Attia et al. (2008): Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer

Reference ↗
Title	Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer
Topic	Vitamin D
Author	Attia, S, Eickhoff, J, Wilding, G, McNeel, D, Blank, J, Ahuja, H, Jumonville, A, Eastman, M, Shevrin, D, Glode, M, Alberti, D, Staab, MJ, Horvath, D, Straus, J, Marnocha, R, Liu, G
Year	2008
Journal	Clinical Cancer Research
DOI	https://doi.org/10.1158/1078-0432.CCR-07-4274

Brief summary

This study investigated the efficacy 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 significant differences between the two arms in terms of treatment response rate, time to disease progression and overall survival. In the vitamin D arm, more cases of diarrhea were reported and in the placebo arm there were more cases of neutropenia (reduced number of immune cells, e.g. white blood cells in the blood). A positive aspect of this study is the double blinding (patients/observers do not know which arm they belong to). On the negative side, however, too few patients were included in this study to be able to calculate statistical effects properly and vitamin D levels were not examined.

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 bedeutsamen Unterschiede zwischen den beiden Armen hinsichtlich der Behandlungsansprechrate, der Zeit bis zum Fortschreiten der Krankheit und der allgemeinen Überlebensrate. Im Vitamin D Arm wurden mehr Fälle von Durchfall berichtet und in Placebo-Arm gab es mehr Fälle von Neutropenie (verminderte Anzahl von Immunzellen, z.B. weiße Blutkörperchen im Blut). Positiv an dieser Studie ist die doppelte Verblindung (Patienten/Beobachter wissen nicht, welchem Arm sie angehören). Negativ ist jedoch, dass in dieser Studie zu wenig Patienten eingeschlossen wurden, um statistische Effekte gut berechnen zu können und das der Vitamin D Spiegel nicht untersucht 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	Monocentric
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	≥18 years of age, histologic diagnosis of prostate adenocarcinoma, radiographic evidence of metastasis, chemotherapy naive (although immunotherapy and experimental therapies were allowed if given ≥4 week before), Eastern Cooperative Oncology Group performance status of ≤2, life expectancy of ≥3 month, and written informed consent; adequate major organ function (WBC count ≥3,000/μL, absolute neutrophil count >1,500/μL, platelet count ≥100,000/μL, hemoglobin ≥10 g/dL, total bilirubin below the institutional upper limit of normal, creatinine ≤1.8 mg/dL, alanine and aspartate transaminases <2.5 times the upper limit of normal, serum calcium ≤10.2 mg/dL, and serum phosphorus ≤5.0 mg/dL)); discontinuation, at least 4 week before, of PC-SPES, saw palmetto, or other herbal supplements used as treatment for prostate cancer; peripheral neuropathy grade ≤1; and prior treatment with bilateral orchiectomy or other primary hormonal therapy with subsequent treatment failure
Exclusion criteria	Second malignancy within 5 years (excluding basal or squamous cell carcinoma of the skin treated curatively); brain metastasis; nephrolithiasis within 10 years; chronic hypercalcemia (i.e., serum calcium >1.0 mg/dL the upper limit of normal); chronic gastrointestinal disease (i.e., malabsorption, surgery affecting absorption, and chronic ulcerative colitis); urinary protein >4 g/24 h; urinary calcium ≥500 mg/24 h; active angina, New York Heart Association class II–IV heart failure, or history of myocardial infarction within 6 month; uncontrolled infection; or hypersensitivity to polysorbate 80, use of digitalis, thiazide diuretics, calcium supplements, anticonvulsants, fluoride, and lithium was not allowed, use of steroids was permitted unless taken for prostate cancer; treatment with suramin, strontium, or other therapeutic radioisotopesor radiotherapy within 4 weeks
N randomized	70
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.	PP Analysis, ITT Analysis
Specifications on analyses	Only patients completing 12 wk of treatment were considered evaluable for objective response using WHO criteria; ITT Analysis for endpoints overall survival and progression-free survival
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline On day 1 of every 28-day cycle

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 prostate cancer
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Docetaxel was supplied commercially. Patients received, on a 28-day cycle, 35 mg/m2 docetaxel i.v. on days 1, 8, and 15 over 1 hour
Previous cancer therapies	Surgery, Immunotherapy, Radiation therapy, Hormone therapy
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Intervention arm: median (range): 72.0 (50.0-85.0) Placebo arm: median (range): 70.0 (52.0-82.0)

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	37
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	7
Drop-out reasons	n=1 elevated serum testosterone at baseline, n=1 use of digoxin discovered before treatment began (one), n=1 received treatment and discovered to have an elevated baseline serum testosterone level, n=4 withdrawn before first post-baseline imaging studies
Intervention	Doxercalciferol
Dosage and regime	Supplied by Genzyme as 2.5 μg soft gel capsules,10 μg (i.e., four capsules of 2.5 μg) of doxercalciferol orally each day of the chemotherapy cycles before breakfast and at the same time, Duration: for 1-12 cycles of chemotherapy (each cycle: 28 days), median duration: 6 cycles
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	Hypercalcemia, grade ≥2 calcium, nephrolithiasis, diarrhea

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	33
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	10 μg of placebo (equal in weight to, and containing only the inactive ingredients found in, the doxercalciferol capsules), orally each day of the chemotherapy cycles before breakfast and at the same time, Duration: for 1-12 cycles of chemotherapy (each cycle: 28 days), median duration: 6 cycles
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	Grade ≥2 creatinine, neohrolithiasis, neutropenia

Outcomes

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Primary
Outcome specification	Serum PSA
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".	No difference between treatment arms in the rate of PSA response, no difference in the median time to PSA response
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	high risk

Tumor response

Outcome type As specificed by the authors	Secondary
Outcome specification	Objective tumor response
Type of measurement	WHO-Scale (World Health Organisation)
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 complete responses were observed, partial objective response rate was not significantly different, neither was stable disease rate
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	some concerns
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	high risk

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
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".	NA
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".	No significant differences in progression-free survival

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	high risk

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
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".	NA
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".	No significant differences in overall survival

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	high risk

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	No
- Reasons for insufficient sample size based on power analysis	This study was closed early after meeting accrual numbers for the planned interim analysis. This decision was due initially to a change in the sponsor’s interest in pursuing an oncologic indication for doxercalciferol. Consequently, a futility calculation was conducted at the planned interim analysis. Based on the low conditional power levels achieved at the interim analysis, there was justification to stop the trial early due to futility.
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	Yes
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	No
- Possibility of attention effects	No
- Possibility of placebo effects	No
- Other reasons	There are no significant results. However, the results may be falsified because it is not known whether the patients of the respective arms differed in their initial 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)	No
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	No
Side effects considered in result interpretation	No
Ethics votum	No

Additional Notes

CONTRA

• No data on baseline vitamin D levels (calcium only)
• Fewer patients than power analysis (< than 60), actually only an interim analysis, but calculation that result would not change with better power
• Group differences to baseline (slightly greater body surface area in arm A [p = 0.047]), not shown in the table
• For some endpoints partially up to A: 35%, B: 30% dropout (for WHO criteria)
• For toxicity: no control for multiple testing