Scher et al. (2011): Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer

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Title	Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer
Topic	Vitamin D
Author	Scher, HI, Jia, X, Chi, KN, Wit, R de, Berry, WR, Albers, P, Henick, B, Waterhouse, DM, Ruether, DJ, Rosen, PJ, Meluch, AA, Nordquist, LT, Venner, PM, Heidenreich, A, Chu, L, Heller, G
Year	2011
Journal	Journal of Clinical Oncology
DOI	https://doi.org/10.1200/JCO.2010.32.8815

Brief summary

In this study, prostate cancer patients were examined, with one half receiving docetaxel and a vitamin D analog (arm A) and the other half docetaxel and prednisone (arm B). Patients in arm A lived significantly shorter than those in arm B. There were no significant differences with regard to events such as pulmonary embolism or thrombosis. A positive aspect of this study is the large sample from different countries. A negative aspect, however, is that the two arms differed with regard to docetaxel treatment and therefore it cannot be conclusively clarified whether the shorter survival time was caused by vitamin D or by the other differences in treatment.

In dieser Studie wurden Prostatakarzinompatienten untersucht, wobei die eine Hälfte Docetaxel und ein Vitamin D-Analog (Arm A) und die andere Docetaxel und Prednison (Arm B) bekam. In Arm A lebten die Patienten bedeutsam kürzer als in Arm B. Hinsichtlich Ereignisse wie Lungenembolie oder Thrombose zeigten sich keine bedeutsamen Unterschiede. Positiv an dieser Studie ist die große Stichprobe aus verschiedenen Ländern. Negativ ist jedoch, dass sich die beiden Arme hinsichtlich der Docetaxel-Behandlung unterschieden und deswegen nicht abschließend geklärt werden kann, ob die verkürzte Überlebenszeit durch Vitamin D oder durch die anderen Unterschiede in der Behandlung hervorgerufen wurde.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Pathologically or cytologically proven adenocarcinoma of the prostate, metastatic disease (documented by computed tomograpghy, magnetic resonance imaging, or bone scan), disease progression after medical or surgical castration (documented by PSA, radiologic imaging of soft-tissue lesions, and/or bone scan; life expectancy longer than 3 months, normal liver and kidney function, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and testosterone lower than 50 ng/dL
Exclusion criteria	Prior cytotoxic chemotherapy (except estramustine monotherapy), bone-seeking radioisotope therapy, prior untreated CNS involvement, or malignancy other than prostate cancer (except adequately treated basal or squamous cell skin cancer or any other cancer from which the individual had been disease free for > 5 years), history of hypercalcemia or vitamin D toxicity, active uncontrolled infection, symptomatic peripheral neuropathy of grade > 2, or hypersensitivity to any treatment component; use of calcium supplements higher than 500 mg and pharmacologic doses of vitamin D or its derivatives (> 400 U or 10 μg)
N randomized	953
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
Countries of data collection	Canada, Czech Republic, Germany, Hungary, Romania, Serbia, Slovakia, United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: within 14 days of random assignment 72 hours preceding each day 2 Follow-Up: after 48 weeks (only for survival)

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Prostate Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Intervention arm: 36 mg/m2 docetaxel for 30-minute infusion on days 2, 9, and 16; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel; nine doses of dexamethasone per 28-day, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression Control arm: 1-hour infusion of docetaxel at 75 mg/m2 body-surface area on day 2; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel infusion; three doses per 21-day cycle, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
Previous cancer therapies	NI
Gender	Male
Gender specifications	100% male
Age groups
Age groups specification	Intervention arm: mean: 70.4 Control arm: mean: 70.9

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	477
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Vitamin D
Dosage and regime	28-day dosing cycles of 45-μg oral DN-101 on days 1, 8, and 15, continue DN-101 for up to 48 weeks or until unacceptable DN-101 toxicity or experimental agents were initiated
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	Overall adverse events 93.5%, severe adverse events: 35%; highest incidence of adverse events occurred in the gastrointestinal system: 79%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent, most common severe adverse events: febrile neutropenia 1.0%, pneumonia 3.1%, dehydration 2.5%, disease progression 2.5%, dyspnea 2.1%, deep vein thrombosis 0.6%, 5.9% hypercalcemia, 0.8% hypercalcemia grade ≥ 3

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
Number of participants (arm) N randomized	476
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Prednisone
Dosage and regime	21-day dosing cycles with 5-mg oral prednisone twice daily
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	Overall adverse events 93.3%, severe adverse events: 33%; highest incidence of adverse events occurred in the gastrointestinal system: 72%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent, most common severe adverse events: febrile neutropenia 4.6%, pneumonia 2.9%, dehydration 2.7%, disease progression 1.3%, dyspnea 1.1%, deep vein thrombosis 2.5%, 0.6% hypercalcemia, 0.2% hypercalcemia grade ≥ 3

Outcomes

OS (Overall Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Time between random assignment and death, regardless of cause
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	At study termination, 129 deaths (13.5%) had occurred; 48 deaths (10.1%) in the control arm and 81 (17.0%) in intervention arm
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Six months after study termination, a total of 312 deaths (32.7%) had occurred: 138 (29.0%) in the control arm and 174 (36.5%) in intervention arm; primary cause of death was prostate cancer in 108 participants (78.3%) in control arm and 142 (81.6%) in intervention arm, median overall survival was 20.2 months (95% CI, 18.8 to 23.0) in control arm and 17.8 months (95% CI, 16.0 to 19.5) in intervention arm, survival rate was significantly lower in the intervention arm (p = .002)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Thromboembolic event rates

Outcome type As specificed by the authors	Secondary
Outcome specification	Defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, and arterial thrombosis
Type of measurement	NI
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Similar rates of thromboembolic events
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	Fees/research allowance from pharmaceutical companies or some authors advice them
Conflicts of Interest	According to given information there are some financial conflicts or conflicts of interest

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	Yes
- Reasons for insufficient sample size based on power analysis	NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	NA
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	There is no data concerning vitamin D levels and the arms are receiving different kinds of chemotherapy

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	Yes
Correction for multiple testing	NA
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	Yes
Side effects considered in result interpretation	No
Ethics votum	Yes

Additional Notes

PRO:

• Ethics vote
• Double blinding
• Active control group
• Large sample size
• Intention-to-treat

CONTRA:

• Vitamin D levels not assessed
• Group differences not excluded
• Different treatment regimens for chemotherapy, per arm, no comparability of arm A and B
• High dropout at follow-up A: 44%, B: 43%