Table 2.
Summary of additional studies comparing intermittent androgen deprivation therapy (IADT) with continuous androgen deprivation therapy (CADT).
| Study | Diagnosis | Study design | Treatment arms | Patients randomized, n | Regimen | PSA levels (ng/mL) (unless otherwise specified) |
Follow-up (month) | Primary endpoint | Time to progression or progression rate | Cancer-specific survival | OS | Adverse events/QoL | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cease treatment | Resume/treatment | ||||||||||||
| Hering.2000 [26] | Metastatic | Compare the efficacy | IADT | 25 | Induction only (10.5 months): CPA 200 mg/day orally | 0.4 | ≥10 (initial ≤20) ± 50% initial (initial >20) | 48 (median) | Time to progression and AEs | NR (IADT) vs. 20.1 months (CADT); NS |
2 (8%) deaths | NR | Hormone resistance, impotence; Better QoL with IADT vs.CADT |
| CADT | 18 | CPA 200 mg/day orally | 2 (11.1%) deaths HR = 0.70 (0.09–5.44) |
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| de Leval. 2002 [16] | Locally advanced, metastatic or recurrent; hormone-naïve | Phase 3, randomized | IADT | 35 | Induction only (3–6 months): flutamide 250 mg, 3 times daily for 15 days; followed by flutamide and goserelin acetate (3.6 mg/month) | ≤4 | ≥10 | 30.8 (mean) | Time to androgen independent prostate cancer | Time to progression or castration-resistant disease: 25.7 months (IADT) vs. 14.4 months (CADT); HR (95%) : 0.57 (0.07–4.64) Estimated 3-year progression rate: significantly lower in IADT (7%) vs. CADT (38.9%); p = 0.0052 |
2 (5.7%) deaths | NR | Hot flashes, loss of libido, and erectile dysfunction improved in men on IADT at least during off-treatment phase |
| CADT | 33 | Goserelin + flutamide (250 mg orally every 8 h) without interruption | 4 (12.1%) deaths HR = 0.46 (0.09–2.35) |
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| Schasfoort. 2003 [27] | Locally advanced or metastatic | NR | IADT | 193 | Buserelin + nilutamide | <4 | ≥20 (for metastatic); ≥10 (for locally advanced) | 25 (median) | Time to progression | 18 months | NA | Not reached while reporting | Hot flashes, erectile dysfunction, gynecomastia, liver dysfunction, and visual disturbance did not differ significantly between the groups |
| CADT | 24 months | ||||||||||||
| Miller. 2007 [28] | Locally advanced or metastatic | Compare the efficacy | IADT | 335 | Induction only (6 months): goserelin + bicalutamide | <4 or 90% initial level | NR | NR | Time to progression | 16.6 months | NR | 51.4 months | Sexual activity, pain, social functioning, emotional well-being, and vitality better with IADT; other AEs including cardiovascular events were similar |
| CADT | Goserelin + bicalutamide | 11.5 months; NS; HR (95%) : 0.69 (0.41–1.16) |
53.8 months; NS; HR (95%CI): 1.04 (0.86–1.28) |
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| Irani. 2008 [29] | Locally advanced or metastatic | Compare the efficacy | IADT | 67 | Induction only (6 months): goserelin 10.8 mg 3-month depot and flutamide 250 mg 3 times daily and resumed 6 months later | 6 months | 6 months | 60 (median) | Health related QoL, time to progression | HR (95%) : 1.1 (0.6–1.8) p = 0.3 favoring IADT | HR (95%) : 0.6 (0.2–1.6) p = 0.12 favoring CADT | HR (95%CI): 0.6 (0.3–1.3) p = 0.06 favoring CADT | No significant differences in QoL score between groups |
| CADT | 62 | Goserelin and flutamide 250 mg 3 times daily continued without interruption | |||||||||||
| Tunn. 2012 [30] | Recurrent (after prostatectomy) | Phase 3, randomized, prospective, non-inferiority | IADT | 109 | Induction only (6 months): goserelin 11.25 mg, 3-month depot, SC or IM + CPA 200 mg/day orally administered for the first 4 weeks to prevent tumor flare | ≤0.5 | ≥3 or when clinical progression was observed | 28 (median) | Androgen independent tumor progression | 976 days | NR | NR | NR |
| CADT | 92 | LHRHa | 986 days; NS |
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| Verhagen.2014 [31] | Asymptomatic metastatic | Open label, randomized | IADT | 131 | Induction only (3–6 months): CPA 100 mg 3 times daily | Good or moderate response | PSA or clinical progression | NR | Time to PSA progression | NS | NS | NS | Physical and emotional function significantly better with IADT (p < 0.05). No observed difference between IADT and CADT for role and social function. Cognitive function significantly reduced in IADT 87% to baseline, 69% (p < 0.05) |
| CADT | 127 | CPA 100 mg 3 times daily | |||||||||||
| Casas. 2016 [32] | Patients with biochemical failure after external beam radical radiotherapy | Non-inferiority, randomized, phase 3 | IADT | 38 | IADT (6 months) and CADT (36 months) |
NR | NR | 48 (median) | NR | No patient with risk of progression 3 with risk of progression | NR | NR | No significant differences in QoL score between groups |
| CADT | 39 | ||||||||||||
| Schulman. 2016 [33] | Non-metastatic relapsing or locally advanced | Phase 3, open-label, randomized | IADT | 340 | 6 months induction with leuprorelin acetate 22.5 mg 3-month depot; Patients were randomized with leuprorelin for 36 months | ≤1 | ≥2.5 | 18 | Time to PSA progression | Time to PSA progression: p = 0.718 NS Estimated 3 years PSA progression comparable between IADT (10.1%) and CADT (10.6%); NS |
NR | 42 deaths | QoL comparable between groups; Hot flushes, hypertension, constipation |
| CADT | 361 | 44 deaths p = 0.969; NS |
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| Tsai. 2017 [34] | Advanced | Compared tolerability | IADT CADT |
9772 | Patients were either treated with IADT or CADT | NR | NR | 54.6 (median) | AEs (serious toxicities) | NR | NR | NR | Lower risk of cardiovascular SAEs with IADT vs. CADT HR (95%CI): 0.64; (0.53–0.77); p < 0.0001 |
AE, adverse event; CADT, continuous androgen deprivation therapy; CI, confidence interval; CPA, cyproterone acetate; HR, hazard ratio; IADT, intermittent androgen deprivation therapy; IM, intra-muscular; ITT, intention to treat; LHRHa, luteinizing hormone releasing hormone agonist; NA, not applicable; NR, not reported; NS, non-significant; OS, overall survival; PSA, prostate-specific antigen; QoL, quality of life.