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
| Reference ↗ | |
|---|---|
| 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 |
Study Note
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%