The FinnProstate Study VII: Intermittent Versus Continuous Androgen Deprivation in Patients With Advanced Prostate Cancer

The FinnProstate Study VII: Intermittent Versus Continuous Androgen Deprivation in Patients With Advanced Prostate Cancer Arto J. Salonen,*,† Kimmo Taari,‡ Martti Ala-Opas, Jouko Viitanen,§ Seppo Lundstedt,储 Teuvo L. J. Tammela¶ and the FinnProstate Group From the Department of Urology, Kuopio University Hospital, Kuopio (AJS); Helsinki University Hospital and University of Helsinki (KT), Helsinki University Hospital (MAO), Helsinki; Pohjois-Karjala Central Hospital, Joensuu (JV); Keski-Suomi Central Hospital, Jyväskylä (SL); and Tampere University Hospital and University of Tampere, Tampere (TLJT), Finland

Abbreviations and Acronyms ADT ⫽ androgen deprivation therapy CAD ⫽ continuous androgen deprivation IAD ⫽ intermittent androgen deprivation LHRHa ⫽ luteinizing hormonereleasing hormone analogue OS ⫽ overall survival PC ⫽ prostate cancer PCS ⫽ prostate cancer specific survival PFS ⫽ progression-free survival PSA ⫽ prostate specific antigen TF ⫽ treatment failure TOFF ⫽ treatment off period TON ⫽ treatment on period TTF ⫽ time to treatment failure

Purpose: We conducted a randomized trial to compare intermittent and continuous androgen deprivationin patients with advanced prostate cancer. We studied time to progression, overall and prostate cancer specific survival, and time to treatment failure. Materials and Methods: Between May 1997 and February 2003, 852 men with locally advanced or metastatic prostate cancer were enrolled to receive androgen deprivation therapy for 24 weeks. Patients in whom prostate specific antigen decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to intermittent or continuous androgen deprivation. In the intermittent therapy arm androgen deprivation therapy was withdrawn and resumed again for at least 24 weeks based mainly on prostate specific antigen decrease and increase. Results: There were 298 patients who did not meet the randomization criteria. The remaining 554 patients were randomized, with 274 (49.5%) to intermittent androgen deprivation and 280 (50.5%) to the continuous androgen deprivation arm. Median followup was 65.0 months. Of these patients 392 (71%) died, including 186 (68%) in the intermittent androgen deprivation arm and 206 (74%) in the continuous androgen deprivation arm (p ⫽ 0.12). There were 248 prostate cancer deaths, comprised of 117 (43%) in the intermittent androgen deprivation and 131 (47%) in the continuous androgen deprivation arm (p ⫽ 0.29). Median times from randomization to progression were 34.5 and 30.2 months in the intermittent androgen deprivation and continuous androgen deprivation arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. Conclusions: Intermittent androgen deprivation is a feasible, efficient and safe method to treat advanced prostate cancer compared with continuous androgen deprivation. Key Words: prostatic neoplasms, androgens, testosterone Submitted for publication October 23, 2011. Supported by AstraZeneca. Study received ethics committee approval. Clinical Trial Registration NCT00293670 (www.clinicaltrials.gov). * Correspondence: Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland (telephone: ⫹358-44-7172248; FAX: ⫹358-17-173749; e-mail: [email protected]). † Financial interest and/or other relationship with Astellas, AstraZeneca, Pfizer and UpViser. ‡ Financial interest and/or other relationship with GSK, Sanofi-Aventis, Pfizer and Astellas. § Financial interest and/or other relationship with Amgen. 储 Financial interest and/or other relationship with GSK, Astellas, Pfizer and Photocure. ¶ Financial interest and/or other relationship with Amgen, Ipsen, Pfizer and Medivation.

See Editorial on page 1956.

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www.jurology.com

0022-5347/12/1876-2074/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

AND

RESEARCH, INC.

Vol. 187, 2074-2081, June 2012 Printed in U.S.A. DOI:10.1016/j.juro.2012.01.122

ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

ANDROGEN deprivation therapy has been the standard treatment for advanced prostate cancer since the 1940s.1 Despite the initial response, many patients are likely to experience significant adverse effects.2,3 Although enthusiasm increases for intermittent androgen deprivation to optimize the ADT efficacy while minimizing adverse effects, only a few published randomized trials concern IAD in the treatment of prostate cancer as summarized in a review by Abrahamsson.4 The FinnProstate Study VII, a randomized multicenter trial, was planned to compare the efficacy of intermittent vs continuous androgen deprivation in the treatment of PC with time to progression as the primary end point. Secondary objectives were to compare the treatment arms in terms of overall survival, PC specific survival and time to treatment failure (ie withdrawal from the trial). Our interim analysis showed that patients with a high tumor burden, high PSA or widely metastasized disease failed to show an adequate biochemical PSA response to ADT, and were not candidates for IAD5 in accordance with others’ findings.6 – 8 Concerning IAD the 2 essential questions addressed by the FinnProstate Study VII are 1) does IAD delay the onset of hormone resistance? and 2) can IAD improve overall survival?9

MATERIALS AND METHODS The FinnProstate Study VII was conducted as an open label, randomized, controlled parallel group multicenter clinical trial at 27 clinics in Finland comparing intermittent vs continuous androgen deprivation in patients with histologically confirmed, locally advanced or metastatic PC (Appendix 1). Study inclusion criteria were M1 disease at any PSA, M0 disease at PSA 60 ng/ml or greater, or T3-4M0 prostate cancer at PSA 20 ng/ml or greater, or previously surgically or radiotherapy treated localized prostate cancer and PSA recurrence of 20 ng/ml or greater; no previous hormonal or medical treatment for PC; and performance status 0 –2 with a life expectancy of at least 12 months. Ethics committees in each center approved the trial protocol and amendments. All patients gave written informed consent. The study is registered with ClinicalTrials.gov, identifier NCT00293670. The study was originally designed to enroll patients with metastatic PC. However, to increase recruitment, the inclusion criteria were widened in June 1998 to include patients with locally advanced or recurrent PC without metastases. With this more heterogeneous patient population, the primary analysis was meant to be completed 14 months later than the specified 36 months. Median time to progression (the primary objective) was estimated as 20.5 months, with a total of 600 patients (300:300) required to detect a hazard ratio of 1.345 with 90% power for CAD vs IAD. The final study visit was in January 2010. All patients recruited received the LHRHa goserelin acetate (3.6 mg) subcutaneously every 28 days for 24

2075

weeks (run in) before randomization. The antiandrogen cyproterone acetate was given in 100 mg twice daily during the first 12.5 days to minimize flare reaction. Patients in whom PSA decreased to less than 10.0 ng/ml or at least by 50% (baseline PSA less than 20.0 ng/ml) were randomized to IAD or CAD at a 1:1 ratio by using the rand function of Excel®. In the CAD arm patients continued with goserelin acetate or underwent bilateral orchiectomy. In the IAD arm LHRHa was withheld after randomization and was resumed, including flare protection with cyproterone acetate, for at least 24 weeks whenever PSA increased more than 20.0 ng/ml or above the baseline value, and was withheld again by the same criteria as for randomization. LHRHa was continued if PSA did not decrease to less than 10.0 ng/ml or decreased less than 50% of baseline. From the randomization forward, the treatment cycle (duration in weeks) was defined as time off treatment plus time on treatment. Time to progression, treatment failure and death were calculated from the date of randomization. The patient was withdrawn from the trial if any criterion for TF was fulfilled. The criteria for TF and disease progression are listed in Appendix 2. Any progression criterion met during TOFF was considered real progression if initiation of ADT failed to relieve the symptoms. After withdrawal, patients were treated according to investigator’s decision (eg maximal ADT, chemotherapy etc). Thereafter, patients were followed every 12 weeks until progression and every 24 weeks until death. Student’s t test, the median test or the chi-square test was used in comparing patient characteristics between treatment arms. PFS, OS and PCS were analyzed using a univariate unadjusted Cox model, and graphically displayed by the Kaplan-Meier method. The hazard ratios were estimated together with the associated 95% CI and p value. Statistical tests were 2-sided at a 5% significance level.

RESULTS Between May 1997 and February 2003, 852 patients were prospectively enrolled to receive ADT. After the run in period 298 (35%) patients failed to meet the randomization criteria and were excluded from study. The remaining 554 (65%) patients were randomized as 274 (49.5%) to the IAD and 280 (50.5%) to the CAD arm. No patients with recurrent PC after prostatectomy or radiotherapy were enrolled in the study. Median followup from randomization was 65.0 months (maximum 11.6 years). No patients were lost to followup. There were 110 patients who continued for more than 5 years in the trial before TF, including 52 (19.0%) in the IAD and 58 (20.7%) in the CAD arm (p ⫽ 0.50). Mean patient age was 71.5 years, with no difference in distribution of patients by age group (younger than 50, 50 to 59, 60 to 69, 70 to 79, 80 years or older). Treatment arms were comparable in terms of advancement of PC, differentiation grade, performance status, concurrent diseases and PSA (table 1). Of these randomized patients 79% achieved a PSA nadir of 4 ng/ml or less. One patient refused the randomized IAD.

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ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

Table 1. Patient characteristics at entry and at randomization in intermittent and continuous treatment arms Intermittent No. pt age (%): Younger than 70 70 or Older No. M category (%): M0 M1 No. TM category (%): T1-2M0 T1-2M1 T3M0 T3M1 T4M0 T4M1 No. WHO grade (%): GI GII GIII No. Gleason score (%):† 6 or Less 3⫹4 4⫹3 8–10 Totals PSA (ng/ml) at baseline: Mean (SD) Median 95% CI PSA (ng/ml) at 6 mos (randomization): Mean (SD) Median 95% CI Testosterone (nmol/l) at baseline: Mean (SD) (No. pts) Median 95% CI Testosterone (nmol/l) at 6 mos Mean (SD) (No. pts) Median 95% CI Alkaline phosphatase (IU/l): Mean (SD) (No. pts) Median 95% CI

Continuous

Overall

p Value

102 172

(37.2) (62.8)

102 178

(36.4) (63.6)

204 350

(36.8) (63.2)

0.85*

140 134

(51.1) (48.9)

137 143

(48.9) (51.1)

277 277

(50.0) (50.0)

0.61*

7 20 101 81 32 33

(2.5) (7.3) (36.9) (29.6) (11.7) (12.0)

12 28 99 73 26 42

(4.3) (10.0) (35.3) (26.1) (9.3) (15.0)

19 48 200 154 58 75

(3.4) (8.7) (36.1) (27.8) (10.5) (13.5)

0.22* 0.31 0.71 0.36 0.43 0.37

32 175 67

(11.7) (63.9) (24.5)

43 164 73

(15.4) (58.6) (26.1)

75 339 140

(13.5) (61.2) (25.3)

0.34*

13 32 57 142 244

(5.3) (13.1) (23.4) (58.2) (100.0)

15 33 55 144 247

(6.1) (13.4) (22.3) (58.3) (100.0)

28 (5.7) 65 (13.2) 112 (22.8) 286 (58.2) 491 (100.0)

0.98*

151.5 67.6

0.31‡

116.0 (173.4) 64.0 95.29–136.61

186.3 (454.4) 70.3 132.75–239.85

2.37 (2.43) 1.40 2.08–2.66

2.45 (2.48) 1.60 2.16–2.74

15.25 (5.87) (261) 14.58 14.53–15.97

14.94 (6.30) (267) 14.30 14.18–15.70

0.84 (0.44) (261) 0.80 0.79–0.90

1.05 (2.18) (267) 0.78 (0.79–1.32)

256.1 (354.9) (268) 176.5 213.38–298.90

297.9 (443.1) (277) 171.0 245.38–350.39

0.71§

15.1 (528) 14.5

0.56§

0.27‡

277 173

(545) 0.22§

* Chi-square test. † Defined by 2 pathologists for 491 patients. ‡ Median test. § T test.

In the IAD arm the median number of cycles was 3 (range 0 to 14) with 1 patient reaching cycle 14. TOFF duration decreased from cycle to cycle (table 2). Plasma testosterone recovered at the end of each TOFF but without reaching its level at the end of the previous TOFF. Thus, mean and median testosterone at the end of TOFFs decreased from cycle to cycle. At study entry 81.2% of patients in the IAD arm had testosterone 10 nmol/l or greater, which decreased to 47.4% in 19 patients at the end of TOFF 10 (table 3). A total of 488 patients (88.1%) were withdrawn from the trial. For 372 patients the study withdrawal was due to death or progression, including

177 (64.6%) in the IAD and 195 (69.6%) in the CAD arm (p ⫽ 0.76, table 4). At the end of the study 392 patients (71%) had died, namely 186 (68%) in the IAD and 206 (74%) in the CAD arm (p ⫽ 0.12). There were 248 (45%) PC deaths (63% of all deaths), with 117 (43%) in the IAD and 131 (47%) in the CAD arm (p ⫽ 0.29). Among patients with end points, median time from randomization to progression in the IAD and CAD arms was 34.5 and 30.2 months, to death (all cause) 45.2 and 45.7 months, to PC death 45.2 and 44.3 months, and to TF 29.9 and 30.5 months, respectively. Although no statistically significant differences appeared between the treatment arms in

ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

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Table 2. Intermittent arm patient and cycle data Mean ⫾ SD Wks (range)/Median Cycle No.

No. Pts (%)

TOFF Duration

TON Duration

Overall Cycle Duration

1 2 3 4 5 6 7 8 9 10 11 12 13 14

273 (99.6)* 206 (75.2) 156 (56.9) 124 (45.3) 94 (34.3) 72 (26.3) 61 (22.3) 45 (16.4) 28 (10.2) 21 (7.7) 15 (5.5) 7 (2.6) 3 (1.1) 1 (0.4)

33.5 ⫾ 41.4 (3.9–312.0)/23.6 25.9 ⫾ 20.7 (3.6–150.9)/21.6 24.2 ⫾ 21.8 (1.0–188.3)/20.1 20.5 ⫾ 13.7 (0.9–95.7)/17.4 19.0 ⫾ 9.0 (1.3–54.0)/18.0 18.0 ⫾ 9.4 (1.3–51.1)/14.5 18.4 ⫾ 9.9 (8.1–63.4)/14.4 16.6 ⫾ 11.6 (1.4–63.9)/13.1 14.6 ⫾ 6.4 (8.0–37.3)/12.0 14.7 ⫾ 5.8 (4.0–28.4)/14.0 13.2 ⫾ 4.1 (9.3–23.3)/11.9 10.0 ⫾ 4.6 (4.0–16.7)/11.1 10.9 ⫾ 3.9 (6.6–14.1)/12.0 13.0 (13.0)/13.0

24.8 ⫾ 10.5 (0.6–106.4)/24.0 27.4 ⫾ 16.3 (1.4–186.9)/24.3 27.3 ⫾ 12.5 (2.7–125.4)/24.4 26.4 ⫾ 14.6 (1.0–142.0)/24.0 30.3 ⫾ 14.3 (13.0–119.0)/24.4 28.0 ⫾ 14.5 (12.0–113.3)/24.1 30.7 ⫾ 17.9 (4.0–108.1)/24.6 25.9 ⫾ 9.4 (8.1–57.0)/24.0 26.7 ⫾ 13.4 (2.7–71.9)/24.0 21.2 ⫾ 6.3 (8.0–28.1)/24.0 29.2 ⫾ 14.7 (10.9–61.4)/24.5 23.8 ⫾ 1.4 (21.9–25.3)/24.1 21.8 ⫾ 3.1 (19.6–24.0)/21.8 10.0 (10.0)/10.0

58.6 ⫾ 42.9 (12.4–338.3)/48.4 52.4 ⫾ 23.6 (21.4–215.1)/47.6 49.5 ⫾ 16.2 (21.0–131.4)/47.1 46.7 ⫾ 17.2 (11.4–152.3)/44.0 49.1 ⫾ 15.9 (24.6–131.0)/46.1 45.5 ⫾ 15.3 (23.4–127.0)/42.2 49.4 ⫾ 19.7 (28.3–133.7)/43.0 42.4 ⫾ 13.2 (16.0–84.6)/38.6 41.4 ⫾ 18.1 (12.0–105.3)/38.3 35.9 ⫾ 8.1 (12.0–45.4)/36.7 43.3 ⫾ 14.8 (24.0–75.9)/38.6 37.1 ⫾ 3.3 (35.1–42.0)/35.6 34.9 ⫾ 1.6 (33.7–36.0)/34.9 23.0 (23.0)/23.0

* One patient refused the intermittent treatment mode.

PFS, OS, PCS or TTF, the risk analysis showed a hazard ratio of 1.08 –1.17 for the CAD arm (fig. 1, table 5). PSA at randomization (PSA less than 1.0, 1.0 to 4.0, greater than 4.0 ng/ml) was associated with PFS (p ⫽ 0.002), PCS (p ⫽ 0.006) and TTF (p ⬍0.001) but not with OS (p ⫽ 0.290) in the study population (fig. 2). Differentiation grade by Gleason scores also had an impact on PFS, OS, PCS and TTF (p ⬍0.001, fig. 3).

DISCUSSION We could not show any significant delay in the onset of hormone resistance or improvement in overall survival. In addition, no significant differences emerged in PCS or TTF between the treatment arms. Thus, IAD was not superior to CAD. Reviewing more than 1,000 patients in 4 randomized phase 3 trials, Seruga and Tannock concluded that compelling data indicate that IAD should be

considered standard therapy for PC based on time to disease progression, survival and quality of life.10 Early clinical trials concerning the efficacy and safety of IAD in the treatment of PC had heterogeneous patient populations and proposed treatment guidelines.4,11,12 Duration of the initial TON ranged from 3 to 12 months, but is commonly 6 to 9 months. The most often used PSA cutoff for ADT withdrawal is 4 ng/ml and for resumption 10 to 20 ng/ml. However, little evidence exists concerning the best limits. The PSA response for induction ADT is essential to determine patient eligibility for IAD. Gleave et al stated that androgen ablation should be continued until maximal castration induced apoptosis and tumor regression are induced, but halted before constitutive development of the androgen independent phenotype.13 Grossfeld et al reported the first nadir PSA was achieved within an average of 6 months,14

Table 3. The number of patients on IAD reaching each quartile of testosterone at TOFF end Testosterone (nmol/l) No. baseline (%) No. TOFF No. (%): 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Less than 1.5

1.5–6.99

7.0–9.99

10 or Greater

Sum

1 (0.4)

16 (6.1)

32 (12.3)

212 (81.2)

261 (100)

9 (3.5) 5 (2.7) 3 (2.1) 0 (0.0) 1 (1.2) 0 (0.0) 2 (3.4) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (33.3) 0 (0.0)

20 (7.7) 16 (8.7) 17 (11.6) 22 (20.2) 17 (20.0) 15 (23.1) 14 (23.7) 12 (29.3) 6 (22.2) 5 (26.3) 5 (33.3) 3 (50.0) 0 (0.0) 0 (0.0)

33 (12.7) 25 (13.6) 28 (19.2) 16 (14.7) 17 (20.0) 12 (18.5) 11 (18.6) 4 (9.8) 9 (33.3) 5 (26.3) 2 (13.3) 3 (50.0) 0 (0.0) 0 (0.0)

197 (76.1) 138 (75.0) 98 (67.1) 71 (65.1) 50 (58.8) 38 (58.5) 32 (54.2) 24 (58.5) 12 (44.4) 9 (47.4) 8 (53.3) 0 (0) 2 (66.7) 1 (100)

259 (100) 184 (100) 146 (100) 109 (100) 85 (100) 65 (100) 59 (100) 41 (100) 27 (100) 19 (100) 15 (100) 6 (100) 3 (100) 1 (100)

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ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

Table 4. Reasons for and prevalence of treatment failures

Death Disease progression Pt did not fulfill eligibility criteria for randomized period of study Adverse drug reaction/serious adverse event Protocol noncompliance Other reason Totals

No. IAD (%)

No. CAD (%)

No. Totals (%)

% (of 488 events)

35 (12.8) 142 (51.8) 1 (0.4) 7 (2.6) 44 (16.1) 6 (2.2)

41 (14.6) 154 (55.0) 0 (0) 10 (3.6) 40 (14.3) 8 (2.9)

76 (13.7) 296 (53.4) 1 (0.2) 17 (3.1) 84 (15.2) 14 (2.5)

15.6 60.6 0.2 3.5 17.2 2.9

235 (85.8)

253 (90.4)

488 (88.1)

100

Chi-square test p ⫽ 0.81.

while Albrecht et al reported a median of 19 weeks.6 We chose an initial TON of 24 weeks, a PSA cutoff for withdrawal of ADT of less than 10 ng/ml, and for resumption greater than 20.0 ng/ml or above baseline. PSA at randomization was associated with prognosis in accordance with results of SEUG trial 940115 and Hussain et al.16 The SEUG trial 9401 used maximal androgen blockade for only 3 months before randomization or withdrawal of ADT with a PSA cutoff of less than 4 ng/ml, and for resumption a PSA cutoff of 10 ng/ml or greater, or 20 ng/ml or greater depending on symptomatic status. Gleason score and metastatic status were predictors of PSA response at randomization, and

metastatic status and PSA at randomization were predictors of progression and PC death. No difference in OS between the treatment arms was demonstrable, but a slightly higher risk of progression and cancer death emerged in the IAD arm.15 Accordingly in a nonrandomized trial of 566 patients on IAD Prapotnich et al demonstrated that age, Gleason score and initial PSA were significant prognostic factors.17 In the present trial Gleason score (7 or less vs 8 –10) had a significant impact on PFS, PCS and OS, as well as on TTF. There were no statistical differences in PFS, PCS, OS or TTF between the treatment arms, but risk analysis showed a mild advantage for IAD.

Progression-free survival

Death (all-cause) survival

1,0

1,0

Treatment

0,6

0,4

Intermittent Continuous

0,8

Cum Survival

Cum Survival

Treatment

Intermittent Continuous

0,8

0,2

0,6

0,4

0,2

0,0

0,0 0,0

25,0

50,0

75,0

100,0

125,0

0,0

25,0

50,0

Months

75,0

100,0

125,0

Months

Death (prostate cancer) survival

Treatment failure survival

1,0

1,0

Treatment

0,6

0,4

0,2

Intermittent Continuous

0,8

Cum Survival

Cum Survival

Treatment

Intermittent Continuous

0,8

0,6

0,4

0,2

0,0

0,0 0,0

25,0

50,0

75,0

Months

100,0

125,0

0,0

25,0

50,0

75,0

100,0

125,0

Months

Figure 1. Kaplan-Meier curves for PFS, OS, PCS and TF survival in intermittent and continuous treatment arms. Cum, cumulative.

ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

Table 5. Risk analysis using univariate unadjusted Cox regression model

Progression: IAD CAD Death (all cause): IAD CAD Prostate Ca death: IAD CAD Treatment failure: IAD CAD

HR

95% CI

p Value

1 1.08

0.90–1.29

0.43

1 1.15

0.94–1.40

0.17

1 1.17

0.91–1.51

0.21

1 1.13

0.95–1.35

0.17

Our median followup was 65 months with no patients lost to followup, and 1 reaching cycle 14 with 11.6 years of followup. In the SEUG trial 9401 followup was up to 12 years (median 51 months).15 Of the patients on IAD 50% were off therapy for at least 52 weeks after randomization and 29% were off therapy for more than 36 months. de Leval et al reported results up to cycle 8 with mean time off therapy from 3.3 to 8.3 months.18 The length and percentage of time spent off therapy decreased by a mean of 20 days (0.9%) with each consecutive cycle. Prapotnich et al reported their 16-year clinical experience with a median followup of 81 months and with 1 patient reaching cycle 12, with a mean of 14 months off therapy. Our mean TOFF was 33.5

p = 0.002

0,8

0,6

< 1.0 1.0 - 4.0 > 4.0 < 1.0-censored 1.0 - 4.0-censored > 4.0-censored

0,4

0,2

PSA

1,0

0,6

0,4

0,2

0,0

0,0 0,0

25,0

50,0

75,0

100,0

125,0

0,0

PSA

p = 0.006

0,6

0,4

0,2

< 1.0 1.0 - 4.0 > 4.0 < 1.0-censored 1.0 - 4.0-censored > 4.0-censored

50,0

75,0

100,0

125,0

PSA

1,0

p < 0.001

0,8

Cum Survival

1,0

0,8

25,0

Death (all-cause) survival

Progression-free survival

Cum Survival

< 1.0 1.0 - 4.0 > 4.0 < 1.0-censored 1.0 - 4.0-censored > 4.0-censored

p = 0.290

0,8

Cum Survival

Cum Survival

weeks (57% of cycle duration) in cycle 1 but decreased to 10.0 weeks (27%) in cycle 12. Our shorter TOFF was probably due to our higher accepted PSA cutoff of less than 10 ng/ml. A short TOFF seems to predict disease progression early in the future. Testosterone recovery is an important issue involving IAD. The recovery rate has been considered to be dependent on ADT duration, baseline testosterone before ADT and patient age.19 –21 In theory, time off therapy should be sufficiently long to permit the recovery of testosterone necessary for testosterone induced tumor cell differentiation to delay hormone resistance, reduce side effects, and recover sexual function and a normal sense of well-being.13 In a randomized trial with 67 patients receiving maximal androgen blockade intermittently for 6 months a year, Irani et al showed that a predetermined TOFF of 6 months was not sufficiently long to achieve normal testosterone values or to imply any difference in quality of life between the IAD and CAD arms.22 Our study measured testosterone systematically every 3 months, and summarized it at the end of each TOFF and TON. Testosterone recovery was clearly evident during TOFF, but the percentage of patients reaching 10 nmol/l or greater decreased with time. This demonstrates that IAD results in impaired testicular function in the long term, or testosterone recovers more slowly than PSA increases to the cutoff for the resumption of ADT. Changes in PSA, decreasing

PSA

1,0

2079

0,6

< 1.0 1.0 - 4.0 > 4.0 < 1.0-censored 1.0 - 4.0-censored > 4.0-censored

0,4

0,2

0,0

0,0 0,0

25,0

50,0

75,0

100,0

Death (prostate cancer) survival

125,0

0,0

25,0

50,0

75,0

100,0

125,0

Treatment failure survival

Figure 2. Kaplan-Meier curves for PFS, OS, PCS and TF survival by PSA at randomization in trial population. PSA less than 1.0 (206), 1.0 to 4.0 (229), greater than 4.0 ng/ml (118) with p values for log rank tests. Of 553 patients 1 refused intermittent trial therapy. Cum, cumulative.

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ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

Gleason 6-7 8-10 6-7-censored 8-10-censored

Cum Survival

0,8

0,6

0,4

0,2

6-7 8-10 6-7-censored 8-10-censored

0,8

0,6

0,4

0,2

0,0

0,0 0,0

25,0

50,0

75,0

100,0

125,0

0,0

Progression-free survival

25,0

50,0

75,0

100,0

125,0

Death (all-cause) survival

Gleason 6-7 8-10 6-7-censored 8-10-censored

0,8

0,6

0,4

0,2

Gleason

1,0

Cum Survival

1,0

Cum Survival

Gleason

1,0

Cum Survival

1,0

6-7 8-10 6-7-censored 8-10-censored

0,8

0,6

0,4

0,2

0,0

0,0 0,0

25,0

50,0

75,0

100,0

125,0

Death (prostate cancer) survival

0,0

25,0

50,0

75,0

100,0

125,0

Treatment failure survival

Figure 3. Kaplan-Meier curves for PFS, OS, PCS and TF survival by differentiation grade of Gleason scores 6–7 (205) and 8–10 (286). Log rank p ⬍0.001. Cum, cumulative.

during TON and increasing during TOFF, were associated with changes in testosterone. This finding is in accordance with that of Keizman et al, who demonstrated that the PSA doubling time after ADT withdrawal was associated with testosterone recovery.23 IAD offers economic benefit with the reduction of pharmaceutical costs during TOFF. However, patients on IAD need more careful followup during TOFF, which means extra costs to the health care system.

CONCLUSIONS Results of the FinnProstate Study VII showed that IAD is feasible, efficient and safe in the treatment of

locally advanced or even metastatic PC. IAD does not carry a higher risk of death than CAD and should be regarded as standard therapy for PC. However, patients with the most advanced and the most aggressive prostate cancer with a high pretreatment PSA do not show an adequate biochemical PSA response to androgen deprivation therapy, and are not candidates for IAD.

ACKNOWLEDGMENTS Jyrki Ollikainen and Hanna L. Koskinen from Tampere University performed the statistical analysis. Pathologists Stig Nordling and Anna Sankila defined Gleason scores for 491 patients.

APPENDIX 1 The FinnProstate Group and Trial Centers Etelä-Karjala Central Hospital, Lappeenranta: Jaakko Permi, Veli-Matti Puolakka; Etelä-Pohjanmaa Central Hospital, Seinäjoki: Mikael Leppilahti, Markku Leskinen, Timo Marttila; Etelä-Savo Central Hospital, Mikkeli: Niilo Hendolin, Tapani Liukkonen; Hatanpää Hospital, Tampere: Jukka Häkkinen; Helsinki University Hospital: Martti AlaOpas, Jussi Aro, Eero Kaasinen, Kari Lampisjärvi, Ilkka Perttilä, Erkki Rintala, Mirja Ruutu, Kimmo Taari; Kainuu Central Hospital, Kajaani: Pentti Kemppainen; KeskiPohjanmaa Central Hospital, Kokkola: Pekka Pellinen; Keski-Suomi Central Hospital, Jyväskylä: Susanna Laaksovirta, Seppo Lundstedt; Kuopio University Hospital: Sirpa Aaltomaa, Antero Heino, Arto Salonen; Kuusankoski District Hospital: Markku Multanen, Markku Onali; Lappi Central Hospital, Rovaniemi: Patrik Ehnström, Risto Kauppinen, Matti Rauvala; Länsi-Pohja Central Hospital, Kemi: Juhani Ottelin; Oulu University Hospital: Pekka Hellström, Jani Kuisma, Olavi Lukkarinen, Aare Mehik, Erkki Ollikkala, Ilkka Paananen, Teija Parpala-Spårman, Panu Tonttila; Pietarsaari District Hospital: Christian Palmberg; Pohjois-Karjala Central Hospital, Joensuu: Jouko Viitanen; Päijät-Häme Central Hospital, Lahti: Kalmer Innos, Taina Isotalo, Kari Lehtoranta, Martti Talja; Satakunta Central Hospital, Pori: Heikki Korhonen, Pekka Salminen; Savonlinna Central Hospital: Raino Terho; Tampere University Hospital: Martti Aho, Juha Koskimäki, Timo Kylmälä, Mika Matikainen, Teuvo Tammela; Turku University Hospital: Kimmo Kuusisto, Matti Laato, Martti Nurmi; Vaasa Central Hospital: Erkki Hansson, Susanna Hirsimäki, Peter Nylund; Valkeakoski District Hospital: Rauno Kulmala; ähtäri District Hospital: Juha Ervasti.

ANDROGEN DEPRIVATION FOR ADVANCED PROSTATE CANCER

2081

APPENDIX 2 Treatment failure and progression criteria Treatment failure

Progression

death; adverse drug reaction requiring cessation of the randomized treatment; cancer progression; patient unwilling or unable to continue according to the protocol; patient refused the randomized treatment; administration of any additional systemic therapy or radiotherapy for prostate cancer, patient lost to followup; investigator’s decision in the patient’s best interest to stop the randomized therapy appearance of any new or worsening of existing bone metastases; increase in dimensions (by 25% or more) of any existing or appearance of any new extraskeletal metastases; ureteral obstruction either by primary tumor or pelvic nodal disease; lymphedema of lower extremities due to pelvic nodal involvement; recurrent vesical obstruction, bleeding (macroscopic hematuria) or pain due to growth of primary tumor; PSA greater than 100 ng/ml or PSA progressively elevated in 2 successive 12 weekly measurements during endocrine treatment (PSA should be greater than 20 ng/ml for patients with baseline PSA 20 ng/ml or greater, or PSA greater than visit 1 with baseline PSA less than 20 ng/ml); death before evidence of objective progression

REFERENCES 1. Huggins C and Hodges CV: Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293. 2. Schwandt A and Garcia JA: Complications of androgen deprivation therapy in prostate cancer. Curr Opin Urol 2009; 19: 322. 3. Taylor LG, Canfield SE and Du XL: Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 2009; 115: 2388. 4. Abrahamsson PA: Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur Urol 2010; 57: 49. 5. Salonen AJ, Viitanen J, Lundstedt S et al: Finnish multicenter study comparing intermittent to continuous androgen deprivation for advanced prostate cancer: interim analysis of prognostic markers affecting initial response to androgen deprivation. J Urol 2008; 180: 915. 6. Albrecht W, Collette L, Fava C et al: Intermittent maximal androgen blockade in patients with metastatic prostate cancer: an EORTC feasibility study. Eur Urol 2003; 44: 505. 7. Prapotnich D, Fizazi K, Escudier B et al: A 10-year clinical experience with intermittent hormonal therapy for prostate cancer. Eur Urol 2003; 43: 233. 8. Studer UE, Collette L, Whelan P et al: Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol 2008; 53: 941.

9. Rambeaud J: Intermittent complete androgen blockade in metastatic prostate cancer. Eur Urol 1999; 35: 32. 10. Seruga B and Tannock IF: Intermittent androgen blockade should be regarded as standard therapy in prostate cancer. Nat Clin Pract Oncol 2008; 5: 574. 11. Boccon-Gibod L, Hammerer P, Madersbacher S et al: The role of intermittent androgen deprivation in prostate cancer. BJU Int 2007; 100: 738. 12. Shore ND and Crawford ED: Intermittent androgen deprivation therapy: redefining the standard of care? Rev Urol 2010; 12: 1. 13. Gleave M, Goldenberg SL, Bruchovsky N et al: Intermittent androgen suppression for prostate cancer: rationale and clinical experience. Prostate Cancer Prostatic Dis 1998; 1: 289. 14. Grossfeld GD, Small EJ, Lubeck DP et al: Androgen deprivation therapy for patients with clinically localized (stages T1 to T3) prostate cancer and for patients with biochemical recurrence after radical prostatectomy. Urology 2001; 58: 56.

17. Prapotnich D, Cathelineau X, Rozet F et al: A 16-year clinical experience with intermittent androgen deprivation for prostate cancer: oncological results. World J Urol 2009; 27: 627. 18. de Leval J, Boca P, Yousef E et al: Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormonenaive prostate cancer: results of a prospective randomized multicenter trial. Clin Prostate Cancer 2002; 1: 163. 19. Nejat RJ, Rashid HH, Bagiella E et al: A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J Urol 2000; 164: 1891. 20. Gulley JL, Figg WD, Steinberg SM et al: A prospective analysis of the time to normalization of serum androgens following 6 months of androgen deprivation therapy in patients on a randomized phase III clinical trial using limited hormonal therapy. J Urol 2005; 173: 1567. 21. Spry NA, Kristjanson L, Hooton B et al: Adverse effects to quality of life arising from treatment can recover with intermittent androgen suppression in men with prostate cancer. Eur J Cancer 2006; 42: 1083.

15. Calais da Silva FE, Bono AV, Whelan P et al: Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 2009; 55: 1269.

22. Irani J, Celhay O, Hubert J et al: Continuous versus six months a year maximal androgen blockade in the management of prostate cancer: a randomised study. Eur Urol 2008; 54: 382.

16. Hussain M, Tangen CM, Higano C et al: Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT0162). J Clin Oncol 2006; 24: 3984.

23. Keizman D, Huang P, Antonarakis ES et al: The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation. Prostate 2011; 71: 1608.