salvage therapy of small volume prostate cancer nodal failures: a review of the literature

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ARTICLE IN PRESSNCH-1809; No. of Pages 12

Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx

Salvage therapy of small volume prostate cancer nodal failures: A reviewof 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

a Radiotherapy Department, Istituto del Radio di Brescia, University of Brescia, Brescia, Italyb Radiotherapy and Radiosurgery, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Milan, Italy

c Radiotherapy Department, Legnago Hospital, Legnago, Italyd Department of Urology, Vita-Salute University San Raffaele, Milan, Italy

e Radiation Therapy, San Raffaele Scientific Institute, Milan, Italyf Department of Radiology, European Institute of Oncology, Milan, Italy

g Nuclear Medicine, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Milan, Italyh 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

ontents

. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. “Oligometastases” and “oligo-recurrence” in prostate cancer patients: in search of a definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Imaging of lymph-nodes by CT and MRI in patients with relapse of prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Androgen deprivation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Role of surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. External beam radiotherapy and stereotactic body radiotherapy for lymph node recurrence from prostate cancer . . . . . . . . . . . . . . . . . 00

. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Fundings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
bstract

New imaging modalities may be useful to identify prostate cancer patients with small volume, limited nodal relapse (“oligo-recurrent”)
otentially amenable to local treatments (radiotherapy, surgery) with the aim of long-term control of the disease, even in a condition traditionally
Please cite this article in press as: De Bari B, et al. Salvage therapy of small volume prostate cancer nodal failures: A review of the literature.Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.11.003

∗ Corresponding author at: Radiotherapy and Radiosurgery, Humanitas Cancer Center, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan,taly. Tel.: +39 0282247454; fax: +39 0282248509.

E-mail addresses: [email protected], [email protected] (F. Alongi).

040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.critrevonc.2013.11.003

dx.doi.org/10.1016/j.critrevonc.2013.11.003


mailto:[email protected]

mailto:[email protected]


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ARTICLE IN PRESSNCH-1809; No. of Pages 12

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onsidered prognostically unfavorable. This report reviews the new diagnostic tools and the main published data about the role of surgery andadiation therapy in this particular subgroup of patients.

2013 Elsevier Ireland Ltd. All rights reserved.

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eywords: Nodal relapse; Prostate cancer; PET prostate; SBRT; Radiotherap

. Introduction

In patients with rising PSA values after primary treatmentf prostate cancer the new imaging modalities allow the iden-ification of patients with an apparently limited burden ofocal and/or metastatic recurrent disease. In the last decade,he new clinical entities termed “oligometastases” and “oligo-ecurrences” have been proposed for this clinical conditionnd are now largely accepted amongst oncologists [1].

Although systemic therapy is the main therapeuticpproach in advanced cancer, investigations suggest thatocal approaches (surgery, radiotherapy) can offer durablerogression-free-survival in these selected groups of patients“chronic curable cancer”) [1,2]. Traditionally, lymph nodeecurrent prostate cancer after the primary loco-regionalreatment has been considered as an unfavorable situation,nd palliative systemic hormonal therapy (Androgen Depri-ation Therapy, ADT) remains the golden standard in thisopulation of patients [3,4]. Despite that, once started, ADThould often be continued for a long period (usually untilrogression, when other hormonal manipulations and/orhemotherapy may be considered) and is related with signif-cant side effects and deterioration of the patients quality ofife [5]. Therefore, because of the long natural history of therostate cancer, local therapies are considered with increas-ng interest, because of their potential efficacy for long termisease control or, even, cure.

The aim of the present review is to provide a correct def-nition of oligo-recurrent disease, with a focus on recentdvances in imaging procedures for the detection of nodalecurrences. Furthermore, all available salvage treatments forodal prostate cancer relapses are presented and thoroughlyiscussed.

. “Oligometastases” and “oligo-recurrence” inrostate cancer patients: in search of a definition

Modern surgical approaches and the advances in radio-herapy treatment planning and dose delivery allow radiationncologists (and surgeons) to offer potentially curative treat-ents also to patients that traditionally candidates only to

alliative systemic therapies, possibly at a reasonable pricen terms of toxicity.

Even if the terms “oligometastases” and “oligo-

Please cite this article in press as: De Bari B, et al. Salvage therapy of smaCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

ecurrence” could be considered as synonyms, they do notepresent the same clinical situation, since the status ofhe primary tumor is not the same. Indeed, oligometastaticatients are those presenting 1–5 metastatic sites and also

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ery; ADT prostate; Salvage lymph node dissection; Oligo-recurrent disease

n active primary lesion, while in the oligo-recurrent status,he primary tumor is cured [6]. On the other hand, if sev-ral reports agree on the idea that an oligo-recurrent diseasehould not present more than 5 lesions, at our knowledgehere are no clear indications about the size of these lesions.sually, trials and studies on oligo-recurrent disease consider

diameter of 5 cm the upper limit to treat an oligo-recurrentisease with ablative doses of RT.

Considering the crucial prognostic role of the local con-rol on the primary tumor [6], it could be easily arguedhat, in theory, an oligo-recurrent disease is more easilymenable to local therapies applied with curative intent thann oligometastasic one.

Last but not least, the possibility to achieve durable tumorontrol in clinically evident metastatic sites could be relevantlso for long term control of the primary tumor or of otherites of micrometastases, following the “seed and soil” andhe “multiple steps cancer progression” theories [7,8], andepresents one of the most important reasons supporting theole of focused surgical and/or radiation therapies also inotentially multi-micrometastatic patients.

. Imaging of lymph-nodes by CT and MRI inatients with relapse of prostate cancer

According to many authors, conventional CT and MRIre approximately equivalent in detecting nodal metastasesLNMs). [9]. As it is shown in Table 1, all nodes exceed-ng a minimal threshold of 6–15 mm could be consideredotentially involved [9–11]. It should be noted that the thresh-ld of 6–7 mm that is used in some studies is extremely low,xplaining its high sensibility, but also probably influencinghe accuracy of the results. Despite that, pathologic reportsn specimens of nodal dissections for prostate cancer showedhat metastatic deposits could be found in about 25% of nor-

al sized LNs [10,12]. Furthermore, it is well known that alsoenign conditions could be responsible of enlarged LNs.

Tables 1 and 2 summarize the most relevant prospectiverials exploring the efficacy of conventional CT scan [12–17]nd MRI [12,17–25] to identify prostate cancer nodal metas-ases, using a reliable pelvic nodal dissection (PLND) orccurate biopsies as reference tests. The sensitivity valuesepresent the great limit of both the techniques: with values

ll volume prostate cancer nodal failures: A review of the literature.013.11.003

anging between 25% and 78% for the CT scan and between% and 86% for the standard MRI, respectively, with a largeumber of LNMs undetected. Saokar et al. compared theensitivity of CT and MRI [26]. They concluded that MRI


ARTICLE IN PRESSONCH-1809; No. of Pages 12

B. De Bari et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx 3

Table 1Performances of the magnetic resonance imaging (MRI) in detecting nodal metastases.

Authors (year of publication) References Number ofpatients

Inferiorthreshold(mm)

LNM % Sensitivity % Specificity % Accuracy %

Heesakkers et al. (2008) 12 375 8–10 16 34 97 NALecouvet et al. (2012) 17 100 10 NA 77 (R3) 82 (R4) 95 (R3) 96 (R4) NABezzi et al. (1988) 18 51 10 25 69 95 88Rifkin et al. (1990) 19 185 10 12.5 4 95 NAJager et al. (1996) 20 63 8. 14 60 98 89Perrotti et al. (1996) 21 56 10 9 0 90 86Harisinghani et al. (2003) 22 80 10 NA 45 (standard MRI) 79 (standard MRI) NA

100 (USPIO-MRI) 96 (USPIO-MRI)Wang et al. (2006) 23 411 8 5.5 27 98 NAEiber et al. (2010) 24 29 6 NA 86a 85 86Budiharto et al. (2011) 25 36 4 47 18.8 97.6 NA

Note: Inferior threshold: Figure above which a lymph node is considered pathological; % LNM: Percentage of patients with positive lymph nodes histopatho-l ide (no

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ogically controlled; USPIO contrast agent: UltraSmall Particles of Iron Oxa Correlation with histopathology in only 10 patients; NA: Not available;

as significantly more accurate than CT in identifying lymphodes in the range 1–5 mm.

MRI potential has been increased by the introduction of new contrast medium and functional sequences. The Dif-usion Weighted MRI (DWI–MRI) is a functional technique,ased on the reduction of water protons mobility in hyper-ellular cancer tissues, giving a higher signal compared tohe surrounding unaffected healthy tissue [10,11]. Studieserformed with DWI–MRI are limited and not yet conclu-ive (Table 2). Eiber et al. [24] performed a comparisonetween DWI–MRI and standard T2W MRI, concluding thathe functional sequences of DWI-MRI were significantlyore accurate than size-based criteria to detect LNMs (Table

I). Moreover, Mir et al. showed that the fusion of DWI-RI with standard T2W images improves the identification

f pelvic LNs in comparison to T2W alone [27], but theseesults were not confirmed by Budiharto et al. in a prospec-


ive histopathology-based evaluation of 11C-choline PET-CTnd DWI-MRI for the detection of LNMs [25]. Despite itsbvious interest, DWI-MRI is still under evaluation.

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able 2erformances of the conventional CT scan in detecting nodal metastases.

uthors (year of publication) References Number of patients Inferior thresho

eesakkers et al. (2008) 12 375 8–10

olimbu et al. (1981) 13 46 10

lanigan et al. (1985) 14 53 15

an Poppel et al. (1994) 15 285 6

orvik et al. (1998) 16 64 10

ecouvet et al. (2012) 17 100 10

errotti et al. (1996) 21 56 10

arisinghani et al. (2003) 22 80 10

ang et al. (2006) 23 411 8

iber et al. (2010) 24 29 6

udiharto T et al. (2011) 25 36 4

ote: Inferior threshold: Figure above which a lymph node is considered pathologicogically controlled; USPIO contrast agent: UltraSmall Particles of Iron Oxide (no

a Correlation with histopathology in only 10 patients; NA: Not available; R3 and

longer commercially available). R2: Two different readers.

As described by the leading study of Harisinghani [22],onfirmed by several other Authors, MR Lymphoangiogra-hy (MRL) showed very promising results with sensitivitynd specificity rates of 82–100% and 93–96%, that areuperior to both standard MRI [22] and modern CT [12].owever, MRL with USPIO (UltraSmall Particles of Ironxide, Ferumoxtran-10) has been substantially abandoned

ince marketing authorization for contrast medium is lacking.A recent meta-analysis about the diagnostic performance

f 18F-choline and 11C-choline PET or PET-CT in theodal staging of prostate cancer showed a pooled sensitiv-ty of 49.2% (95% confidence interval [CI], 39.9–58.4) and

pooled specificity of 95% (95% CI, 92–97.1) [28].The definition of a PSA cut-off value to refer prostate

ancer patients with biochemical failure to [11C]CholineET/CT scanning would be helpful for the clinical man-gement of these patients. Unfortunately, there is currently


o consensus on such a cut-off value. Using ROC analy-is in a large sample, Giovacchini et al. found that positivend negative [11C]Choline PET/CT scans could be best

ld (mm) LNM % Sensitivity % Specificity % Accuracy %

16 34 97 NA37 30 93 7026.5 50 100 9116 78 100 96.515 25 98 NANA 77 (R3) 95 (R3) NA

82 (R4) 96 (R4)9 0 90 86NA 45 (standard MRI) 79 (standard MRI) NA

100 (USPIO-MRI) 96 (USPIO-MRI)5.5 27 98 NANA 86a 85 8647 18.8 97.6 NA

al; % LNM.: Percentage of patients with positive lymph nodes histopatho-longer commercially available.

R4: Two different readers.



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B. De Bari et al. / Critical Reviews in

iscriminated using a PSA cut-off value of 1.4 ng/ml, with sensitivity of 73% and a specificity of 72% while only 24%f patients with a PSA value below 1.4 ng/ml can have posi-ive PET/CT findings [29]. Krause et al. reported a detectionate by [11C]Choline PET/CT of 36% with PSA levels lowerhan 1 ng/ml [30], while Vees et al. reported a detection ratef about 50% with a similar range [31]. In a recent study byicchio et al., a potential role of PET, particularly in patientst high risk of relapse with a fast PSA kinetics, was shownven in presence of low PSA values [32].

The discrepancies reported by authors from differentnstitutions can be attributed to differences in clinical andathological characteristics of the samples, and statisticalncertainty derived from small sample sizes.

Also for these reasons, the EAU Guidelines clearly dis-ourage the routinely use of [11C]-choline PET/CT for thearly diagnosis of nodal relapses from prostate cancer.

These guidelines underline that the detection rate of11C]Choline PET/CT appears to depend strongly on PSAevels at the time of diagnosis, pathologic stage at time ofnitial diagnosis, previous biochemical failure, and older ages recently demonstrated in a cohort of 358 patients with PSAelapse following radical prostatectomy and a mean PSA levelf 3.97–6.94 ng/ml at the time of evaluation [29]. Further-ore, the probability of false-positive results in up to 20% of

atients has to be considered when interpreting PET results4].Summary:

Conventional contrast enhanced CT and MRI still remainthe standard for lymph node relapse detection;

In this setting, DWI–MRI is interesting, but data about itsusefulness are not conclusive yet;

Despite its diffusion in the clinical practice, [11C]CholinePET/CT, remains object of investigation due to the uncer-tainness regarding PSA value related to its accuracy.

. Androgen deprivation therapy

ADT, as systemic therapy, is suggested as an appropriatereatment option for advanced and metastatic disease and itas been largely adopted, despite the fact that conflicting datarom non randomized trials are available and that the scientificupport for this approach is weak.

Nevertheless, in the case of proven metastatic disease,lthough not curative, ADT as monotherapy remains the up-ront standard treatment. ADT is frequently able to provideery good short-term symptom and biochemical control,efore the emergence of castration-resistant clones, whenecond-line hormonal therapy, novel agents, and chemother-py with docetaxel are instead suggested [4].

In the pre-PSA era, ADT has primarily been used in


etastatic disease, especially for symptomatic patients. Inhe post-PSA era, ADT has progressively been adminis-ered also to metastatic prostate cancer patients with longerife expectancies to maintain biochemical control, often in

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ogy/Hematology xxx (2013) xxx–xxx

bsence of symptoms or in adjuvant setting after radical treat-ent, particularly when high risk factors of systemic disease

re present [34].However, the optimal timing to administer ADT in patients

ith a biochemical failure after radical prostatectomy or aadical course of RT remains controversial. After failure,DT has been shown to be inadequate to extinguish the

ntire cancer population, and benefits of the ADT shoulde evaluated also considering its potential deleterious sideffects, especially for long term schedules [35–39]. Indeed,ome of these side effects can negatively affect the qual-ty of life, especially in young men, while others mayontribute to an increased risk for health age-related prob-ems. In this scenario, ADT in salvage setting could belso delayed until symptoms appearance, or when a mea-urable lesion, as well as nodal relapses, is clearly detected atmaging.

In this context, even in the absence of well-structured stud-es, various experiences (mainly in the adjuvant postsurgicaletting)showed the possibility to achieve a long term can-er control in selected patients with a minimal lymph nodenvolvement, with the addition of hormonal therapy [40–42],ith results which did not differ from those of patients with-ut lymph node metastases [43,44]. Radiotherapy associatedo ADT has also been shown in retrospective studies to obtainong term disease control and survival in patients with nodalisease at presentation [45].

The evidence about ADT for the treatment of clinicallyvident isolated nodal relapses of prostate cancer after pri-ary treatment is instead really scarce. This is somewhat

aradoxical, since, to date, the standard treatment for thisondition is ADT itself.

On the whole, most information on the use of ADT forodal involvement in prostate cancer refers to patients givenDT integrated with primary treatment (surgery or radio-

herapy) for locally advanced disease and therefore to thedjuvant setting.

There are still no clear evidences of overall and/or clinicalisease free survival difference when ADT is immediatelydded, with the exception of few retrospective data [46] andf a single prospective trial [47], showing a positive signifi-ant impact of immediate ADT on overall, disease-specific,nd progression-free survival compared to the observationrm, where ADT was deferred until disease progression afterhe local treatment. However, this positive impact of immedi-te ADT has not been confirmed in other large retrospectivetudies addressing this issue [48].

The role of ADT, delivered concomitantly to local thera-ies (such as RT) in the treatment of node positive patients,as studied in the RTOG 85-31 randomized trial, where early

ndrogen suppression plus RT versus RT and delayed HTere prospectively compared [49]. This study represents the


nly level 1 evidence trial addressing this issue and showed positive statistical impact of the RT in this clinical setting,ut it included only a relatively small number of patientsurgically staged.



B. De Bari et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx 5

Table 3Studies including patients with lymph node recurrent prostate cancer treated with either open or laparoscopic salvage lymph node dissection.

Authors (year of publication) References Number ofpatients

Mean PSA atsalvage lymphnode dissection

Mean number oflymph nodes removed(Range and site)

Earlypost-operativePSA < 0.2 ng/ml

Complication rates(grade II-IV)

Rinnab et al. (2008) 54 15 2.56 NA 8% Paralytic ileus 1/15Temporaryhydronephrosis 1/15Lymphocele requiringdrainage 1/15

Winter et al. (2010) 55 11 3.02 NA 40%Martini et al. (2012) 56 8 1.82 11.6 (1–24, pelvic

nodes)50% NA

Schilling et al. (2008) 57 10 1a vs 15.1b 18 (1–22, directedregionallymphadenectomy,based on 11C-cholinePET/CT results, notdescribed otherwise)

NA Any

Rigatti et al. (2011) 58 72 3.73 30.6(4–87, pelvic nodes in72/72 patients andretroperitoneal nodesin 56/72 patients)

56.9% Lyphocele requiringdrainage 10/72Deep venousthrombosis 2/72Pulmonary embolism1/72Wound dehiscence3/72Ureteral injury 1/72Ileus 14/72Surgicalreintervention 2/72

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A, 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 nodesositive patients treated after surgery with adjuvant HT plusT and of patients treated with adjuvant HT alone [46]. After

median follow-up of 100 months, adjuvant RT plus hor-one therapy significantly improved outcome of pT2-4 pN1

atients, who had a 2.5-fold higher chance of being free fromancer mortality, with significantly higher cancer specific andverall survivals rates.

The dilemma regarding the selection criteria to identify the+ patients which should receive ADT plus local treatments

nd the correct timing in delivering them is a major issue.ndeed, not all node-positive patients seem to have the samerogression and death risk. [50,51]. In various experiences,umor stage, preoperative PSA level, Gleason score beforend after RP, pathological tumor stage and DNA-ploidy of aumor have been indicated as important prognostic factors touide treatment decision [52]. Roach and coworkers showedhat the indications to ADT seem to be stronger when the+ status is associated with higher Gleason score and more

dvanced T category [53].Summary


ADT remains the standard of care; high level evidences about ADT in this clinical scenario

are lacking;

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perspective, well structured trials are needed to assess theoptimal timing and schedule of delivery;

. Role of surgery

To date, there are only a few investigational studies repor-ing the outcomes of patients treated after primary therapyith salvage lymph node dissection (sLND) [54–58] for bio-

hemical recurrence (BCR) associated with evidence of nodalptake at CT-PET (Table 3). None of these studies comparedhe oncologic outcome of the surgical approach to the onessociated with standard treatments, such as ADT.

Moreover, a distinction should be made in the differentypes of sLND, as in the different published series differenturgical procedures have been proposed [54–60].

The introduction of sophisticated imaging modalities,uch as [11C]Choline PET/CT scan, has contributed to theelection of candidates for sLND. However, it should be keptn mind that any available imaging modality might signif-cantly underestimate the presence of nodal metastases at


ecurrence. Therefore, a substantial number of these patientsight be affected by more disseminated disease, even in the

resence of solitary or limited nodal uptake at [11C]CholineET/CT [60,61]. This limitation, together with poor patient



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election, might represent the main reason for the limitedurable cancer response of sLND that has been reported inome series. However, it has been hypothesized that sLNDight also aim at reducing tumor burden in the possible

ontext of cytoreductive therapy, as proposed for other solidumors [62]. Even though sLND might not be associated with

durable response over time, tumor load might be decreasednd further cancer progression might possibly be delayed.elaying further cancer progression with surgery might rep-

esent a significant endpoint for some men with clinicallyecurrent prostate cancer who have been previously submittedo several therapies, since few treatment options are availableor them. In addition to decreasing tumor volume, it mighte speculated that this new surgical option might also aim atostponing the delivery of ADT in a proportion of selectedatients, therefore reducing the exposure to such systemicherapies that are not devoid of significant side effects [63].his should, however, be balanced with the potential sideffects of sLND.

Rinnab et al. evaluated, in 15 patients with [11C]CholineET/CT positive nodes patients, the oncologic outcomefter surgery. Authors concluded that, despite the potentialf the [11C]Choline PET/CT in detection of lymph nodeetastases when rising PSA occurs, the benefit that can be

chieved through [11C]Choline PET/CT and subsequent sal-age lymph node dissection is rather small [54].

Recently, Rigatti et al. published the largest prospectiveeries with 72 patients treated with pelvic/retroperitonealLND [58]. The authors found that PSA at surgery (<4 ng/ml),ime to biochemical relapse (<24 months) and negativeymph nodes at previous RP were independent predictorsf PSA response to surgery. The 5-year BCR free sur-ival, clinical recurrence and cancer specific survival ratesere 19%, 34% and 75%, respectively. At multivariable

nalyses, only PSA >4 ng/ml and the presence of retroperi-oneal uptake at the pre-salvage LND [11C]Choline PET/CTepresented independent preoperative predictors of clini-al recurrence. Similarly, the presence of pathologic nodesn the retroperitoneum, higher number of positive lymphodes and the evidence of a biochemical response (PSA0.2 ng/ml) assessed 40 days after sLND represented post-perative independent predictors of clinical recurrence afteralvage surgery.

These data seem to show that [11C]Choline PET/CT andLND might be considered for highly selected patients withiochemical relapse of prostate cancer associated with evi-ence of nodal recurrence. However, only a minority ofatients submitted to salvage surgery showed a durable PSAemission, while in the majority of the cases PSA increasedfter an initial response post surgery. A possible explanationor this might reside on the insufficient selection of the patientohort included, which might have contributed to dilute the


ffect of salvage surgery. However, although larger studies areeeded to better identify the best candidates for this surgicalpproach, these preliminary data are hypothesis generating:LDN seems to achieve the highest success rates in selected

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atients with limited pelvic nodal recurrence after primaryreatment. Moreover, even if in a significant proportion ofatients authors failed in showing a durable cancer control, itight be argued that in patients with complete or partial ini-

ial PSA response after surgery, the delay of salvage medicalherapy (i.e. hormonal blockade) might represent a benefitelated to this surgical approach [58].

The role of adjuvant RT after salvage surgery for a nodalelapse remains to be investigated. Jilg et al. reported databout 47 patients operated for a nodal relapse of a previouslyreated prostate cancer, with 27/47 patients irradiated afteralvage surgery. Authors confirm the positive predictive valuef the Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/bOR 5.91, p = 0.042) and of the N0 status at primary therapyOR 8.01, p = 0.011) and the negative predictive value of clin-cal progression of the preoperative Gleason 8–10 (HR 3.5,

= 0.039) of the presence of retroperitoneal positive lymphodes (HR 3.76, p = 0.021) and of an incomplete biochemicalesponse (HR 4.0, p = 0.031), but adjuvant RT did not showo have a significant impact on the outcome of the patients64].

Any salvage “targeted” nodal therapy given in prostateancer should take into account a potential significant under-stimation of nodal recurrence even at [11C]Choline PET/CT54–58,61]. This is due to the relatively limited spatial res-lution of any imaging technique, which might be thusssociated with a certain risk of missing micro-metastaticisease. For this reason, another drawback of the surgicalreatment resides in the fact that removing only the nodes thatesulted positive at imaging might lead to frequent long-termailure rates, but more extensive surgical procedures impliesbviously an increased surgical risk.

Summary:

sLND should be still considered experimental, given thelack of prospective, comparative studies [4];

the available literature seems to support the surgicalapproach only in very selected cases of nodal oligo-recurrent prostate cancer;

the therapeutic value of the surgical approach would beconfirmed only after mature data on the efficacy (in termsof overall and cancer-specific survival) and in terms ofsafety.

. External beam radiotherapy and stereotactic bodyadiotherapy for lymph node recurrence fromrostate cancer

Radiotherapy is commonly used in the treatment ofrimary and metastatic prostate cancer lesions [4,65–69].owever, there are very few data on the irradiation of


odal oligo-recurrent disease. Radiation can be deliveredith external beam approach (external beam radiotherapy,BRT) or stereotactic body radiotherapy (SBRT). EBRT issually delivered to wider volumes using a 3-Dimensional


Please cite

this article

in press

as: D

e B

ari B

, et

al. Salvage

therapy of

small

volume

prostate cancer

nodal failures:

A review

of the

literature.C

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http://dx.doi.org/10.1016/j.critrevonc.2013.11.003

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No.

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12

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(2013) xxx–xxx

7

Table 4Summary of the published series of salvage external beam irradiation (EBRT) for lymph node metastases from prostate cancer.

Authors (year ofpublication)[reference]

Number of ptstreated for LNrelapse (thewhole series)

Concomitantsystemictherapy

EBRTtechnique

Re-irradiation Treatedvolume

Median totaldose/nrfraction(dose/fraction)

Medianfollow-up(months)

Localcontrolrate ± patternof failure

Overallsurvival

Toxicity

Engels et al. (2009)[75]

8 pts(28 pts)

ADT in all pts HelicalTomotherapy

No PTV1:prostatePTV2:positive LNregionsPTV3: pelvicLN

SIB:PTV1:70.5 Gy/30frPTV2:60 Gy/30frPTV3:54 Gy/30fr(2.35–1.8-2 Gy/fr)

? ? ? aAcute GI:G2 7%, G3 0%aAcute GU:G2 14%G3 4%

Alongi et al. (2010)[76]

1 (1) Estramustine +ADT

HelicalTomotherapy

Yes PTV 1:positive LNPTV 2:bilateral iliacLN

SIB:PTV1:67.2 Gy/28frPTV2:50.4 Gy/28 fr(2.4–1.8 Gy/fr)

24 No localprogres-sion at 24mos

Alive at 24months

0

Ricchetti et al. (2011)[74]

1 (4) ADT HelicalTomotherapy

Yes PTV 1:positive LNPTV 2: pelvicLN

SIB:PTV1:60 Gy/30frPTV2:46 Gy/30fr(2–1.53 Gy/fr)

12 No localprogres-sion at 12mos butDM at 16mos

Alive at 16months

0

Jereczek-Fossa et al.(2009) [85]

14 ADT in 7 pts,CHT + ADT in1 pt

SBRT: Linac7pts – CBK 7pts

Yes PTV1:positive LN

30 Gy/3fr(10 Gy/fr)

18 No localprogres-sion, 2 ptswith DMand 3 ptswith LNrelapse

1 pt died ofcardiovascularreason

Acute: 0Late GI G2 1pt

Jereczek-Fossa et al.(2012) [84]

b16 (34) ADT in 75%of pts

SBRT (CBK) Yes PTV1:positive LN

33 Gy/3 fr(11 Gy/fr)

22 No localprogres-sion, 5 ptswith DM

All pts alive at22 months

Acute GU: G31 ptLate GU: G1:2pts, G2 1 pt,G3 1 ptLate GIG1 1 pt

Scorsetti et al. (2011)[79]

1 (12 LN andwhole series:95 pts)

No SBRT(VMAT-RA)

No PTV1:positive LN

45 Gy/6 fr(7.5 Gy/fr)

a12 Localcontrol:10/11 LNpts

NA aAcute GI G13 pts/95ptsaLate GI G1 1pts/12 LN pts

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.



8 Oncol

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onformal Radiation Therapy (3D-CRT) or Intensity Mod-lated modality (IMRT). IMRT is now commonly employedn radical or post-prostatectomy setting, in particular if aelvic nodal irradiation is necessary [70,71]. As far as sal-age setting is concerned, prophylactic irradiation of pelvicodal area might play a potential role owing to the risk ofccult lymph-nodal metastases [71,33,72,73]. This questions currently addressed in the ongoing trial of the Radiationherapy Oncology Group (RTOG 05-34) where the patientsith a rising PSA after prostatectomy are randomized toelvic lymph node or prostate bed only irradiation (withr without short androgen deprivation). As far as salvageBRT is concerned, a MEDLINE search shows only oneeries of 8 patients and 2 reports of single cases treatedsing Tomotherapy a particular form of image guided anddaptive IMRT (Table 4) [74–77]. IMRT seems of valuen case of irradiation of pelvic nodal chains using simulta-eous integrated boost (SIB) approach (with 2 dose levels:ower elective dose to non-involved neighboring lymph nodereas and high radical dose to the clinically positive lymphodes).

SBRT is a novel radiotherapy modality that takes advan-age of the technological progress in image guidance andadiation dose delivery, and it is able to direct high abla-ive doses to small target lesion with acceptable toxicity78]. It can be delivered with a large number of commer-ially available systems including those LINAC-based, likeolumetric modulated arc therapy [79,80], robotic imageuided [80], and other image guided modalities. SBRTeems particularly advantageous for radioresistant tumors,reviously irradiated lesions, and small volume tumors.ypofractionation, which is almost always used when SBRT

s chosen, could be of particular value for prostate cancer.ecent in vivo and clinical data suggest that prostate canceray benefit from hypofractionation as its alpha/beta ratio

s lower than that of the rectum and other pelvic organs81]. Although the data on the alpha/beta ratio of recurrentesions are not available, a similar benefit can be expectedhen using this approach for oligo-recurrent prostate can-

er.Again, although SBRT is employed in the management

f primary or secondary solid tumors and organ confinedrostate cancer [82], few series exist exploring the role ofBRT for the treatment of lymph node recurrence and in par-

icular lymph node recurrence of prostate cancer [83–85].mall series on the resection of a solitary prostate canceretastasis (lung, adrenal gland, lymph node lesions) or radio-

urgery (stereotactic radiotherapy given in single fraction) torain metastases from prostate cancer showed good local con-rol, confirming the potential interest of ablative treatmentsas SBRT) in oligometastatic and oligo-recurrent prostateancer patients [85–89]. Three series on the SBRT for isolated


ymph node recurrent prostate cancer have been publishedecently by two groups (Table 4) [79,84,85].

In the vast majority of both EBRT and SBRT patients, theiagnosis of isolated lymph node recurrence was based on

-


he [11C]Choline PET/CT obtained after PSA progression.n some patients recurrent prostate cancer was confirmed byymph node biopsy.

Obviously, no firm conclusion can be drawn from thesemall series due to short follow-up, extremely low numberf patients, treated with different EBRT and SBRT modali-ies using heterogeneous fractionation schedules and dosesor a variety of limited lymph node recurrences (in sameeries also metastatic lombo-aortic nodes were included). Theajority of patients had heavily pretreated prostate cancer

nd many received concomitant systemic therapy or wereeceiving castration resistant disease. Despite these limi-ations, the results presented in Table 4 suggest that highrecision hypofractionated irradiation offers excellent in-led local control with a very low toxicity profile. Theatterns of failure is predominantly out-field and in theBRT patients recurrence in the neighboring lymph nodeight be observed suggesting the role of regional lymph

ode area irradiation, but this should be counterbalancedgainst potentially higher toxicity (due to larger volumes)nd longer overall treatment time (extreme hypofraction-tion cannot be applied to large volumes). Importantly,

complete biochemical response was observed in almost0% of the lesions treated with radiation alone [84]. Longreatment-free-interval has also been reported in the sameeries [84].

Looking at the toxicity rates, Jereczek-Fossa et al. recentlyublished one of the largest series of patients treated withBRT (Sixty-nine patients, 94 lesions, median SBRT dose4 Gy/3 fractions) for nodal abdominal relapse from sev-ral cancer types (urological, gastrointestinal, gynecologic,nd other malignancies) [83]. After a median follow-upf 20 months, SBRT seems to be well tolerated, withnly two grade 3 acute and one grade 4 late toxicityvents.

These rates compare well with those published bycorsetti et al. reporting early results about 37 consecutiveatients treated with SBRT for abdominal targets (12 of themor abdominal node relapses): both acute and late toxicitieseported were minimal [79]. Recent studies have been pub-ished reporting dosimetric constraints for SBRT and resultsf the reported studies seems to show that the respect of thesendications allow to obtain very low rates of toxicity, also withncreasing doses of RT [90,91].

Summary:

EBRT and SBRT represent promising non-invasiveanatomically-targeted treatment for oligo-recurrentprostate cancer;

these therapies seem to offer excellent in-field tumor con-trol 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.



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. Conclusion

The therapeutic approach to nodal oligo-recurrent prostateancer patients is still object of debate and no firm conclu-ions could be drawn. Up to now, hormonal therapies shoulde still considered the standard of care in this clinical setting.

possible limit to the diffusion of these local approachesould be the lack of accurate imaging techniques to detect theiffusion of the disease. Despite that, a growing interest onhe clinical outcomes of the local surgical and not-surgicallternatives has been recently highlighted in the literature.urgery could be, in very selected cases, a therapeutic option,ut the balance between benefits and potential severe sideffects should be strictly considered. Radiotherapy and, inarticular, SBRT, seems to be a viable therapeutic option inhis clinical setting, also considering the low toxicity pro-le showed in the few published experiences. The correctelection of the patients is crucial in this clinical scenario, inrder to identify patients that would really benefit of a localpproach in a context of potentially disseminated disease.oreover, the optimal combination of local therapies with

ystemic treatments remains to be prospectively investigated.

onflict of interest

None to be declared.

undings

No fundings to be declared.

eviewers

Helen Boyle, M.D., Centre Léon Bérard, 28 Rue Laennec,yon, 69008, France.

Sergio Bracarda, M.D., U.O.C. Medical Oncology, Oncol-gy, Via Pietro Nenni, 20, Arezzo, AR 52100, Italy.

Prof. John Fitzpatrick, Irish Cancer Society, Ireland.

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crHc(tn1Icgroup of AIRO (Italian society of Radiation Oncology) and


observational study of veterans with prostate cancer. J Natl CancerInst 2010;102:39–46.

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iographies

Berardino De Bari, MD, Radiation Oncologist andlinical investigator. He published more than 30 articlesindexed/Peer reviewed Journals) and one book chapter. Mainopics of his activity are: prostate cancer, GI cancer, neuro-ncology and IGRT. He is ESTRO (European Society ofadiation Oncology) fellow and coordinator of the ESTROontouring workshops in the context of the FALCON Project,ncluding also prostate cancer. He speaks regularly at inter-ational conferences and teaching events.

Filippo Alongi, MD, Radiation Oncologist and clini-al investigator. He is associate chief of Radiotherapy andadiosurgery department in Istituto Clinico Humanitas atumanitas Cancer Center. He is Radiation Oncologist and

linical investigator. He published more than 50 articlesindexed/Peer reviewed Journals), 3 book chapters and morehan 150 abstracts presented as oral presentation or posters atational and international scientific congress. His h-index is1. Main topics of his activity are: SBRT, hypofractionation,GRT, molecular imaging in Radiation Oncology, prostateancer. From 2012, he is the national coordinator of young


e is in the board of AIRO prostate working group. He isember of Editorial board of “Tumori” and “Technology inancer Treatment express”.















































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































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Michela Buglione, MD, Radiation Oncologist and assis-ant professor. She published 19 articles (indexed/Peereviewed Journals). Main topics of her activity are: brainumors, hematological malignancies, and IGRT. She is coor-inator for the Group of Neurooncology of the Italianssociation of Radiation Oncology. She is member of EORTCrain Tumour Group.

Franco Campostrini, MD, Radiation Oncologist andlinical investigator. He published more than 20 articlesindexed/Peer reviewed Journals). Main topics of his activ-ty are: prostate cancer and Head and Neck cancers. Directorf the Department of Radiotherapy of the Legnago, he isember of the board of AIRO prostate working group.

Alberto Briganti, MD, Urologist and Assistant Professort the University of San Raffaele (Milan – Italy). Head of therostate Unit of his Department. His main research interests

nclude urologic malignancies and in particular prostate can-er. He is an author of about 130 full papers and of 3 bookhapters and he speaks regularly at international and nationalonferences and teaching events.

Giuseppe Petralia, MD, radiologist and assistant of theepartment of Radiology of the European Institute of Oncol-gy (Milan – Italy). Main research interests include MRI ofrostate cancer. He is an author of about 50 full papers andpeaks regularly at international conferences and teachingvents.

Massimo Bellomi, MD, Radiologist and Professor of theniversity of Milan (Milan – Italy). Head of the Radiologyept. of the European Institute of Oncology (Milan – Italy).is main research interests include imaging of pelvic malig-ancies. He is an author of about 150 full papers and speaksegularly at international conferences and teaching events.

Arturo Chiti, MD, Medical Doctor and clinical investi-ator in Nuclear medicine. Director of Nuclear Medicineepartment of Istituto Clinico Humanitas (Milan – Italy).e published more than 70 articles (indexed/Peer reviewed

ournals), several book chapters. Main topics of his activ-ty are: molecular imaging in Radiation Oncology, head andeck and prostate cancer. From 2012, he is the president ofANM (European Association of Nuclear Medicine).

Nazareno Suardi, MD, Urologist at the University of


an Raffaele (Milan – Italy). His main research interestsnclude urologic malignancies and in particular prostate can-er. He is an author of about 120 full papers and he speaks

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egularly at international and national conferences and teach-ng events.

Marta Scorsetti, MD, Radiation Oncologist and clinicalnvestigator. Director of Radiation Therapy Department ofstituto Clinico Humanitas in Milan (Milan – Italy). Sheublished more than 60 articles (indexed/Peer reviewed Jour-als), several book chapters. Main topics of her activityre: SBRT, hypofractionation, IGRT, Radiosurgery, lung androstate cancer.

Roberto Orecchia, MD, Radiation Oncologist and Profes-or of the University of Milan (Milan – Italy) and Head of theiv. of Radiotherapy of the European Institute of Oncology

Milan – Italy). His main research interests include breastnd prostate cancer. He published almost 250 full papers andpeaks regularly at international conferences and teachingvents.

Francesco Montorsi, MD, Urologist and Professor of Vita-alute San Raffaele University (Milan – Italy) and Head of theiv. of Urology of the San Raffaele Hospital (Milan – Italy).is main research interests include urologic malignancies

nd in particular prostate cancer. He published almost 750ull papers and several book chapters and he speaks regularlyt national and international conferences and teaching events.

Stefano Maria Magrini, MD, Radiation Oncologist androfessor of the University of Brescia (Brescia – Italy) andead of the Department of Radiotherapy of the Spedaliivili of Brescia (Brescia – Italy). His main research inter-sts include prostate cancer, brain tumors and Head and Neckancers, combined modality treatments and new radiotherapyechniques. He has been member of the ESTRO board andf several ESTRO committees; he has been member of theIRO board and coordinator of the AIRO prostate cancerorking group. He published more than 250 full papers and

peaks regularly at international conferences and teachingvents.

Barbara Alicja Jereczek-Fossa, MD, PhD, Radiationncologist and Assistant Professor of the University of Milan

Milan – Italy) and Senior Deputy Director of the Div. ofadiotherapy of the European Institute of Oncology (Milan

Italy). Her main research interests include prostate cancer,ombined modality treatments and high precision radiothe-


apy. She is an author of about 100 full papers and bookhapters and speaks regularly at international conferencesnd teaching events.


salvage therapy of small volume prostate cancer nodal failures: a review of the literature

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