Oncology

The Effect of Androgen DeprivationTherapy Before Salvage Whole-glandCryoablation After Primary RadiationFailure in Prostate Cancer Treatment

Roger Li, Herbert C. Ruckle, Amy E. Schlaifer, Ahmed El-Shafei, Changhong Yu, andJ. Stephen Jones

OBJECTIVE To define the effects of androgen deprivation therapy (ADT) used prior to salvage cryoablation

Financial Disclosure: The authoFunding Support: The Cryo Onresearch grant from Endocare/HWatermark, an independent resephysician board.From the Department of Urol

Linda, CA; and the GlickmanCleveland, OH; Urology DepartAddress correspondence to: He

Linda University School of MedLinda, CA 92354. E-mail: hrucSubmitted: December 1, 2014

ª 2015 Elsevier Inc.All Rights Reserved

(SC) for the treatment of recurrent localized prostate cancer after radiation.

METHODS Patients from the Cryo On-Line Database registry undergoing SC after radiation failure were

divided according to whether they had previously received or not received ADT. Baselinecharacteristics including demographics and presalvage cancer risk were compared. Biochemicalprogression-free survival (bPFS) as defined by the Phoenix criteria was compared between the 2groups as a whole and also in D’Amico risk-stratified subgroups. In addition, postsurgical com-plications such as urinary fistula, retention, incontinence, and erectile dysfunction werecompared.

RESULTS Two groups consisting of 254 and 486 patients with and without pre-SC ADT were analyzed. The

patients who received ADT were younger (P ¼ .003) and had higher presalvage D’Amico risks(P <.001). The 5-year bPFS was 63.8% and 39.3% for the hormone-naïve and the pre-SC ADTpatients, respectively (P <.001). On subgroup analysis, the difference in 5-year bPFS was sig-nificant only for patients with a high D’Amico cancer risk (54.3% vs 30.5%; P ¼ .013). Onmultivariate analysis, presalvage prostate-specific antigen (hazard ratio [HR], 1.7), Gleasonscore �8 (HR, 2.5), and use of pre-SC ADT (HR, 1.7) correlated with biochemical recurrence.Additionally, patients receiving pre-SC ADT experienced less urinary retention (P ¼ .001) andincontinence (P ¼ .008) but were more likely to be impotent (P ¼ .010).

CONCLUSION Patients receiving ADT before SC, especially those with high-risk prostate cancer, had worse

5-year bPFS. Added caution is needed when selecting patients having previously received ADTfor salvage cryotherapy. UROLOGY -: -e-, 2015. � 2015 Elsevier Inc.

ecurrent prostate cancer can occur in 22%-69%of patients after primary radiation therapy.1-3

RDefinitive salvage treatment options for local-

ized recurrent cancer include radical prostatectomy,brachytherapy, and cryoablation. Although salvageradical prostatectomy affords reasonable oncologic con-trol, it is associated with high incidence of complications,including urinary incontinence (10%-79%), anastomoticstricture (7%-41%), and rectal injury (0%-28%).4

rs declare that they have no relevant financial interests.-line Database registry is sponsored by an unrestrictedealthTronics. The data were held and analyzed byarch company under the direction of an independent

ogy, Loma Linda University Medical Center, LomaUrological and Kidney Institute, Cleveland Clinic,ment, Medical School, Cairo University, Giza, Egyptrbert C. Ruckle, M.D., Department of Urology, Lomaicine, 11234 Anderson Street, Room A560, Lomakle@llu.edu, accepted (with revisions): December 19, 2014

h

Recently, salvage cryoablation (SC) has emerged as aless-invasive alternative with lower perioperativemorbidity profile.5-7

However, with cancer recurrence after SC rangingfrom 37%-49%,5-7 several investigators have attempted toidentify predictors of SC failure to improve patient se-lection. Preradiation oncologic parameters includingGleason score, prostate-specific antigen (PSA), andclinical stage,8,9 as well as presalvage parameters such asGleason score, PSA,10 and PSA doubling time,11 weresome factors found to correlate with cancer recurrenceafter SC. In addition, after SC, PSA nadir was also pre-dictive of treatment failure.7,10

In large, randomized, phase III studies, androgendeprivation therapy (ADT) given neoadjuvantly and/orcontinued through and after primary radiation treatmenthas been shown to improve cancer-specific and overallsurvival for intermediate- and high-risk prostate cancerpatients.12-15 In contrast, a recent study demonstratedthat neoadjuvant ADT did not affect biochemical

ttp://dx.doi.org/10.1016/j.urology.2014.12.0250090-4295/15

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Excluded patients with postop adjuvant and with biochemical failure (71)

Total number after excluding missing bPFS (n= 811)

Excluded patients with missing follow-upPSA (bPFS) (82)

Total number after excluding postop ADT without recurrence (740) –Neo-adjuvant (254) and No-Neo-

adjuvant (486)

Figure 1. Selection of whole-gland salvage cryotherapy patients. ADT, androgen deprivation therapy; bPFS, biochemicalprogression-free survival; postop, postoperative; PSA, prostate-specific antigen. (Color version available online.)

recurrence after primary cryoablation of the prostate.16

The role of ADT in the salvage setting remains unclear.In this study, we use information obtained from the CryoOn-Line Database (COLD) in an attempt to define theeffects of ADT before salvage prostate cryoablation. Wealso evaluate whether neoadjuvant ADT can serve as apredictor of success for salvage cryoablation.

METHODS

The COLD registry is a database consisting of informationgathered from >40 sources including both academic centers andcommunity urologists. It has been sponsored by an unrestrictedresearch grant from Endocare (Endocare, Austin, TX), and thedata are held and analyzed by the independent research com-pany, Watermark, under the direction of an independentphysician board.6 The selection criteria, techniques, and tech-nology used for SC are determined by individual surgeons.Baseline characteristics included patient demographics andoncologic parameters on postradiation recurrence includingPSA, Gleason score, and clinical stage. The use of ADT beforeand after salvage treatment, as well as post-SC oncologic pa-rameters including PSA, biopsy outcomes, and postoperativemorbidity, were also recorded. Patients undergoing partialsalvage cryotherapy, with incomplete follow-up data, and whowere started on adjuvant ADT after SC before biochemicalfailure were excluded. All patients had universally terminatedADT before undergoing SC.

The cohort was separated into 2 groups: patients havingreceived or not received ADT before SC. Baseline characteris-tics including age, race, prostate volume, and D’Amico risk

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score17 on postradiation recurrence were compared. The primaryoutcome of the study was the biochemical progression-free sur-vival (bPFS) as defined by the Phoenix criteria (PSA nadirþ 2).18

Other outcome variables including PSA nadir after SC, use ofadjuvant ADT after SC, as well as postsurgical complicationssuch as urinary fistula, urinary retention, urinary incontinence,and the loss of potency, were also compared. Specifically, uri-nary retention was defined by the requirement for ancillarytherapy (intermittent catheterization, indwelling catheter, ortransurethral resection of the prostate) 12 months after SC.Incontinence was defined by the use of any absorbent pads12 months after SC. Potency was defined by the ability toachieve vaginal penetration and complete intercourse12 months postoperatively. Patients were excluded from thefunctional outcome analysis if they had any of the aforemen-tioned conditions preoperatively.As the reason for startingADTbefore SCwas not queried in the

questionnaire, it was presumed that ADT was begun on suspicionfor cancer recurrence. Thus, the grouping of patients by whetherADTwas used before SC could potentially lead to confounding asthe higher risk patients have a higher probability of cancerrecurrence leading to them receiving pre-SCADT. To correct forpotential confounding, we performed subgroup analysis wherepatients were stratified by their presalvage D’Amico cancer risk,and the bPFS were compared between the patients who had andhad not received pre-SC ADT within each group.Statistical analysis was carried out using the open source sta-

tistical package R-3.0.2 (RStudio, Inc, Boston,MA). Continuousvariables were compared using theMann-WhitneyU test, and thecategorical variables were compared using the chi-square or theFisher exact test if the expected counts were <5. Kaplan-Meieranalysis was used to generate biochemical disease-free survival

UROLOGY - (-), 2015

Table 1. Patient baseline characteristics

Variable No Pre-SC ADT (n ¼ 486) Pre-SC ADT (n ¼ 254) P Value

Age (y) 72 (46-93) 70 (45-88) .003Race .781White 234 66African American 36 13Other 17 5

PSA (ng/mL) 4.7 (0-64.2) 6 (0-117.2) <.001Gleason score, n (%)�6 169 (36.8) 73 (31.1) .0307 154 (33.6) 69 (29.4)

�8 136 (29.6) 93 (39.6)D’Amico risk, n (%)Low 159 (32.8) 52 (20.5) <.001Intermediate 159 (32.8) 65 (25.6)High 167 (34.4) 1372 (53.9)

Prostate volume 22.9 (3.6-92.2) 22 (6-74) .875

ADT, androgen deprivation therapy; PSA, prostate-specific antigen; SC, Salvage cryoablation.Bold values represent statistical significance.

Table 2. Outcome variables

Variable No Pre-SC ADT Pre-SC ADT P Value

PSA nadir (ng/mL) 0.1 (0-42.5) 0.1 (0-96) .201bPFS 369 (75.9) 171 (67.3) .012Adjuvant ADT 51 (10.9) 42 (16.8) .024Complications, n (%)Fistula 22 (4.7) 11 (4.4) .859Retention 102 (21.7) 30 (12) .001Incontinence 148 (33.3) 52 (23.3) .008Potency 75 (28.7) 15 (15.5) .010

bPFS, biochemical progression-free survival; other abbreviationsas in Table 1.

Bold values represent statistical significance.

curves, and the difference among survival curves was examinedwith the log-rank test. A multivariate Cox regression analysis wasbuilt to investigate the effect of neoadjuvant ADT on the bPFSafter adjusting for risk factors including age, serum PSA level,Gleason score, clinical stage, and prostate volume. Missing valuesin the predictors were multiply imputed using the MultivariateImputations by Chained Equations before conducting themultivariate regression analysis to effectively use the sample sizeand avoid potential selection bias. A P value of<.05 was deemedstatistically significant.

RESULTSA total of 998 patients had undergone salvage cryotherapyfor localized recurrent prostate cancer after primary radi-ation therapy from July 1992 to April 2014. Of those, 105patients receiving subtotal salvage cryotherapy and 82patients who had insufficient follow-up data wereexcluded. Seventy-one patients who received post-SCadjuvant ADT before biochemical failure were excludedas biochemical recurrence cannot be reliably detected inthis group. The patients who received adjuvant ADT afterbiochemical failure were included in the analysis. Afterexclusion, 740 patients were included in the analysis,consisting of 254 patients receiving ADT before salvagecryotherapy and 486 who had not (Fig. 1). Median follow-up period for the pre-SC ADT and the nonepre-SC ADT

UROLOGY - (-), 2015

groups was 14.4 months (0-185.6 months) and 18.2months (0.2-249.5 months), respectively (P ¼ .154).

Baseline characteristics for the 2 groups are outlined inTable 1. The patients who received ADT before SC wereyounger (70 vs 72 years; P ¼ .003) and tended to havehigher presalvage PSA levels (6 vs 4.7 ng/mL; P <.001)and Gleason scores (P ¼ .030). Consequently, theirD’Amico risks were higher than the patients who avoidedADT before SC (P <.001).

Outcome variables are outlined in Table 2. Despite thedifferences in preradiation disease characteristics, the PSAnadir achieved after SC was similar between the 2 groups(P ¼ .201). However, the bPFS was much higher in thepatients without pre-SCADT(75.9%vs 67.3%;P¼ .012).Kaplan-Meier analysis estimated 5-year bPFS was 63.8%and 39.3% for patients without and with pre-SC ADT,respectively (P <.001; Fig. 2A). On multivariate analysis,presalvage PSA (hazard ratio [HR], 1.7; 95% confidenceinterval [CI], 1.3-2.3; P <.001), presalvage Gleason scoreof �8 (HR, 2.5; 95% CI, 1.8-3.6; P<.001), and the use ofpre-SC ADT (HR, 1.7; 95% CI, 1.3-2.4; P <.001) allcorrelated with biochemical recurrence (Table 3).

Subsequent to SC, more patients who had receivedpre-SC ADT were placed back on ADT (16.8% vs10.9%; P ¼ .024). Patients receiving pre-SC ADTexperienced less urinary retention and incontinence at12 months after salvage therapy but were less likely to bepotent (Table 2). The incidences of urinary fistula weresimilar between the 2 groups.

On subgroup analysis, a difference in the 5-year bPFSbetween the pre-SC ADT (30.5%) and the non-ADTgroups (54.3%) emerged only in the D’Amico high-riskcancer group (P ¼ .013). No clear difference wasobserved in the low (P ¼ .06) and intermediate D’Amicorisk (P ¼ .263) groups (Fig. 2B-D).

COMMENTThe role of ADT in treating prostate cancer continues toevolve since its original description by Huggins et al in

3

Months since salvage cryoablation

lavivruseerf-noiss ergo rplaci

mehcoiB

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

486 309 204 151 111 81 No

254 160 96 67 46 33 Yes

No

Yes

Stratified By Preop Adjuvant Therapy

P < 0.001

A

Months since salvage cryoablation

lavivruseerf-noiss ergor placi

mehcoiB

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

159 103 72 58 41 29 No

52 34 28 22 12 9 Yes

No

Yes

Low Risk Patients By Preop ADT

P = 0.060

B

Months since salvage cryoablation

lavivruseerf-noiss ergor placi

mehcoiB

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

159 102 58 41 27 19 No

65 44 24 18 14 10 Yes

No

Yes

Intermediate Risk Patients By Preop ADT

P = 0.263

C

Months since salvage cryoablation

lavivruseerf-noissergorplaci

mehcoiB

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

167 103 73 51 43 33 No

137 82 44 27 20 14 Yes

No

Yes

High Risk Patients By Preop ADT

P = 0.013

D

Figure 2. Kaplan-Meier (KM) plot of biochemical progression-free survival (bPFS) in the overall study population receivingpreoperative androgen deprivation therapy (ADT) and not receiving preoperative ADT (A) and in stratified groups according tothe pre-salvage cryoablation D’Amico risks (B-D). *P value was based on the log-rank test between these 2 survival curves.*The KM estimated 5-year bPFS was 63.8% and 39.3% for patients without and with preoperative ADT, respectively. *The KMestimated 5-year bPFS was 70.7% and 55.4% for patients without and with preoperative ADT, respectively. *The KM esti-mated 5-year bPFS was 69.8% and 61.6% for patients without and with preoperative ADT, respectively. *The KM estimated5-year bPFS was 54.3% and 30.5% for patients without and with preoperative ADT, respectively. ADT, androgen deprivationtherapy; Preop, preoperative.

1941. One of the breakthroughs in prostate cancer treat-ment strategy was the addition of ADT to radiation forpatients with intermediate- and high-risk disease. Manylarge, prospective, randomized studies have repeatedlyshown that the use of neoadjuvant and/or adjuvant ADTin combination with primary radiation therapy canimprove bPFS, cancer-specific survival, and overall sur-vival for patients with high-risk features.12-15 In contrast,

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the oncologic benefit of using ADT after primary radiationtherapy failure is unclear. To date, there is no prospectivestudy linking the use of ADT in the salvage setting withprolonged survival. Instead, salvage ADT may delay pro-gression to metastasis in patients with aggressive recurrentdisease19,20 and provide symptomatic relief.21 Despite thelack of evidence for oncologic benefit, ADT is oftenindiscriminately used for patients with biochemical

UROLOGY - (-), 2015

Table 3. Predictors of biochemical progression from themultivariate Cox proportional hazards regression

Predictor Variable

Hazard Ratio(95% Confidence

Interval)P

Value

Age (77 vs 66.2 y) 1.1 (0.9-1.4) .385*Race (white vs black) 1.3 .671Prostate volume(30 vs 19)

0.8 (0.7-1.1) .161

Presalvage PSA(8.1 vs 3 ng/mL)

1.7 (1.3-2.3) <.001

Presalvage Gleason score�6 17 1 (0.7-1.6)

�8 2.5 (1.8-3.6) <.001Clinical stageT2 vs T1 1 .974T3 vs T1 1T4 vs T1 0.7

Pre-SC ADT 1.7 (1.3-2.4) <.001

Abbreviations as in Table 1.Bold values represent statistical significance.

* Hazard ratio for continuous variables was based on the contrastof Q3 vs Q1 due to nonlinear relationship.

recurrence after radiation failure.1,22 Subsequently, thewindow of opportunity to treat localized recurrent cancerfor many patients can easily be missed.

On the other hand, when used appropriately, ADTmay provide survival benefits in the salvage setting.Studies have shown that adjuvant ADT in combinationwith salvage radiation for postprostatectomy biochemicalfailure can improve postsalvage bPFS and metastasis-freesurvival.23,24 The present study aims to clarify whetherthe use of neoadjuvant ADT before salvage Cryoablationcan prolong cancer-free survival. We hypothesized that asneoadjuvant ADT showed no benefit before primarywhole-gland cryotherapy,16 the use of ADT afterbiochemical recurrence will also have little oncologicbenefit. On the contrary, the administration of ADT maydelay definitive salvage therapy, thus missing the thera-peutic window for many patients who initially presentwith localized recurrent disease and subsequently progress.

Extracting from the COLD registry, we accrued thelargest cohort of patients with radiorecurrent prostatecancer undergoing SC to date. The COLD registry rep-resents clinical patterns in both the community and ac-ademic settings. As expected, the pre-SC ADT group hada higher baseline prostate cancer risk. To correct for thisdiscrepancy, each study group was further divided ac-cording to preradiation D’Amico risk, and subgroup an-alyses were conducted to compare ADT use vs no ADTuse before SC within each D’Amico risk group. Multi-variate analysis was carried out controlling for baselinecharacteristics that may influence bPFS.

The overall estimated 5-year bPFS of 39.3% and 63.8%for the pre-SC ADT and no ADT groups, respectively, wassimilar to rates reported in literature.6,9-11 Furthermore, thepresent study also corroborates with previous studiesshowing that presalvage Gleason score and PSA may be

UROLOGY - (-), 2015

related to SC success.10 When assessing the role played byADT before SC, the biggest difference in post-SC bPFSwas observed between the comparison groups with highD’Amico cancer risk. One possible explanation is that theadministration of ADT before salvage cryotherapy mayhave concealed a rising PSA level in those patients withmicrometastasis undetected by the metastatic radiographicworkup. Consequently, patients with systemic disease mayhave been unintentionally subjected to local salvagetherapy. With incidence of micrometastasis being thehighest among the high D’Amico cancer risk patients, thiseffect may have led to the large discrepancy in outcomesbetween those receiving pre-SC ADT vs those who hadnot. Furthermore, after controlling for other variablesinfluencing bPFS, preoperative ADT remained a statisti-cally significant predictor for biochemical recurrence forthe entire cohort consisting of patients with high, inter-mediate, and low D’Amico cancer risks. A possibleexplanation is that the initiation of salvage ADT beforeSC was prompted by the recognition of high-risk diseasefeatures by the treating physician. As such, these patientswith higher risk cancers ultimately had poor outcomesfrom local salvage therapy. These results confirm theimportance of careful patient selection to achieve disease-free survival after SC. Added caution should be exercisedwhen selecting for SC candidates among patients withhigh-risk cancer features and those who were started onadjuvant or salvage ADT. The possibility of maskeddistant micrometastases needs to be considered. Addi-tionally, our results corroborate the lack of benefit forneoadjuvant ADT in combination with cryotherapy.16

Overall, the low urinary fistula rates occurring in bothpre-SC ADT and no ADT groups testified to theimproved safety of the newer generations of cryotherapytechnology. The lower incidence of urinary retention andincontinence in patients receiving pre-SC ADT may berelated to the cytoreductive effect provided by neo-adjuvant ADT.25,26 The higher incidence of loss of po-tency is consistent with previous reports.27 However,these findings can only be regarded as hypothesis gener-ating in this study group as different proportions of pa-tients in each group were started back on ADT for diseaserecurrence. As salvage ADT may have been started before12 months, the differences seen in the rates of side effectsmay be affected by the use of salvage ADT.

The present study is limited by its retrospective nature.Additionally, as the data have been collected from anational registry, some information was not available.The modality, dose, and field size of the primary radiationtreatment was not recorded. However, as the technologyof radiation therapy continues to evolve rapidly, it wouldbe difficult to accumulate a large study population withrecurrent prostate cancer after undergoing a standard ra-diation protocol. The timing, duration, reason for startingADT, and the type of ADT used were also not collected.Although precedence of combining analysis of patientsundergoing different modalities of ADT exists in prostatecancer literature,21 the omission of the timing and

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duration of ADT certainly may cloud the analysis ofbPFS. However, ADT was uniformly terminated beforestarting salvage cryotherapy in the present study popula-tion. Follow-up periods after salvage cryotherapy wererelatively short in this cohort. However, as salvage cryo-therapy represents a relatively new treatment modality,long-term results remain scarce. Although the studypopulation represented a conglomerate of different pa-tient selection criteria, treatment techniques, and post-SC follow-up, it nonetheless represents clinical practicepatterns in both academic and community settings.

CONCLUSIONThe administration of ADT on recurrence of prostatecancer after primary radiation therapy and before defini-tive local salvage cryotherapy was associated with a worse5-year bPFS. This phenomenon was especially apparentin patients with high-risk prostate cancer. It seems ADTmay hamper proper patient selection and should be heldif the intention is to proceed to salvage cryotherapy.Additional studies are needed to define appropriate use ofADT in association with salvage cryotherapy.

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