Chan et al. (2011): Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer

Reference ↗
Title	Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer
Topic	Lycopene
Author	Chan, J, Weinberg, V, Magbanua, M, Sosa, E, Simko, J, Shinohara, K, Federman, S, Mattie, M, Hughes-Fulford, M, Haqq, C, Carroll, P
Year	2011
Journal	Cancer Causes Control
DOI	https://doi.org/10.1007/s10552-010-9684-5

Brief summary

This study compared three groups of patients, all of whom had prostate cancer and were on an active surveillance program. They were given a lycopene tablet (15mg), a fish oil tablet or a matching placebo twice a day for 3 months. The “prostate specific antigen” (PSA) is an important indicator of the development of prostate cancer and was therefore measured in all participants before and after the intervention. The groups were comparable before treatment. After treatment, no difference in PSA development was found between the groups. However, the sample was very small overall, which makes the statistical calculation unreliable. Therefore, an effect cannot be ruled out. In addition, the study has other methodological flaws: 9% of the participants withdrew their participation after group allocation. It is not clear whether this could have anything to do with the (negative) effect of the intervention. In addition, both the lycopene product and the placebo also contained soybean oil. This in turn could have mitigated or even reversed a possible effect of lycopene.

In dieser Studie wurden drei Gruppen von Patienten miteinander verglichen, welche alle Prostatakrebs hatten und in einem aktiven Überwachungsprogramm waren. Sie haben 3 Monate lang zwei Mal am Tag eine Lycopin-Tablette (15mg), eine Fischöl-Tablette oder einen passenden Placebo bekommen. Das „prostataspezifische Anitgen“ (PSA) ist ein wichtiger Hinweis auf die Entwicklung des Prostatakrebses und wurde daher bei allen Teilnehmern vor und nach der Intervention erhoben. Die Gruppen waren vor der Behandlung vergleichbar. Nach der Behandlung konnte kein Unterschied zwischen den Gruppen in der PSA-Entwicklung gefunden werden. Allerdings war die Stichprobe insgesamt sehr klein, was die statistische Berechnung unzuverlässig macht. Man kann einen Effekt also auch nicht ausschließen. Darüber hinaus hat die Studie andere methodische Mängel: 9% der Teilnehmer haben nach der Gruppenzuteilung ihre Teilnahme zurückgezogen. Es ist nicht klar, ob dies etwas mit dem (negativen) Effekt der Intervention zu tun haben könnte. Zudem enthielten sowohl das Lycopin-Produkt wie auch der Placebo zusätzlich Sojaöl. Dies könnte wiederum einen möglichen Effekt von Lycopin abgemildert oder sogar umgekehrt haben.

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	3

Study characteristics

Inclusion criteria	Low-burden prostate cancer; choosing active surveillance for disease management; histologically documented prostate adenocarcinoma; extended pattern biopsy within 2 years of enrollment with a Gleason sum six or lower with no pattern four or five; no more than 33% of biopsy cores positive for cancer; no more than 50% of the length of a tumor core involved by carcinoma; three serum prostate-specific antige (PSA) levels done at least 2 weeks apart over the year prior to randomization; all PSA levels <10 ng/ml; life expectancy >3 months; ECOG (Eastern Cooperative Oncology Group) performance score <2
Exclusion criteria	No prior or concurrent treatment for prostate cancer; patients with a PSA doubling time <3 months; use of lycopene, fish oil or any other dietary or nutritional supplement within 4 weeks of study entry; use of Finasteride, Dutasteride, Saw Palmetto or any other herbal/nutritional preparation indicated to affect hormone levels within 4 weeks of study entry; use of NSAIDs, COX-2 inhibitors and/or aspirin for more than 7 days over the 1 month prior to study; history of allergic reactions attributed to tomatoes, fish, soybean or olive oil, gelatin capsules, or compounds of similar chemical or biologic composition to lycopene (carotenoids) or fish oil; uncontrolled intercurrent illness including, but not limited to, ongoing infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric condition that would limit compliance with study requirements
N randomized	92
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	Baseline characteristics were compared among the three study arms using analysis of variance methods (ANOVA) for continuous variables and chi-square tests for categorical variables. To test the two primary hypotheses to detect a decrease in the mean changes in IGF-1 (or COX-2) gene expression between the lycopene (or fish oil) and placebo arms a t statistic was used with significance set at a probability <0.025 to adjust for the two comparisons. The same method was used to test for a decrease in IGF-1R with the lycopene supplement without any adjustment for multiple testing. Fisher’s exact test to determine whether a greater proportion of patients on the supplement arm achieved at least a 2-fold decrease in IGF-1 (or COX-2) expression when compared with the placebo group was used. An exploratory analyses was conducted using 2-way ANOVA methods to investigate the change in gene expression (pre to post-intervention) in DCT on the log2 scale due to the study arm (supplement or placebo), baseline tomato/fish intake (high or low) or their interaction. If statistical significance was observed, the Newman-Keuls post hoc test was used to identify which subsets were significantly different. Mean baseline and change from baseline results were presented on the log2 scale.
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after 12 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.	Active surveillance
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	?
Specifications on cancer stages	NA
Comorbidities	NI
Current cancer therapies	Active surveillance
Specifications on cancer therapies	NA
Previous cancer therapies	NI
Gender	Male
Gender specifications	Male n (%): 92 (100)
Age groups	Adults (18+)
Age groups specification	Age in years, mean (SD): 61 (7.8)

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	29
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	Insufficient RNA quality or quantity (n=7)
Intervention	Lyc-O-Mato® (lycopene based on soybean oil) + all standard daily multivitamin (Dixon/Akyma)
Dosage and regime	2x 15mg 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.	84
Side effects / Interactions	Digestive disorder (n=2), migraine (n=1)

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	27
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	6
Drop-out reasons	Insufficient RNA quality or quantity (n=6)
Intervention	Fish oil + docosahexane fatty acid + all standard daily multivitamin (Dixon/Akyma)
Dosage and regime	3x 1g daily + 549mg
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.	84
Side effects / Interactions	No side effects / interactions

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	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Insufficient RNA quality or quantity (n=2)
Intervention	Placebo + all standard daily multivitamin (Dixon/Akyma)
Dosage and regime	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.	84
Side effects / Interactions	No side effects / interactions reported

Outcomes

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Primary
Outcome specification	Prostate specific antigen (PSA) levels before the intervention and after the intervention
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".	NI
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".	After 12 weeks mean difference: lycopene: 0.53 ng/ml, fish oil: 0.20 ng/ml, placebo: -0.46 ng/ml; p(lycopene vs. placebo)= 0.26, not significant; p(fish oil vs. placebo) = 0.39, not 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	Lyc-O-Mato ® was sponsored by Lyco-Red, Israel, and fish oil was sponsored by Dr. Howard Fine of Roche Vitamins, Parsippany, NJ.
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	NI
- Reasons for insufficient sample size based on power analysis	NI
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	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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	?