodal oligorecurrent prostate cancer;
- the therapeutic value of the surgical approach would be
confirmed only after mature data on the efficacy (in terms
of overall and cancer-specific survival) and in terms of
safety.
6. External beam radiotherapy and stereotactic body
radiotherapy for lymph node recurrence from
prostate cancer
Radiotherapy is commonly used in the treatment of
primary and metastatic prostate cancer lesions [4,65–69].
However, there are very few data on the irradiation of
nodal oligo-recurrent disease. Radiation can be delivered
with external beam approach (external beam radiotherapy,
EBRT) or stereotactic body radiotherapy (SBRT). EBRT is
usually delivered to wider volumes using a 3-Dimensional
30
Table 4
Summary of the published series of salvage external beam irradiation (EBRT) for lymph node metastases from prostate cancer.
Number of pts
treated for LN
relapse (the
whole series)
Concomitant
systemic
therapy
EBRT
technique
Re-irradiation
Treated
volume
Median total
dose/nr
fraction
(dose/fraction)
Median
follow-up
(months)
Local
control
rate ± pattern
of failure
Overall
survival
Toxicity
Engels et al. (2009)
[75]
8 pts
(28 pts)
ADT in all pts
Helical
Tomotherapy
No
PTV1:
prostate
PTV2:
positive LN
regions
PTV3: pelvic
LN
?
?
?
a Acute GI:
G2 7%, G3 0%
a Acute GU:
G2 14%
G3 4%
Alongi et al. (2010)
[76]
1 (1)
Estramustine +
ADT
Helical
Tomotherapy
Yes
PTV 1:
positive LN
PTV 2:
bilateral iliac
LN
24
No local
progression at 24
mos
Alive at 24
months
0
Ricchetti et al. (2011)
[74]
1 (4)
ADT
Helical
Tomotherapy
Yes
PTV 1:
positive LN
PTV 2: pelvic
LN
SIB:
PTV1:70.5 Gy/30fr
PTV2:
60 Gy/30fr
PTV3:
54 Gy/30fr
(2.35–1.82 Gy/fr)
SIB:
PTV1:
67.2 Gy/28fr
PTV2:
50.4 Gy/28 fr
(2.4–1.8 Gy/fr)
SIB:
PTV1:
60 Gy/30fr
PTV2:46 Gy/30fr
(2–1.53 Gy/fr)
12
Alive at 16
months
0
Jereczek-Fossa et al.
(2009) [85]
14
ADT in 7 pts,
CHT + ADT in
1 pt
SBRT: Linac
7pts – CBK 7
pts
Yes
PTV1:
positive LN
30 Gy/3fr
(10 Gy/fr)
18
1 pt died of
cardiovascular
reason
Acute: 0
Late GI G2 1
pt
Jereczek-Fossa et al.
(2012) [84]
b 16
ADT in 75%
of pts
SBRT (CBK)
Yes
PTV1:
positive LN
33 Gy/3 fr
(11 Gy/fr)
22
No local
progression at 12
mos but
DM at 16
mos
No local
progression, 2 pts
with DM
and 3 pts
with LN
relapse
No local
progression, 5 pts
with DM
All pts alive at
22 months
Scorsetti et al. (2011)
[79]
1 (12 LN and
whole series:
95 pts)
No
SBRT
(VMAT-RA)
No
PTV1:
positive LN
45 Gy/6 fr
(7.5 Gy/fr)
a 12
Local
control:
10/11 LN
pts
NA
Acute GU: G3
1 pt
Late GU: G1:
2pts, G2 1 pt,
G3 1 pt
Late GI
G1 1 pt
a Acute GI G1
3 pts/95pts
a Late GI G1 1
pts/12 LN pts
(34)
Legend: pts – patients, ADT – androgen deprivation therapy, SBRT – stereotactic body radiotherapy, CBK – CyberKnife Robotic Radiosurgery System (Accuray Inc., Sunnyvale, CA), LN – lymph nodes, SIB –
simultaneous integrated boost, fr – fraction.
a Data from the whole cohort of pts.
b Including updated information of 7 pts from previous series [84], PTV – planning target volume, CHT – chemotherapy, RA-VMAT – volumetric intensity modulated arc therapy delivered with RapidArc
(Varian Medical Systems, Palo Alto, CA), NA – not available, GU – genitourinary, GI – gastrointestinal.
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
Authors (year of
publication)
[reference]
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
Conformal Radiation Therapy (3D-CRT) or Intensity Modulated modality (IMRT). IMRT is now commonly employed
in radical or post-prostatectomy setting, in particular if a
pelvic nodal irradiation is necessary [70,71]. As far as salvage setting is concerned, prophylactic irradiation of pelvic
nodal area might play a potential role owing to the risk of
occult lymph-nodal metastases [71,33,72,73]. This question
is currently addressed in the ongoing trial of the Radiation
Therapy Oncology Group (RTOG 05-34) where the patients
with a rising PSA after prostatectomy are randomized to
pelvic lymph node or prostate bed only irradiation (with
or without short androgen deprivation). As far as salvage
EBRT is concerned, a MEDLINE search shows only one
series of 8 patients and 2 reports of single cases treated
using Tomotherapy a particular form of image guided and
adaptive IMRT (Table 4) [74–77]. IMRT seems of value
in case of irradiation of pelvic nodal chains using simultaneous integrated boost (SIB) approach (with 2 dose levels:
lower elective dose to non-involved neighboring lymph node
areas and high radical dose to the clinically positive lymph
nodes).
SBRT is a novel radiotherapy modality that takes advantage of the technological progress in image guidance and
radiation dose delivery, and it is able to direct high ablative doses to small target lesion with acceptable toxicity
[78]. It can be delivered with a large number of commercially available systems including those LINAC-based, like
volumetric modulated arc therapy [79,80], robotic image
guided [80], and other image guided modalities. SBRT
seems particularly advantageous for radioresistant tumors,
previously irradiated lesions, and small volume tumors.
Hypofractionation, which is almost always used when SBRT
is chosen, could be of particular value for prostate cancer.
Recent in vivo and clinical data suggest that prostate cancer
may benefit from hypofractionation as its alpha/beta ratio
is lower than that of the rectum and other pelvic organs
[81]. Although the data on the alpha/beta ratio of recurrent
lesions are not available, a similar benefit can be expected
when using this approach for oligo-recurrent prostate cancer.
Again, although SBRT is employed in the management
of primary or secondary solid tumors and organ confined
prostate cancer [82], few series exist exploring the role of
SBRT for the treatment of lymph node recurrence and in particular lymph node recurrence of prostate cancer [83–85].
Small series on the resection of a solitary prostate cancer
metastasis (lung, adrenal gland, lymph node lesions) or radiosurgery (stereotactic radiotherapy given in single fraction) to
brain metastases from prostate cancer showed good local control, confirming the potential interest of ablative treatments
(as SBRT) in oligometastatic and oligo-recurrent prostate
cancer patients [85–89]. Three series on the SBRT for isolated
lymph node recurrent prostate cancer have been published
recently by two groups (Table 4) [79,84,85].
In the vast majority of both EBRT and SBRT patients, the
diagnosis of isolated lymph node recurrence was based on
31
the [11C]Choline PET/CT obtained after PSA progression.
In some patients recurrent prostate cancer was confirmed by
lymph node biopsy.
Obviously, no firm conclusion can be drawn from these
small series due to short follow-up, extremely low number
of patients, treated with different EBRT and SBRT modalities using heterogeneous fractionation schedules and doses
for a variety of limited lymph node recurrences (in same
series also metastatic lombo-aortic nodes were included). The
majority of patients had heavily pretreated prostate cancer
and many received concomitant systemic therapy or were
receiving castration resistant disease. Despite these limitations, the results presented in Table 4 suggest that high
precision hypofractionated irradiation offers excellent infiled local control with a very low toxicity profile. The
patterns of failure is predominantly out-field and in the
SBRT patients recurrence in the neighboring lymph node
might be observed suggesting the role of regional lymph
node area irradiation, but this should be counterbalanced
against potentially higher toxicity (due to larger volumes)
and longer overall treatment time (extreme hypofractionation cannot be applied to large volumes). Importantly,
a complete biochemical response was observed in almost
60% of the lesions treated with radiation alone [84]. Long
treatment-free-interval has also been reported in the same
series [84].
Looking at the toxicity rates, Jereczek-Fossa et al. recently
published one of the largest series of patients treated with
SBRT (Sixty-nine patients, 94 lesions, median SBRT dose
24 Gy/3 fractions) for nodal abdominal relapse from several cancer types (urological, gastrointestinal, gynecologic,
and other malignancies) [83]. After a median follow-up
of 20 months, SBRT seems to be well tolerated, with
only two grade 3 acute and one grade 4 late toxicity
events.
These rates compare well with those published by
Scorsetti et al. reporting early results about 37 consecutive
patients treated with SBRT for abdominal targets (12 of them
for abdominal node relapses): both acute and late toxicities
reported were minimal [79]. Recent studies have been published reporting dosimetric constraints for SBRT and results
of the reported studies seems to show that the respect of these
indications allow to obtain very low rates of toxicity, also with
increasing doses of RT [90,91].
Summary:
- EBRT and SBRT represent promising non-invasive
anatomically-targeted treatment for oligo-recurrent
prostate cancer;
- these therapies seem to offer excellent in-field tumor control with very good toxicity profile;
- data regarding large series and/or prospective studies still
remain lacking also for EBRT and SBRT;
- the optimal combination of high precision radiation therapy
with systemic treatment remains to be investigated.
32
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
7. Conclusion
The therapeutic approach to nodal oligo-recurrent prostate
cancer patients is still object of debate and no firm conclusions could be drawn. Up to now, hormonal therapies should
be still considered the standard of care in this clinical setting.
A possible limit to the diffusion of these local approaches
could be the lack of accurate imaging techniques to detect the
diffusion of the disease. Despite that, a growing interest on
the clinical outcomes of the local surgical and not-surgical
alternatives has been recently highlighted in the literature.
Surgery could be, in very selected cases, a therapeutic option,
but the balance between benefits and potential severe side
effects should be strictly considered. Radiotherapy and, in
particular, SBRT, seems to be a viable therapeutic option in
this clinical setting, also considering the low toxicity profile showed in the few published experiences. The correct
selection of the patients is crucial in this clinical scenario, in
order to identify patients that would really benefit of a local
approach in a context of potentially disseminated disease.
Moreover, the optimal combination of local therapies with
systemic treatments remains to be prospectively investigated.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Conflict of interest
None to be declared.
Fundings
[16]
[17]
No fundings to be declared.
[18]
Reviewers
Helen Boyle, M.D., Centre Léon Bérard, 28 Rue Laennec,
Lyon, 69008, France.
Sergio Bracarda, M.D., U.O.C. Medical Oncology, Oncology, Via Pietro Nenni, 20, Arezzo, AR 52100, Italy.
Prof. John Fitzpatrick, Irish Cancer Society, Ireland.
[19]
[20]
[21]
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Biographies
Berardino De Bari, MD, Radiation Oncologist and
clinical investigator. He 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 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.
Filippo Alongi, MD, Radiation Oncologist and clinical investigator. He is associate chief of Radiotherapy and
radiosurgery department in Istituto Clinico Humanitas at
Humanitas Cancer Center. He is Radiation Oncologist and
clinical investigator. He published more than 50 articles
(indexed/Peer reviewed Journals), 3 book chapters and more
than 150 abstracts presented as oral presentation or posters at
national and international scientific congress. His h-index is
11. Main topics of his activity are: SBRT, hypofractionation,
IGRT, molecular imaging in Radiation Oncology, prostate
cancer. From 2012, he is the national coordinator of young
group of AIRO (Italian society of Radiation Oncology) and
he is in the board of AIRO prostate working group. He is
member of Editorial board of “Tumori” and “Technology in
Cancer Treatment express”.
B. De Bari et al. / Critical Reviews in Oncology/Hematology 90 (2014) 24–35
Michela Buglione, MD, Radiation Oncologist and assistant professor. She published 19 articles (indexed/Peer
reviewed Journals). Main topics of her activity are: brain
tumors, hematological malignancies, and IGRT. She is coordinator for the Group of Neurooncology of the Italian
association of Radiation Oncology. She is member of EORTC
Brain Tumour Group.
Franco Campostrini, MD, Radiation Oncologist and
clinical investigator. He published more than 20 articles
(indexed/Peer reviewed Journals). Main topics of his activity are: prostate cancer and Head and Neck cancers. Director
of the Department of Radiotherapy of the Legnago, he is
member of the board of AIRO prostate working group.
Alberto Briganti, MD, Urologist and Assistant Professor
at the University of San Raffaele (Milan – Italy). Head of the
Prostate Unit of his Department. His main research interests
include urologic malignancies and in particular prostate cancer. He is an author of about 130 full papers and of 3 book
chapters and he speaks regularly at international and national
conferences and teaching events.
Giuseppe Petralia, 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.
Massimo Bellomi, MD, Radiologist and Professor of the
University of Milan (Milan – Italy). Head of the Radiology
Dept. 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.
Arturo Chiti, MD, Medical Doctor and clinical investigator in Nuclear medicine. Director of Nuclear Medicine
Department of Istituto Clinico Humanitas (Milan – Italy).
He published more than 70 articles (indexed/Peer reviewed
Journals), several book chapters. Main topics of his activity are: molecular imaging in Radiation Oncology, head and
neck and prostate cancer. From 2012, he is the president of
EANM (European Association of Nuclear Medicine).
Nazareno Suardi, MD, Urologist at the University of
San Raffaele (Milan – Italy). His main research interests
include urologic malignancies and in particular prostate cancer. He is an author of about 120 full papers and he speaks
35
regularly at international and national conferences and teaching events.
Marta Scorsetti, MD, Radiation Oncologist and clinical
investigator. Director of Radiation Therapy Department of
Istituto Clinico Humanitas in Milan (Milan – Italy). She
published more than 60 articles (indexed/Peer reviewed Journals), several book chapters. Main topics of her activity
are: SBRT, hypofractionation, IGRT, Radiosurgery, lung and
prostate cancer.
Roberto Orecchia, MD, Radiation Oncologist and Professor of the University of Milan (Milan – Italy) and Head of the
Div. of Radiotherapy of the European Institute of Oncology
(Milan – Italy). His main research interests include breast
and prostate cancer. He published almost 250 full papers and
speaks regularly at international conferences and teaching
events.
Francesco Montorsi, MD, Urologist and Professor of VitaSalute San Raffaele University (Milan – Italy) and Head of the
Div. of Urology of the San Raffaele Hospital (Milan – Italy).
His main research interests include urologic malignancies
and in particular prostate cancer. He published almost 750
full papers and several book chapters and he speaks regularly
at national and international conferences and teaching events.
Stefano Maria Magrini, 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 member of the ESTRO board and
of several ESTRO committees; he has been member of the
AIRO board and coordinator of the AIRO prostate cancer
working group. He published more than 250 full papers and
speaks regularly at international conferences and teaching
events.
Barbara Alicja Jereczek-Fossa, MD, PhD, Radiation
Oncologist and Assistant Professor of the University of Milan
(Milan – Italy) and Senior Deputy Director of the Div. 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.