6
Original Article: Clinical Investigation Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy Hiroshi Sasaki, 1 Masahito Kido, 1 Kenta Miki, 1 Hidetoshi Kuruma, 1 Hiroyuki Takahashi, 2 Manabu Aoki 3 and Shin Egawa 1 Departments of 1 Urology, 2 Pathology and 3 Radiology, Jikei University School of Medicine, Tokyo, Japan Abbreviations & Acronyms ADT = androgen deprivation therapy Ant = anterior BCR = biochemical recurrence CT = computed tomography CTV = clinical target volume DW = diffusion-weighted EBRT = external beam radiotherapy LDR-BT = low-dose rate brachytherapy Lt SV = left seminal vesicle MRI = magnetic resonance imaging NA = not available PSA = prostate-specific antigen PSADT = prostate-specific antigen doubling time Rec = recovery Rt SV = right seminal vesicle Sal BT = salvage regional low-dose-rate brachytherapy T2W = T2-weighted Tx = treatment Correspondence: Hiroshi Sasaki M.D., Department of Urology, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: [email protected] Received 2 July 2013; accepted 17 November 2013. Online publication 23 December 2013 Objectives: To characterize local recurrence of prostate cancer and to assess the effect of salvage partial brachytherapy after primary 125-iodine low-dose rate brachytherapy with or without external beam radiotherapy in Japanese men. Methods: Between 2003 and 2010, a total of 616 consecutive patients underwent low- dose rate brachytherapy-based therapy for clinically localized prostate cancer at Jikei Univer- sity Hospital in Tokyo, Japan. Biochemical recurrence occurred in 45 (7.3%) patients at a median of 30 months (range 11–93 months). A total of 20 patients subsequently underwent transperineal template prostatic biopsy; of those, eight had positive cores at the base of the prostate or at the seminal vesicles. These eight patients had underdosed areas identified at initial low-dose rate brachytherapy corresponding to the positive biopsy sites. All were con- firmed to have only localized recurrence, and seven underwent salvage partial low-dose rate brachytherapy. Results: Median prostate-specific antigen nadir level in the eight patients with biopsy- proven local recurrence after initial low-dose rate brachytherapy was 0.75 ng/mL (range 0.39–2.06). The seven retreated patients tolerated the salvage partial low-dose rate brachytherapy well, and showed a decrease in prostate-specific antigen level at follow up. Two patients later developed biochemical and clinical progression at 11 and 13 months, respectively. Prostate-specific antigen level continued to be low in the remaining five patients. No significant genitourinary or gastrointestinal toxicity was encountered. Conclusions: Salvage partial low-dose rate brachytherapy for biopsy-proven localized prostate cancer recurrence appears rational, technically feasible and safe. Optimal patient selection is of utmost importance for long-term success. Larger studies with longer follow up are warranted. Key words: local recurrence, prostate cancer, salvage partial brachytherapy. Introduction Selection of ideal treatment for localized prostate cancer recurrence after definitive radiotherapy is controversial, owing to the lack of evidence based on randomized controlled trials. According to guidelines from the National Comprehensive Cancer Network, local salvage therapy should be considered for patients with solitary local recurrence. Such therapy includes radical prostatec- tomy, cryosurgery and brachytherapy, and some authorities also recommend salvage high- intensity focused ultrasound. However, because of the toxicities associated with these modalities, physicians often choose palliative treatment with ADT instead. 1,2 Potentially curative treatment is thus withheld from many patients. Salvage LDR-BT can be a useful treatment option for localized prostate cancer. 3–7 However, conventional salvage LDR-BT, with re-implantation of the entire prostate, 2 might be associated with serious adverse events. Gastrointestinal or genitourinary grade 3 toxicity has been reported in up to 47% of patients, and can develop prostatic urethral fistulas requiring surgical repair, if proper dosimetric constraints are not applied. 2,7 Salvage LDR-BT of the entire gland can be suboptimal if inappropriately applied. Localized persistence of prostate cancer after radiotherapy might result from radioresistant cell clones in the primary tumor. However, such persistence can more often be the result of inhomogeneous dosimetric distribution of irradiation within the prostate, so that the tumor does not incur uniformly lethal damage. 2,7,8 In such cases, underdosed regions or “cold spots” would be expected to correspond to areas of local recurrence. 8 The target volume could then be defined based on the initial dosimetric record, coupled with information from template-style biopsy International Journal of Urology (2014) 21, 572–577 doi: 10.1111/iju.12373 572 © 2013 The Japanese Urological Association

Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

  • Upload
    shin

  • View
    221

  • Download
    0

Embed Size (px)

Citation preview

Page 1: Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

Original Article: Clinical Investigation

Salvage partial brachytherapy for prostate cancer recurrence afterprimary brachytherapyHiroshi Sasaki,1 Masahito Kido,1 Kenta Miki,1 Hidetoshi Kuruma,1 Hiroyuki Takahashi,2 Manabu Aoki3

and Shin Egawa1

Departments of 1Urology, 2Pathology and 3Radiology, Jikei University School of Medicine, Tokyo, Japan

Abbreviations & AcronymsADT = androgendeprivation therapyAnt = anteriorBCR = biochemicalrecurrenceCT = computedtomographyCTV = clinical targetvolumeDW = diffusion-weightedEBRT = external beamradiotherapyLDR-BT = low-dose ratebrachytherapyLt SV = left seminal vesicleMRI = magnetic resonanceimagingNA = not availablePSA = prostate-specificantigenPSADT = prostate-specificantigen doubling timeRec = recoveryRt SV = right seminalvesicleSal BT = salvage regionallow-dose-ratebrachytherapyT2W = T2-weightedTx = treatment

Correspondence: HiroshiSasaki M.D., Department ofUrology, Jikei University Schoolof Medicine, 3-25-8Nishi-Shimbashi, Minato-ku,Tokyo 105-8461, Japan. Email:[email protected]

Received 2 July 2013; accepted17 November 2013.Online publication 23 December2013

Objectives: To characterize local recurrence of prostate cancer and to assess the effect ofsalvage partial brachytherapy after primary 125-iodine low-dose rate brachytherapy with orwithout external beam radiotherapy in Japanese men.Methods: Between 2003 and 2010, a total of 616 consecutive patients underwent low-dose rate brachytherapy-based therapy for clinically localized prostate cancer at Jikei Univer-sity Hospital in Tokyo, Japan. Biochemical recurrence occurred in 45 (7.3%) patients at amedian of 30 months (range 11–93 months). A total of 20 patients subsequently underwenttransperineal template prostatic biopsy; of those, eight had positive cores at the base of theprostate or at the seminal vesicles. These eight patients had underdosed areas identified atinitial low-dose rate brachytherapy corresponding to the positive biopsy sites. All were con-firmed to have only localized recurrence, and seven underwent salvage partial low-dose ratebrachytherapy.Results: Median prostate-specific antigen nadir level in the eight patients with biopsy-proven local recurrence after initial low-dose rate brachytherapy was 0.75 ng/mL (range0.39–2.06). The seven retreated patients tolerated the salvage partial low-dose ratebrachytherapy well, and showed a decrease in prostate-specific antigen level at follow up.Two patients later developed biochemical and clinical progression at 11 and 13 months,respectively. Prostate-specific antigen level continued to be low in the remaining five patients.No significant genitourinary or gastrointestinal toxicity was encountered.Conclusions: Salvage partial low-dose rate brachytherapy for biopsy-proven localizedprostate cancer recurrence appears rational, technically feasible and safe. Optimal patientselection is of utmost importance for long-term success. Larger studies with longer follow upare warranted.

Key words: local recurrence, prostate cancer, salvage partial brachytherapy.

Introduction

Selection of ideal treatment for localized prostate cancer recurrence after definitive radiotherapyis controversial, owing to the lack of evidence based on randomized controlled trials. Accordingto guidelines from the National Comprehensive Cancer Network, local salvage therapy should beconsidered for patients with solitary local recurrence. Such therapy includes radical prostatec-tomy, cryosurgery and brachytherapy, and some authorities also recommend salvage high-intensity focused ultrasound. However, because of the toxicities associated with these modalities,physicians often choose palliative treatment with ADT instead.1,2 Potentially curative treatment isthus withheld from many patients.

Salvage LDR-BT can be a useful treatment option for localized prostate cancer.3–7 However,conventional salvage LDR-BT, with re-implantation of the entire prostate,2 might be associatedwith serious adverse events. Gastrointestinal or genitourinary grade ≥3 toxicity has been reportedin up to 47% of patients, and can develop prostatic urethral fistulas requiring surgical repair, ifproper dosimetric constraints are not applied.2,7 Salvage LDR-BT of the entire gland can besuboptimal if inappropriately applied.

Localized persistence of prostate cancer after radiotherapy might result from radioresistantcell clones in the primary tumor. However, such persistence can more often be the result ofinhomogeneous dosimetric distribution of irradiation within the prostate, so that the tumor doesnot incur uniformly lethal damage.2,7,8 In such cases, underdosed regions or “cold spots” wouldbe expected to correspond to areas of local recurrence.8 The target volume could then be definedbased on the initial dosimetric record, coupled with information from template-style biopsy

bs_bs_banner

International Journal of Urology (2014) 21, 572–577 doi: 10.1111/iju.12373

572 © 2013 The Japanese Urological Association

Page 2: Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

mapping. We carried out the present study to test this hypoth-esis, in order to better define the safety and technical feasibilityof salvage partial LDR-BT for undertreated areas.

Methods

Patients

Between October 2003 and April 2010, 616 Japanese patientsunderwent LDR-BT for localized prostate cancer at JikeiUniversity Hospital. LDR-BT was administered using anultrasound-guided technique with a Mick applicator as previ-ously described.9 LDR-BT monotherapy was administered in167 low-risk, 124 intermediate-risk and two high-risk patientsas defined by D’Amico’s risk stratification. A total of 17patients in the intermediate-risk and nine patients in the high-risk group received trimodality therapy consisting of LDR-BT,ADT, and EBRT. A total of 90 patients enrolled in theSHIP0804 randomized controlled trial for intermediate-riskprostate cancer had 3-month neoadjuvant ADT before LDR-BT; none of them received EBRT. An additional 43 patientsfrom the SHIP0804 study received 9-month adjuvant ADT.9

BCR was defined as a PSA increase of >2 ng/mL above thePSA nadir level (Phoenix definition).10 A total of 45 patients(7.3%) developed BCR after initial LDR-BT at a median of30 months (range 11–93 months). Patients with BCR within24 months had significant clinical progression or continuousincreasing PSA levels, thus minimizing the possibility of PSAbounce phenomenon. Admittedly, this diagnosis is primarilymade based on clinical judgment, as there are no solid diagnos-tic criteria available to exclude this possibility, especiallyduring the early phase after LDR-BT. A total of 20 patientssubsequently underwent template transperineal biopsy toconfirm local recurrence as described by Satoh et al.11 A total of22 tissue cores were obtained in general from the prostate; 16from the mid-prostate to the base including seminal vesicles,and six cores from the distal half of the gland. All histology wasreviewed by one pathologist (HT). The remaining patients didnot undergo prostatic biopsy after BCR, either because distantmetastases were diagnosed (n = 19) or because the patientrefused the procedure (n = 6). These latter patients are currentlyfollowed without further treatment.

Patients with positive biopsy results were further evaluatedwith the use of CT, MRI (T2W and DW at 1.5T, beginning in2007) and bone scintigraphy to exclude the possibility ofdistant metastases. Local recurrence and its location within theprostate were visually evaluated using DW imaging.

Eight patients had positive cores at the base of the prostate orthe seminal vesicles (Table 1). Those eight patients were con-firmed to have localized recurrence only. All eight patients hadunderdosed areas identified at initial LDR-BT, and those areascorresponded to the positive biopsy sites. Seven of the eightpatients underwent salvage partial LDR-BT using 125-iodinewith real-time transrectal ultrasound-guided transperinealloading. The eighth patient opted for surveillance.

Median follow up after initial LDR-BT for these eightpatients with isolated local recurrence was 88.5 months(range 36–108 months). No patients received ADT after initialLDR-BT before BCR. Seven patients had been initially treatedwith 144 Gy 125-iodine LDR-BT monotherapy, and the

Tab

le1

Dem

ogra

phi

csof

pat

ient

sat

pre

sent

atio

nw

hola

ter

dev

elop

edlo

calr

ecur

renc

eaf

ter

125-

iod

ine

LDR

-BT-

bas

edra

dio

ther

apy

Patie

nts

Age

(yea

rs)

PSA

(ng/

mL)

Stag

eB

iop

syG

leas

on

scor

e

Bio

psy

core

sno

.

pos

itive

/tot

al

Ris

kst

ratifi

catio

nSo

urce

Pro

stat

ic

volu

me

(cc)

V10

0D

90P

SAna

dir

afte

rin

itial

BT

168

11.7

T1c

3+

4=

74/

6In

term

edia

teI-1

2530

.086

.813

5.9

1.20

264

9.5

T1c

3+

3=

65/

6Lo

wI-1

2511

.784

.612

4.7

0.72

368

34.0

T1c

3+

4=

72/

6H

igh

I-125

EBRT

28.8

99.1

113.

0

0.48

469

7.9

T1c

3+

3=

61/

6Lo

wI-1

2538

.089

.014

2.3

0.78

569

13.8

T1c

3+

4=

75/

6In

term

edia

teI-1

2541

.887

.113

4.8

2.06

666

14.8

T2a

4+

3=

73/

8In

term

edia

teI-1

2530

.798

.118

9.9

0.39

769

6.8

T1c

3+

3=

62/

8Lo

wI-1

2531

.089

.814

3.3

1.69

869

12.2

T2a

4+

3=

73/

8In

term

edia

teI-1

2519

.794

.812

3.9

0.49

Med

ian

68.5

12.0

30.4

89.0

†13

5.9†

0.75

†Pat

ient

no.3

excl

uded

.

Salvage partial brachytherapy

© 2013 The Japanese Urological Association 573

Page 3: Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

remaining patient had undergone combined modality therapywith partial-dose 110 Gy 125-iodine implantation and 45 Gy ofEBRT. Median follow up after salvage partial LDR-BT forthese seven patients with isolated local recurrence was27 months (range 3–62 months).

Defining CTV at salvage partialprostate brachytherapy

Salvage partial LDR-BT was designed to deliver 144 Gy torecurrent regions, defined as sites of positive biopsy corre-sponding to underdosed areas at initial LDR-BT. The term“underdosed” was understood to mean that the area receivedless than the prescribed dose of radioactivity. As fusion imagingwas not available, the CTV was manually delineated as aregion of local recurrence with biopsy positivity and initialunderdosage according to the MRI imaging and the initial CTdosimetry. The treatment was deliberately designed to reducerectal and urinary morbidity by positioning needles away fromthe urethra and rectal wall. Regions with sufficient coverageduring initial LDR-BT were carefully avoided. The dose wasprescribed to the isodose line covering the CTV. The planningtarget volume included the CTV plus a 5-mm margin (5-mmposterior margin). Prostatic MRI showed no abnormalitiesoutside the targeted area.

Patient follow up

All patients underwent a CT scan for post-implant dosimetry1 month after salvage partial LDR-BT. Post-treatment followup was quarterly for the first 2 years and semiannually there-after, with PSA measurement and rectal examination at eachvisit. Toxicities were recorded using Common Toxicity Criteriaversion 3.0. Written informed consent was obtained from allpatients. Multiple imaging studies, including chest X-ray, CTscan (chest, abdomen), bone scintigraphy and pelvic MRI, werecarried out in cases of BCR (Phoenix definition) to search forclinical recurrence.

Results

Characteristics of isolated local recurrenttumors after initial LDR-BT and/or EBRT

Eight patients were histologically confirmed to have isolatedlocal recurrence of prostate cancer (Table 1). The median timeto BCR was 58.5 months. The median initial PSA was12.0 ng/mL (range 6.8–34.0). At initial LDR-BT, median D90and median V100 were 135.9 Gy (range 123.9–189.9) and89.0% (range 84.6–98.1), respectively. Median nadir PSA levelafter initial LDR-BT was 0.75 ng/mL (range 0.39–2.06).Median PSA level at the time of BCR was 3.66 ng/mL (range2.88–4.39). Of the 12 patients with negative biopsy, fourpatients had declined PSA over a median period of 21.5 monthsafter biopsy (from a median of 3.58 to 0.63 ng/mL). Theremaining patients still sustain rising PSA trend at last followup. The median time to BCR in these 12 patients with negativebiopsy was 26.0 months, and that for four patients with declin-ing PSA after biopsy was 22.5 months, respectively. Positivebiopsy sites were in the anterior base in five patients, posteriorbase in one patient and seminal vesicles in two patients. Theseregions corresponded precisely to the underdosed area at

dosimetry 1 month after initial LDR-BT. No anatomical vari-ations, such as protruding median lobe, were observed in any ofthese cases. The number of positive cores ranged from 1 to 3(median 2), located exclusively in the base (6 patients) andseminal vesicles (2 patients). The maximum cancer lengthranged from 1 to 14 mm (median 7 mm). Only a mild radiationeffect was noted histologically, as defined by Crook et al.12

Assigned Gleason scores were 6–7. MRI was carried out in sixpatients after histological confirmation of recurrence. In five ofthose six patients, MRI findings showed local recurrence ofprostate cancer at the base and/or seminal vesicle (Table 2).These tumors typically appeared as low-intensity lesions onT2WI and high-intensity lesions on DWI, ranging from 10 to18 mm in size. All of these lesions were located in underdosedareas with positive biopsy.

Quality assessment of salvage partial LDR-BT

The median number of seeds for salvage partial LDR-BT was50 (range 20–70). The activity of seeds was 0.29–0.33 mCi perseed. All patients tolerated the procedure well and showeddecreased PSA (median 14.5% at 7 months) (Fig. 1). Twopatients later developed biochemical and clinical progression at11 and 13 months after salvage partial LDR-BT, respectively.The PSA response persisted in the remaining patients. Time toBCR after the initial LDR-BT in the two patients who devel-oped clinical progression was shorter (18 and 27 months,respectively) than in the other five patients. The median PSADTbefore BCR was calculated as log × 2 / the slope of the logPSA line (the difference in the 2 log PSA value divided by thetime between readings in months). For these patients, themedian PSADT before BCR was 13.2 months (range 8.4–32.3 months). The PSADT was 8.4 and 13.3 months, respec-tively, for the two patients with disease progression. Nosignificant genitourinary or gastrointestinal toxicity was noted.

Case presentation

A 69-year-old man with Gleason score 6, T1cN0M0 prostatecancer (patient no. 4 in Tables 1,2) had undergone initialLDR-BT in August 2004. A CT scan 4 weeks after the implantshowed D90 to be 142.3 Gy and V100 to be 89.0%, and showedan underdosed area at the anterior base of the prostate (Fig. 2a).The PSA nadir after LDR-BT was 0.78 ng/mL. BCR was diag-nosed in April 2011; the PSA level was 4.18 ng/mL, and onepositive core was detected at the right anterior base of theprostate. On MRI, the recurrent tumor appeared as a low-intensity lesion on T2WI, and a high-intensity lesion on DWI atthe base (Fig. 2b,c). Salvage partial LDR-BT was carried out inSeptember 2011. The well-defined cold area was re-implantedwith 50 seeds of 125-iodine (Fig. 2d). The post-salvage PSAlevel remained low at 0.06 ng/mL 13 months later. No signifi-cant genitourinary or gastrointestinal toxicity was noted.

Discussion

Optimal patient selection is critical for the success of salvagetherapy after definitive radiotherapy. Identification of candi-dates has been proposed on the basis of pretreatment clinicaland pathological factors, as well as on post-treatment PSAkinetics, such as PSADT.13,14 Stock et al. have analyzed patterns

H SASAKI ET AL.

574 © 2013 The Japanese Urological Association

Page 4: Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

of failure after LDR-BT for localized prostate cancer,13 andsuggested that time to BCR, Gleason score and PSADT were allpredictive of distant metastases.13 Local therapy should be indi-cated for those with the highest probability of purely localizedrecurrence. Lee et al. reported that ideal candidates for salvagelocal therapy meet the following criteria: (i) low risk at initialtreatment and prediagnostic PSA velocity <2 ng/mL during theyear before diagnosis; (ii) BCR occurred more than 3 yearsafter treatment, PSADT at the time of recurrence >12 monthsand low absolute PSA value before initiating salvage localtherapy (<1 ng/mL).14

Accurate diagnosis of local recurrence can sometimes beconfounded by the well-known PSA bounce phenomenon afterradiotherapy.15 BCR was diagnosed in 45 men at a median of30 months after initial LDR-BT in the present study. Of the 20patients who agreed to have prostatic biopsy, eight were diag-nosed with isolated local recurrence of prostate cancer. Inter-estingly, four patients with negative biopsy later showeddeclined PSA, suggesting the possibility of PSA bounce. Diag-nosis of BCR and indication of biopsy need to be furtherrefined.

Seven of those eight with positive biopsy subsequentlyunderwent salvage partial LDR-RT. Two of those patients laterdeveloped distant metastases. Both had less time to BCR and ashorter PSADT than any of the other five patients. The use ofsystemic therapy, such as simultaneous ADT, or some investi-gational protocol-based therapy might be an option for suchpatients with peculiar PSA kinetics. Awareness and more timelydiagnosis should maximize treatment efficacy for better diseasecontrol.

Of the several available options, salvage partial LDR-BTcould be the treatment of choice for certain patients with BCR.In the present study, the prostatic base was the most commonregion for biopsy positivity (6/8 patients). This region is oftenunderdosed and thus undertreated.8 Difficulty in identifying anddelineating the boundary between prostate and seminal vesi-cles, especially in cases of median lobe protrusion, could leadto planning errors that account for this tendency. Appropriateseed placement at the base of the gland can also be technicallychallenging. In the present study, for eight patients, according

Tab

le2

Clin

icop

atho

logi

calfi

ndin

gsof

pat

ient

sw

ithlo

calr

ecur

renc

eaf

ter

125-

iod

ine

LDR

-BT-

bas

edra

dio

ther

apy

Patie

nts

PSA

atB

CR

(ng/

mL)

Tim

eto

BC

R

(mon

ths)

PSA

DT

(mon

ths)

MR

Ifind

ing

T2W

and

DW

Bio

psy

core

sno

.

pos

itive

/tot

al

Bio

psy

pos

itive

loca

tion

Bio

psy

Gle

ason

scor

e

Bio

psy

max

imum

canc

er

leng

th(m

m)

Txaf

ter

BC

R

Tim

eto

sal

BT

afte

r

initi

alB

T

(mon

ths)

SalB

T,

num

ber

ofse

eds

Rec

afte

r

salB

T

Follo

wup

afte

rsa

lBT

(mon

ths)

PSA

atla

st

follo

wup

(ng/

mL)

13.

9060

13.1

–1/

12R

tSV

3+

31

SalB

T70

30–

382.

12

22.

8818

8.4

NA

2/22

Ant

bas

e3

+4

8Sa

lBT

3120

+(1

3m

)62

4.6†

33.

1065

18.4

+1/

23A

ntb

ase

4+

37

SalB

T82

6514

0.35

44.

1880

10.3

+1/

22A

ntb

ase

3+

47

SalB

T85

50–

130.

06

54.

3927

13.3

NA

3/22

Post

bas

e4

+3

14Sa

lBT

3030

+(1

1m

)54

0.11

63.

4157

16.4

+1/

22Lt

SV3

+4

6Sa

lBT

6050

–27

0.14

73.

9270

32.3

+2/

22A

ntb

ase

3+

35

SalB

T82

70–

30.

70

83.

1336

9.0

+2/

22A

ntb

ase

4+

38

Surv

eilla

nce

––

––

Med

ian

3.66

58.5

13.2

770

5027

†Pat

ient

no.2

and

no.5

wer

egi

ven

horm

one

ther

apy

afte

rth

ere

curr

ence

afte

rsa

lvag

ep

artia

lLD

R-B

T.

0

2

4

6

8

10

12

14

16

0 10 20 30 40

PSA

(ng/

mL)

Time after salvage regional LDR-BT (months)

Fig. 1 Changes of PSA with time after salvage regional LDR-BT. , Pt1; ,

Pt2; , Pt3; , Pt4; , Pt5; , Pt6; , Pt7.

Salvage partial brachytherapy

© 2013 The Japanese Urological Association 575

Page 5: Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

to Table 2, the median time to BCR was 58.5 months, which ismuch more in keeping with local failure. Six of the eightpatients with local recurrence were treated when we were stillrelatively inexperienced with this procedure (<150 cases). Thisre-emphasizes the importance of initial treatment, which shouldbe carried out with care. The development of a practical real-time dosimetry system should improve dose distribution byidentifying isodose holes intraoperatively, so that more seedscan be added immediately in the affected regions.16

Two patients were diagnosed with tumor recurrence in theseminal vesicles (patient no. 1 and 6). As seminal vesicles hadnot been included in the target volume at the initial LDR-BT,salvage partial LDR-BT was thought to offer a second chance

for a cure. Seeds were successfully placed with no sign ofmigration, possibly because of desmoplasia in the surroundingtissue. PSA decreased after the procedure. An intraprostatic“cold spot” at the base beside the urethra was noted in patientno. 3, despite the successful dosimetry of V100 and D90 valuesof LDR-BT. Time to BCR was 65 months after initial LDR-BT.The cause is not readily certain; however, EBRT coveragemight have been suboptimal for this high-risk disease.

Because all tumors were diagnosed in the underdosed areas,undertreatment was thought to be the primary cause of recur-rence. However, aggressive radioresistant clones in the primarycancer can give rise to longer-term tumor recurrence(radiorecurrence). Correct and timely identification of localrecurrence is ideal for establishing effective treatment strat-egies. Multiparametric MRI techniques, which include T2WI,DWI, dynamic contrast enhanced imaging and MR spectros-copy, are expected to encourage efficient diagnosis of locallyrecurrent prostate cancer after EBRT.17–19 These techniquesmight prove clinically useful by identifying individual localizedfoci within the prostate to facilitate focal salvage therapy.20

After radiotherapy, the prostate generally shows low signalintensity in T2-weighted images because of fibrotic changes inthe gland.21 In the present study, with the use of T2WI and DWIMRI, five out of six patients showed positive findings indica-tive of local recurrence, corresponding to positive biopsy/underdosed areas. More effective imaging technology is clearlyrequired for thorough evaluation of the prostate outside theunderdosed area. With better imaging options, template typetransperineal biopsy mapping to localize disease might becomeunnecessary in the future.

The present study had several limitations. First, this studywas carried out in a single institution and was small in size, asonly a fraction of the patients with BCR had prostatic biopsy.Second, the appropriateness of salvage partial therapy has notyet been established. Though biopsy-positive underdosed areaswere targeted in the present study, we do not know if this formof targeting can provide a robust response or can be applied toradiorecurrent lesions previously covered with sufficientdosage at initial LDR-BT. Further collaborative work is war-ranted in order to establish a logical approach to the treatmentof recurrent tumors after radiotherapy.

In conclusion, seven patients underwent salvage partialLDR-BT. At a median follow up of 27 months, PSA levelsremained under control in five (71.4%). Salvage partialLDR-BT for biopsy-proven localized prostate cancerrecurrence with the corresponding underdosed area is a rationaland practical approach for local control of the disease.

Acknowledgment

This study was supported in part by a SHIP0804 grant(NCT00664456).

Conflict of interest

None declared.

References1 Saigal CS, Gore JL, Krupski TL et al. Androgen deprivation therapy

increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110: 1493–500.

(a)

(b)

(d)

(c)

Fig. 2 A case of local recurrence of prostate cancer after primary 125-iodine

LDR-BT (patient no. 4 in Tables 1,2). (a) The dosimetry on CT-imaged axial slices of

the prostatic gland after initial LDR-BT (light green line showing prescribed dose,

144 Gy, red line showing contouring of the prostate, yellow arrows showing

underdosed area). (b) Axial T2WI of MRI after BCR, the recurrent tumor appears

as a low-intensity lesion (arrow). (c) DWI of MRI, the recurrent tumor appears as

a high-intensity lesion (arrow). (d) The dosimetry on CT-imaged axial slices of the

prostatic gland after salvage.

H SASAKI ET AL.

576 © 2013 The Japanese Urological Association

Page 6: Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy

2 Nguyen PL, D’Amico AV, Lee AK et al. Patient selection, cancer control,and complications after salvage local therapy for postradiationprostate-specific antigen failure: a systematic review of the literature. Cancer

2007; 110: 1417–28.3 Beyer DC. Salvage brachytherapy after external-beam irradiation for prostate

cancer. Oncology (Huntingt.) 2004; 18: 151–8.4 Moman MR, van den Berg CA, Boeken Kruger AE et al. Focal salvage

guided by T2-weighted and dynamic contrast-enhanced magnetic resonanceimaging for prostate cancer recurrences. Int. J. Radiat. Oncol. Biol. Phys.

2010; 76: 741–6.5 Pucar D, Hricak H, Shukla-Dave A et al. Clinically significant prostate cancer

local recurrence after radiation therapy occurs at the site of primary tumor:magnetic resonance imaging and step-section pathology evidence. Int. J.

Radiat. Oncol. Biol. Phys. 2007; 69: 62–9.6 Hsu CC, Hsu H, Pickett B et al. Feasibility of MR Imaging/MR

Spectroscopy-Planned Focal Partial Salvage Permanent Prostate Implant (PPI)for Localized Recurrence After Initial PPI for Prostate Cancer. Int. J. Radiat.

Oncol. Biol. Phys. 2013; 85: 370–7.7 Cellini N, Morganti AG, Mattiucci GC et al. Analysis of intraprostatic

failures in patients treated with hormonal therapy and radiotherapy:implications for conformal therapy planning. Int. J. Radiat. Oncol. Biol. Phys.

2002; 53: 595–9.8 Hughes L, Waterman FM, Dicker AP. Salvage of suboptimal prostate seed

implantation: reimplantation of underdosed region of prostate base.Brachytherapy 2005; 4: 163–70.

9 Miki K, Kiba T, Sasaki H et al. Transperineal prostate brachytherapy, usingI-125 seed with or without adjuvant androgen deprivation, in patients withintermediate-risk prostate cancer: study protocol for a phase III, multicenter,randomized, controlled trial. BMC Cancer 2010; 10: 572–8.

10 Roach M III, Hanks G, Thames H Jr et al. Defining biochemical failurefollowing radiotherapy with or without hormonal therapy in men withclinically localized prostate cancer: recommendations of the RTOG-ASTROPhoenix Consensus Conference. Int. J. Radiat. Oncol. Biol. Phys. 2006; 65:965–74.

11 Satoh T, Matsumoto K, Fujita T et al. Cancer core distribution in patientsdiagnosed by extended transperineal prostate biopsy. Urology 2005; 66:114–18.

12 Crook JM, Bahadur YA, Robertson SJ et al. Evaluation of radiation effect,tumor differentiation, and prostate specific antigen staining in sequentialprostate biopsies after external beam radiotherapy for patients with prostatecarcinoma. Cancer 1997; 79: 81–9.

13 Stock RG, Cesaretti JA, Unger P, Stone N. Distant and local recurrence inpatients with biochemical failure after prostate brachytherapy. Brachytherapy

2008; 7: 217–22.14 Lee A, D’Amico A. Utility of prostate-specific antigen kinetics in addition to

clinical factors in the selection of patients for salvage local therapy. J. Clin.

Oncol. 2005; 23: 8192–7.15 Crook J, Gillan C, Yeung I et al. PSA kinetics and PSA bounce following

permanent seed prostate brachytherapy. Int. J. Radiat. Oncol. Biol. Phys.

2007; 69: 426–33.16 Reed D, Wallner K, Merrick G et al. Isodose patterns in patients with

inadequate prostate brachytherapy coverage. Int. J. Radiat. Oncol. Biol. Phys.

2003; 56: 1480–7.17 Rouviere O et al. Recurrent prostate cancer after external beam radiotherapy:

value of contrast-enhanced dynamic MRI in localizing intraprostatic tumor –correlation with biopsy findings. Urology 2004; 63: 922–7.

18 Kim CK et al. Prediction of locally recurrent prostate cancer after radiationtherapy: incremental value of 3T diffusion-weighted MRI. J. Magn. Reson.

Imaging 2009; 29: 391–7.19 Haider MA et al. Dynamic contrast-enhanced magnetic resonance imaging for

localization of recurrent prostate cancer after external beam radiotherapy. Int.

J. Radiat. Oncol. Biol. Phys. 2008; 70: 425–30.20 Wallace T, Avital I, Stojadinovic A et al. Multi-parametric MRI-directed focal

salvage permanent interstitial brachytherapy for locally recurrentadenocarcinoma of the prostate: a novel approach. J. Cancer 2013; 4:146–51.

21 Sugimura K, Carrington BM, Quivey JM, Hricak H. Postirradiation changesin the pelvis: assessment with MR imaging. Radiology 1990; 175: 805–13.

Salvage partial brachytherapy

© 2013 The Japanese Urological Association 577