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. 2017 Dec 26;2017(12):CD006250. doi: 10.1002/14651858.CD006250.pub2

ZAPCA.

Methods Recruitment period:

  • May 2008 to December 2010.


End points:

  • overall survival, SREs, disease progression, adverse events.


Pain assessment tool:

  • not reported.


Randomization:

  • intervention vs control.
Participants Eligibility criteria:

  • men age ≥ 20 years;

  • histopathologically or cytologically confirmed prostate cancer;

  • bone metastasis on bone scan;

  • sensitivity to androgen blockade therapy;

  • ECOG performance status ≤ 2;

  • PSA level ≥ 30 ng/mL;

  • leukocyte count ≥ 3000/µL;

  • Hb ≥ 9.0 g/dL;

  • platelet count 7.5 × 104/µL;

  • serum creatinine level ≤ 3.0 mg/dL;

  • corrected serum calcium ≥ 8.5 mg/dL and ≤ 11.5 mg/dL;

  • total bilirubin ≤ 1.8 mg/dL;

  • AST level ≤ 90 IU/L;

  • ALT level ≤ 100 IU/L.


Exclusion criteria:

  • poorly controlled dental caries;

  • poorly controlled hypertension or cardiovascular disease;

  • double cancer requiring treatment;

  • systematical use of steroid drugs;

  • active HIV or hepatitis virus infections;

  • prior androgen blockade therapy;

  • prior or concurrent other anticancer therapy;

  • prior or concurrent immunologic adjuvant therapy;

  • prior or concurrent use of bisphosphonates (excluding zoledronic acid);

  • prior systemic chemotherapy.


Participants randomized:

  • 227, 115 intervention, 112 control.


Median age:

  • 72.0 years, 73.0 years intervention, 71.5 years control.


Country of participants:

  • Japan.
Interventions Previous interventions:

  • all participants were treatment‐naive.


Interventions during study period:

  • intervention: zoledronic acid 4 mg IV every 4 weeks from study entry and androgen blockade therapy with LHRH analogue + bicalutamide for 2 years;

  • control: androgen blockade therapy with LHRH analogue + bicalutamide for 2 years.
Outcomes Reported and analyzed in this review:

  • none.
Funding sources Funding sources:

  • "The ZAPCA trial was supported by Grant for Urologic Research No. 200040700148 from Kyoto University Hospital."
Declarations of interest Conflicts of interest:

  • Tomomi Kamba: honorarium from Astellas Pharma;

  • Toshiyuki Kamoto: research funding and honoraria from Astellas Pharma;

  • Fuminori Sato: research funding from Janssen Pharmaceutical and Astellas Pharma;

  • Naoya Masumori: honoraria from Novartis Pharma and Daiichi Sankyo, and research funding from Daiichi Sankyo;

  • Shin Egawa: research funding from Astellas Pharma and Takeda Pharmaceutical;

  • Hideki Sakai: research funding from Astellas Pharma and Takeda Pharmaceutical, and honoraria from Astellas Pharma and AstraZeneca;

  • Osamu Ogawa: honorarium from Astellas Pharma.
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote: "Computer‐based randomization was conducted at the Translational Research Informatics Center (TRI; Kobe, Japan) with stratification according to the treatment institution, baseline PSA concentration (<200 or ≥200 ng/mL), baseline extent of disease (EOD) grade [13] (≤2 or ≥3), and biopsy Gleason score (≤7 or ≥8). [...] The system automatically evaluated the eligibility of each patient and randomly assigned participants to each group."
Allocation concealment (selection bias) Low risk Quote: "Computer‐based randomization was conducted at the Translational Research Informatics Center (TRI; Kobe, Japan) with stratification according to the treatment institution, baseline PSA concentration (<200 or ≥200 ng/mL), baseline extent of disease (EOD) grade [13] (≤2 or ≥3), and biopsy Gleason score (≤7 or ≥8). [...] The system automatically evaluated the eligibility of each patient and randomly assigned participants to each group."
Blinding of participants and personnel (performance bias) 
 All outcomes High risk Open‐label trial.
Blinding of outcome assessment (detection bias) 
 Objective outcomes Unclear risk Insufficient information on blinding of outcome assessor.
Blinding of outcome assessment (detection bias) 
 Subjective outcomes High risk Open‐label trial.
Incomplete outcome data (attrition bias) Low risk Quote: "All 224 patients who received at least one dose of LH–RH agonist were included in the Safety Assessment Set (SAS)."
Selective reporting (reporting bias) High risk Study investigators initially planned to analyze QoL and pain as outcomes, but the authors did not provide any data on these end points in their publications.
Other bias Unclear risk Quote: "The ZAPCA trial was supported by Grant for Urologic Research No. 200040700148 from Kyoto University Hospital. [...] Tomomi Kamba accepted an honorarium from Astellas Pharma. Toshiyuki Kamoto accepted research funding and honoraria from Astellas Pharma. Fuminori Sato accepted research funding from Janssen Pharmaceutical and Astellas Pharma. Naoya Masumori accepted honoraria from Novartis Pharma and Daiichi Sankyo, and research funding from Daiichi Sankyo. Shin Egawa accepted research funding from Astellas Pharma and Takeda Pharmaceutical. Hideki Sakai accepted research funding from Astellas Pharma and Takeda Pharmaceutical, and honoraria from Astellas Pharma and AstraZeneca. Osamu Ogawa accepted an honorarium from Astellas Pharma."

ALT: alanine aminotransferase; AST: aspartate transaminase; BPI: Brief Pain Inventory; BUN: blood urea nitrogen; CNS: central nervous system; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; Hb: hemoglobin; Inst: institution; ITT: intention to treat; IV: intravenous; LHRH: luteinizing hormone releasing hormone; MRI: magnetic resonance imaging; PFS: progression‐free survival; PO: orally; PPI: Present Pain Intensity; PSA: prostate‐specific antigen; QoL: quality of life; SRE: skeletal‐related event; ULN: upper limit of normal; VAS: visual analog scale; WHO: World Health Organization.