| 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
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| Topic
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Vitamin D
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| 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
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2007
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| Journal
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Journal of Clinical Oncology
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| DOI
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https://doi.org/10.1200/JCO.2006.06.8197
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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
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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
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Double
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| Is randomized
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Yes
|
| Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control
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No
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| Number of arms
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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
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| N randomized
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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.
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| Countries of data collection
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NI
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| LoE Level of evidence
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1b Oxford 2009
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| Outcome timeline Data collection times
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Every 4 weeks
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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.
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Curative
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included
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Prostate Cancer
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| 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
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Advanced Stage
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| Specifications on cancer stages
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Metastatic adenocarcinoma of the prostate with evidence of progression
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| Comorbidities
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No
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| Current cancer therapies
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Chemotherapy, Hormone therapy
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| Specifications on cancer therapies
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Weekly docetaxel 36 mg/m2 intravenously and dexamethasone (4 mg orally 12 hours before, 1 hour before, and 12 hours after docetaxel administration)
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| Previous cancer therapies
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No therapy
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| Gender
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Male
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| Gender specifications
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100% male
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| Age groups
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Adults (18+)
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| Age groups specification
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Intervention arm: median (range): 68 (45-87)
Placebo arm: median (range): 70 (47-92)
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Arms
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Intervention
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| Number of participants (arm) N randomized
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125
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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0
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| Drop-out reasons
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NA
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| Intervention
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Calcitriol
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| Dosage and regime
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DN-101 (45 μg) orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
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| One-time application
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No
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| 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.
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-999
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| Side effects / Interactions
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No increase in toxicity was seen with the addition of DN-101 to docetaxel
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| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Placebo
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| Number of participants (arm) N randomized
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125
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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0
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| Drop-out reasons
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NA
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| Intervention
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Placebo
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| Dosage and regime
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Placebo orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
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| One-time application
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No
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| 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
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| Side effects / Interactions
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?
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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
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Primary
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| Outcome specification
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PSA response (≥ 50% PSA reduction, confirmed at least 4 weeks later)
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| Type of measurement
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Blood Test
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| 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)
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| 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".
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NI
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
|
some concerns
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| Bias due to deviation from intended intervention (assignment to intervention)
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low risk
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
|
low risk
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| Bias in measurement of the outcome
|
low risk
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| Bias in selection of the reported result
|
some concerns
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| Other sources of bias
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NA
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| Overall RoB judgment
|
some concerns
|
Tumor response
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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Tumor response rate
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| Type of measurement
|
RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
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| 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".
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No significant differences
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| 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".
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NI
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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some concerns
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| Bias due to deviation from intended intervention (assignment to intervention)
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low risk
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
|
low risk
|
| Bias in measurement of the outcome
|
low risk
|
| Bias in selection of the reported result
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low risk
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| Other sources of bias
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NA
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| Overall RoB judgment
|
low risk
|
PFS (Progression-Free Survival)
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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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)
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| Type of measurement
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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".
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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
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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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
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Secondary
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| 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
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| Type of measurement
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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
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| Outcome specification
|
NI
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| Type of measurement
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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
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| 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
