Beer et al. (2007): Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators

Reference ↗
Title	Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators
Topic	Vitamin D
Author	Beer, T, Ryan, CW, Venner, PM, Petrylak, DP, Chatta, GS, Ruether, DJ, Redfern, CH, Fehrenbacher, L, Saleh, MN, Waterhouse, DM, Carducci, MA, Vicario, D, Dreicer, R, Higano, CS, Ahmann, FR, Chi, KN, Henner, WD, Arroyo, A, Clow, FW
Year	2007
Journal	Journal of Clinical Oncology
DOI	https://doi.org/10.1200/JCO.2006.06.8197

Brief summary

This study investigated the effectiveness of vitamin D in combination with docetaxel (a chemotherapeutic agent) in prostate cancer patients. One arm received docetaxel and vitamin D and the other arm docetaxel and placebo. There were no differences between the arms in terms of treatment response rate and time to disease progression, but patients in the vitamin D arm lived longer on average. In addition, although there were no fewer side effects overall in the vitamin D arm, there were fewer serious side effects than in the other arm. Positive aspects of this study are the large sample size and the double blinding (observers/patients do not know which arm they belong to). However, a major criticism of this study is that the vitamin D level was not recorded and taken into account. Thus, there is no verification of whether there was a vitamin D deficiency at the beginning of the study and whether the vitamin D treatment worked (i.e. that patients in the vitamin D arm had higher levels due to vitamin D supplementation).

In dieser Studie wurde die Wirksamkeit von Vitamin D in Kombination mit Docetaxel (ein Chemotherapeutikum) bei Prostatakrebspatienten untersucht. Ein Arm bekam Docetaxel und Vitamin D und der andere Arm Docetaxel und Placebo. Es zeigten sich keine Unterschiede zwischen den Armen hinsichtlich der Ansprechrate der Behandlung und der Zeit bis zum Krankheitsfortschreiten, aber der Vitamin-D Arm lebten die Patienten im Durchschnitt länger. Zudem traten im Vitamin-D-Arm zwar insgesamt nicht weniger Nebenwirkungen auf, aber es gab weniger schwerwiegende Nebenwirkungen als im anderen Arm. Positiv an dieser Studie sind die große Stichprobe und die doppelte Verblindung (Beobachter/Patienten wissen nicht, welchem Arm sie angehören). Ein großer Kritikpunkt dieser Studie ist jedoch, dass der Vitamin D Spiegel nicht erhoben und berücksichtigt wurde. Somit gibt es keine Überprüfung, ob zu Beginn der Studie ein Vitamin D Mangel bestand und ob die Vitamin D Behandlung funktioniert hat (d.h. dass Patienten im Vitamin-D-Arm durch Vitamin D Präparat einen höheren Spiegel hatten).

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	Men with histopathologically or cytologically proven metastatic adenocarcinoma of the prostate with evidence of progression (the development of new metastatic lesions or rising PSA) despite standard hormonal management (orchiectomy, gonadotropin-releasing hormone agonist or antagonist including withdrawal of antiandrogens, if applicable; 6 weeks for bicalutamide, 4 weeks for flutamide or nilutamide) were eligible; serum PSA ≥ 5.0 ng/mL, serum testosterone level ≤ 50 ng/dL, Eastern Cooperative Oncology Group performance status ≤ 2, life expectancy ≥ 3 months, age ≥ 18 years, patient agreement to use adequate contraception, and patient ability to give informed consent.
Exclusion criteria	Active malignancy within 5 years (except nonmelanoma skin cancer), significant active medical illness that would preclude protocol treatment, a history of hypercalcemia or vitamin D toxicity, or hospitalization for treatment of angina, myocardial infarction, or congestive heart failure in the previous 12 months; kidney stones (calcium salt) within 5 years, hypersensitivity to calcitriol or drugs formulated with polysorbate-80, grade 2 or higher peripheral neuropathy, neutrophil count less than 1,500/mm3 , platelet count lower than 100,000/ mm3 , serum creatinine more than upper limit of normal (ULN), serum calcium more than ULN, conjugated bilirubin more than ULN, alkaline phosphatase more than 4 x ULN (patients with known bone involvement and a normal conjugated bilirubin, ALT, and AST were not excluded), ALT or AST more than 2.0 x ULN when alkaline phosphatase is less than 2.5 x ULN, ALT or AST more than 1.5 x ULN when alkaline phosphatase is more than 2.5 x ULN, prior investigational therapy or use of calcitriol within 30 days, prior chemotherapy for prostate cancer except for adjuvant therapy more than 12 months before enrollment, prior chemotherapy with docetaxel, treatment with radiotherapy within 4 weeks or treatment with other radiopharmaceuticals within 8 weeks
N randomized	250
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	Primary analysis for efficacy was on the intention to treat population and toxicity was evaluated in the as-treated population. These two populations were identical.
Countries of data collection	NI
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	Every 4 weeks

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	Advanced Stage
Specifications on cancer stages	Metastatic adenocarcinoma of the prostate with evidence of progression
Comorbidities	No
Current cancer therapies	Chemotherapy, Hormone therapy
Specifications on cancer therapies	Weekly docetaxel 36 mg/m2 intravenously and dexamethasone (4 mg orally 12 hours before, 1 hour before, and 12 hours after docetaxel administration)
Previous cancer therapies	No therapy
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Intervention arm: median (range): 68 (45-87) Placebo arm: median (range): 70 (47-92)

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	125
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	Calcitriol
Dosage and regime	DN-101 (45 μg) orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
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	No increase in toxicity was seen with the addition of DN-101 to docetaxel

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	125
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	Placebo
Dosage and regime	Placebo orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
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	?

Outcomes

"EFS (Event-Free Survival)" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Primary
Outcome specification	PSA response (≥ 50% PSA reduction, confirmed at least 4 weeks later)
Type of measurement	Blood Test
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".	Within 6 months of enrollment: no significant differences in PSA decline; at any time while on study: PSA decline achieved in 52% of placebo- treated patients and 63% of DN-101-treated patients (p = .07); median time to PSA response was 5.3 months in placebo-treated patients and 2.9 months in DN-101-treated patients (p = .06)
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	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Tumor response

Outcome type As specificed by the authors	Secondary
Outcome specification	Tumor response rate
Type of measurement	RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
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".	No significant differences
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	low risk

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	PSA (defined by consensus criteria), tumor, and clinical progression-free survival (defined as either tumor progression, occurrence of a skeletal-related event, or death from any 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".	No significant differences in median duration of PSA progression-free survival; median duration of tumor progression-free survival and median duration of clinical progression-free survival could not be reliably assessed due to the lack of regularly scheduled tumor imaging
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	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	Defined as the time from random assignment to a skeletal-related event or death from any cause, skeletal-related events were defined as pathologic bone fracture, spinal cord compression, surgery to the bone, or radiation to the bone
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".	No significant differences
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	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
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".	After adjustment for baseline characteristics of hemoglobin and Eastern Cooperative Oncology Group performance status, overall survival showed a promising improvement in intervention arm over the placebo arm with a HR of 0.67 (95% CI, 0.45 to 0.97; p = .04)
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	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	All adverse events are reported regardless of perceived relationship to treatment
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".	The incidence of any grade 3 or 4 adverse events was not significantly different; serious adverse events, generally those requiring hospitalization, were observed in 41% of placebo-treated patients and 27% of DN-101-treated patients (p = .023); Among the grade 3 or 4 nonhematologic toxicities, the most common were fatigue (16% placebo; 8% DN-101), infection (13% placebo; 8% DN- 101), and hyperglycemia (12% placebo; 6% DN-101)
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	low risk

Funding and Conflicts of Interest

Funding	Some authors receive honoraria/research funding from various pharmaceutical companies or they advise them
Conflicts of Interest	According to information financial conflicts of interest may exist

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	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	No
- Possibility of placebo effects	No
- Other reasons	We do not know whether the arms had baseline values without significant differences in vitamin D levels.

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	No
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	Yes
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	NI

Additional Notes

PRO:

• Ethics vote
• Double blinding
• Large sample according to power analysis
• Low dropout (8%) and intention-to-treat analysis

CONTRA:

• Vitamin D levels not assessed
• Group differences not excluded
• Fewer endpoints calculated for PFS than specified in the protocol