Paur et al. (2017): Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA

Reference ↗
Title	Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA
Topic	Lycopene
Author	Paur, I, Lilleby, W, Bøhn, S K, Hulander, E, Klein, W, Vlatkovic, L, Axcrona, K, Bolstad, N, Bjøro, T, Laake, P, Taskén, K A, Svindland, A, Eri, L M, Brennhovd, B, Carlsen, M H, Fosså, S D, Smeland, S S, Karlsen, A S, Blomhoff, R
Year	2017
Journal	Clinical Nutrition
DOI	https://doi.org/10.1016/j.clnu.2016.06.014

Brief summary

In this well-conducted study, prostate cancer patients were divided into one of three groups three weeks before their planned prostate removal or radiotherapy. The first group was to consume a minimum amount of tomato products daily, the second group was to additionally consume other products such as green tea, pomegranate and grape juice and the third group was to maintain their normal eating habits. Various blood values and the prostate-specific antigen (PSA), which is an important indicator of the development of prostate cancer, were measured. The groups were comparable in all respects before the start of this dietary change. The PSA values were measured again shortly before the operation/radiotherapy. Although it could be shown that the lycopene levels in the blood had approximately doubled in the two groups that had changed their diet, no differences in PSA levels could be shown between the groups. In a subsequent analysis, however, it was shown that certain patients may have benefited from the change in diet, namely patients in the medium risk range and patients who had a particularly strong increase in lycopene in their blood (i.e. who were able to absorb lycopene particularly well into their bodies). The PSA value fell in these patients. However, as these correlations were only found in subsequent analyses, it is not possible to determine the extent to which they are purely coincidental. This would have to be verified in further studies.

In dieser gut durchgeführten Studie wurden Prostatakrebspatienten jeweils drei Wochen vor der geplanten Prostataentfernung oder Radiotherapie in eine von drei Gruppen eingeteilt. Die erste Gruppe sollte täglich eine Mindestangabe von Tomatenprodukten zu sich nehmen, die zweite Gruppe zusätzlich noch andere Mittel wie grünen Tee, Granatapfel- und Traubensaft und die dritte Gruppe sollte ihre normale Essgewohnheit beibehalten. Es wurden verschiedene Blutwerte und das prostataspezifische Antigen (PSA) erhoben, welches ein wichtiger Hinweis auf die Entwicklung des Prostatakrebses ist. Die Gruppen waren vor Beginn dieser Ernährungsumstellung in allen Belangen vergleichbar. Kurz vor der OP/Radiotherapie wurden die PSA-Werte erneut erhoben. Obwohl gezeigt werden konnte, dass sich die Lycopin-Werte im Blut bei den beiden Gruppen, die eine Ernährungsumstellung vorgenommen haben, ungefähr verdoppelt hatten, konnten kein Unterschiede im PSA-Wert zwischen den Gruppen gezeigt werden. In einer nachträglichen Analyse konnte allerdings gezeigt werden, dass bestimmte Patienten von der Ernährungsumstellung womöglich doch profitiert haben, nämlich die Patienten im mittleren Risikobereich und die Patienten, die einen besonders starken Lycopin-Anstieg im Blut hatten (die Lycopin also besonders gut in ihren Körper aufnehmen konnten). Bei ihnen sank der PSA-Wert. Da diese Zusammenhänge allerdings erst in nachträglichen Analysen gefunden wurden, lässt sich nicht bestimmen, inwiefern sie nur ein reines Zufallsprodukt sind. Dies müsste in weiteren Studien überprüft werden.

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	Single
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	Patients diagnosed with non-metastatic prostate cancer (N0 and M0 as confirmed by negative chest X-ray, bone scintigraphy and pelvic MRI or CT); scheduled for either radical prostatectomy or high-dose radiotherapy consisting of a combination of high-dose rate brachytherapy and pelvic external beam radiotherapy
Exclusion criteria	White blood cells outside normal reference window; Hb < 11 g/dL; prior endocrine treatment; <5 year life-expectancy; ECOG score >1; incontinence/urinary retention; critical comorbidity (e.g. cardiovascular disease, chronic obstructive pulmonary disease, insulin dependent diabetes mellitus, vasculitis, inflammatory bowel syndrome or other conditions with potential influence on radiation therapy)
N randomized	86
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	The number of samples analyzed per endpoint differs slightly since some samples were not available for analysis. Pre-intervention values and PSA changes during the intervention were not normally distributed and were thus tested statistically using Kruskal Wallis test and Mann-Whitney test. Fishere-Freemane-Halton test was used to identify statistical differences in categorical data and contingency tables. For tests of correlation, Spearman's Correlation Coefficient was calculated.
Countries of data collection	Norway
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T1: before intervention T2: after intervention (directly before radiotherapy/surgery)

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.	Neo-adjuvant
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	NO and M0
Comorbidities	NI
Current cancer therapies	No therapy
Specifications on cancer therapies	NA
Previous cancer therapies	NI
Gender	Male
Gender specifications	Male n (%): 86 (100)
Age groups	Adults (18+)
Age groups specification	Age in years, mean (range): 63.49 (48-75)

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	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Surgery (n=1)
Intervention	Tomato products
Dosage and regime	Tomato products with 30 mg lycopene daily from 3 weeks before radiotherapy/surgery until radiotherapy/surgery for median (range)=21.5 (12-24) days
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.	21
Side effects / Interactions	No side effects/interactions with lycopene

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	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Withdrew consent (n=1); hospital switch (n=1); postponed surgery (n=1)
Intervention	Tomato-plus intervention
Dosage and regime	Tomato products with 30 mg lycopene daily + 1 cup of green and black tea + 330ml pomegranate and grape juice + 200mg soy isoflavones + 200µg 1-selenemethionine + 3.13g n-3 fatty acids daily from 3 weeks before radiotherapy/surgery until radiotherapy/surgery for median (range)=22 (20-24) days
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.	21
Side effects / Interactions	One case of vomiting probably related to the fish oil supplement

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	30
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Dropped out (n=1); acute unrelated illness (n=2)
Intervention	Usual diet
Dosage and regime	Daily from 3 weeks before radiotherapy/surgery until radiotherapy/surgery
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.	21
Side effects / Interactions	NA

Outcomes

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Primary
Outcome specification	Levels of prostate specific antigen (PSA) before intervention and after intervention (directly before radiotherapy/surgery)
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".	Median-difference (range): no significant differences between all three arms: tomato arm: 0.00 (-3.30, 2,40), tomato-plus arm: 0.14 (-12.40, 4.80), control arm: 0.41 (-8.53, 4.0), p=0.416, not significant Subgroup analysis (post-hoc) for medium-risk patients: significantly better values in tomato arm than in control arm; no significant differences between tomato-plus arm and control arm (tomato arm: -0.23 (-1.12, 1.90); tomato-plus arm: 0.28 (-0.78, 1.20); control arm: 0.45 (-0.26, 2.24); p(tomto vs. control)=0.016, significant; p(tomato-plus vs. control)=0.094, significant No significant differences in the other risk groups

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	?

Carotenoid concentration

Outcome type As specificed by the authors	Primary
Outcome specification	Plasma concentration of carotenoids
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".	Plasma lycopene values more than doubled in intervention arms, values in control arm remained the same, significant difference, median, range: tomato arm: 0.25 (-0.12, 0.68); tomato-plus arm: 0.32 (-0.29, 0.75); control arm: -0.02 (-0.15, 0.53); p(tomato / tomato-plus vs. control) <0.001, significant; p(tomato vs. tomato-plus)<0.05, p(tomato-plus)<0.05, 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	Supported by Throne Holst Foundation, Research Council of Norway and The Norwegian Cancer Society
Conflicts of Interest	RB has interests in Vitas AS. Vitas AS was established by Oslo Innovation Center.

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	?