Freedland et al. (2020): A Randomized Controlled Trial of a 6-month low carbohydrate intervention on disease progression in men with recurrent prostate cancer: Carbohydrate and Prostate Study 2 (CAPS2)

Reference ↗
Title	A Randomized Controlled Trial of a 6-month low carbohydrate intervention on disease progression in men with recurrent prostate cancer: Carbohydrate and Prostate Study 2 (CAPS2)
Topic	Low-carbohydrate or ketogenic diet
Author	Freedland, S J, Allen, J, Jarman, A, Oyekunle, T, Armstrong, A J, Moul, J W, Sandler, H M, Posadas, E, Levin, D, Wiggins, E, Howard, L E, Wu, Y, Lin, P-H
Year	2020
Journal	Clinical Cancer Research
DOI	https://doi.org/10.1158/1078-0432.CCR-19-3873

Brief summary

In this study, 57 patients with prostate cancer were randomly divided into 2 groups. One group was then asked to follow a low-carbohydrate diet for 6 months, while the other group was asked to make no changes to their diet. The PSA doubling time was investigated. Data from 45 of the 57 patients were then evaluated in an interim analysis. After 6 months, there was no difference between the groups for PSA doubling time. In a subsequent analysis, after adjusting the model to important characteristics of the test subjects, a difference was found, with an advantage for the diet group in terms of a slower doubling time. However, as this analysis is not based on previously formulated hypotheses, but is an exploratory analysis, the results cannot be considered reliable. The study convinces with statistical accuracy and detailed descriptions of the study. Overall, however, the sample must be considered small and it is not possible to clearly distinguish between the influence of the carbohydrate deficit in the body or the associated significant weight loss in the diet group.

In dieser Studie wurden 57 Patienten mit Prostatakarzinom zufällig in 2 Gruppen eingeteilt. Eine Gruppe sollte sich dann über 6 Monate an eine kohlenhydratarme Diät halten, während die andere Gruppe keine Veränderungen in der Ernährung durchführen sollte. Untersucht wurde die PSA- Verdoppelungszeit. Bei einer Zwischenanalyse wurden dann Daten 45 von den 57 Patienten ausgewertet. Es zeigte sich nach 6 Monaten kein Unterschied zwischen den Gruppen für die PSA-Verdoppelungszeit. In einer nachgeschobenen Analyse konnte nach der Anpassung des Modells an wichtige Charakteristika der Probanden dann doch ein Unterschied gefunden werden, mit einem Vorteil für die Diätgruppe im Sinne einer langsameren Verdoppelungszeit. Da diese Analyse allerdings nicht auf vorher formulierten Hypothesen beruht, sondern eine explorative Analyse darstellt, können die Ergebnisse nicht als zuverlässig betrachtet werden. Die Studie überzeugt mit statistischer Sorgfalt und detaillierten Beschreibungen der Studie. Insgesamt ist jedoch die Stichprobe als klein zu betrachten und es kann nicht klar getrennt werden zwischen dem Einfluss des Kohlenhydratdefizits im Körper oder dem damit einhergegangenem bedeutsamen Gewichtsverlust in der Diätgruppe.

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	No
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	Primary treatment for prostate cancer (radical prostatectomy or definitive local radiation including external beam radiation, brachytherapy or both); prostate specific antigen (PSA) within the past two months of between 3 and 20ng/ml if prior local radiation or between 0.4 and 20 ng/ml if prior radical prostatectomy; prostate specific antigen doubling time (PSADT) >3 and <36 months; BMI ≥24 kg/m2
Exclusion criteria	Symptomatic metastatic disease; anticipation of needing secondary prostate cancer therapy within the next 6 months; current use of weight loss medications or enrollment in a diet/weight loss program; current therapy aimed at lowering testosterone levels (including GnRH agonist/antagonist; prior bilateral orchiectomy; oral anti-androgens, or 5-alpha reductase inhibitors; testosterone replacement was allowed but treatment should be stable during the entire study); already consuming an low carbohydrate diet; being vegetarian/vegan; weight loss >5% of body weight in the last 6 months based on self-report; medical comorbidities that in the opinion of the investigator limits the patient’s ability to complete the study
N randomized	57
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
Specifications on analyses	Results are calculated and analyzed as the mean of log-transformed PSADT, but back transformed for presentation and interpretation. An amendment to the study protocol was added to conduct a two-step interim analysis to test for efficacy and/or futility after 44 of the targeted 60 patients had completed the study. First, efficacy was assessed by comparing the mean PSADT between arms using a two-sided, two-sample t-test at alpha level of 0.01. Next, given a non-significant efficacy test, treatment futility was assessed by calculating the conditional power of the t-test given the interim data with conditional power <0.2 determining futility.
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: baseline T1: after 3 months T2: after 6 months

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.	No therapy setting
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	No therapy
Specifications on cancer therapies	n = 45 Surgery, n (%): 36 (80) Radiation, n (%): 9 (20)
Previous cancer therapies	Surgery, Radiation therapy
Gender	Male
Gender specifications	Male, n (%): 57 (100)
Age groups	Adults (18+), Elderly (65+)
Age groups specification	Age in years, median (range): 72 (66-74)

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	30
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	Started ADT treatment (n=2); withdrew (n=1); started radiation (n=1)
Intervention	Low-carbohydrate diet (LCD) Supervision by dietician
Dosage and regime	Low-carbohydrate diet with ≤20g carbohydrates per day Supervision by dietician by telephone weekly in the first 3 months and then every 2 weeks in the last 3 months
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.	180
Side effects / Interactions	Weight loss; moderate nausea; diarrhea, constipation, headache, fatigue, feeling of weakness (asthenia)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	27
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8
Drop-out reasons	Started ADT treatment (n=6); withdrew (n=1); lost to follow up (n=1)
Intervention	Control (no diet)
Dosage and regime	NA
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.	180
Side effects / Interactions	Moderate nausea; diarrhea, constipation, headache, fatigue, feeling of weakness (asthenia)

Outcomes

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Primary
Outcome specification	Prostata cancer growth was measured by prostate specific antigen doubling time (PSADT) On-study PSADT was calculated as ln(2) divided by the slope of the linear regression line of ln(PSA) over time, using the baseline, 3, and 6-month on-study PSA values
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".	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 arm differences in the mean PSA doubling time (intervention arm 21 months vs. control arm 15 months; p=0.446, not significant) Post hoc analysis: after adjustment for key demographic variables and PSA levels possibly reduced by weight loss and associated altered hemoconcentration measurement: slowed PSA doubling in intervention arm compared to control arm; however, questionable

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

Weight

Outcome type As specificed by the authors	NI
Outcome specification	Weight, fasting blood levels (insulin, HbA1c, C-reactive protein)
Type of measurement	Scale
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".	Significant weight loss in the LCD arm compared to control arm (-12.1 vs -0.50kg; p<0.001, significant)

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

Funding and Conflicts of Interest

Funding	This work was supported by NCI K24 CA160653 and the Hartford Foundation.
Conflicts of Interest	NI

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

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
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?