Lissoni et al. (1998): Biotherapy with the Pineal Immunomodulating Hormone Melatonin versus Melatonin plus Aloe vera in Untreatable Advanced Solid Neoplasms

Reference ↗
Title	Biotherapy with the Pineal Immunomodulating Hormone Melatonin versus Melatonin plus Aloe vera in Untreatable Advanced Solid Neoplasms
Topic	Aloe vera
Author	Lissoni, P, Giani, L, Zerbini, S, Trabattoni, P, Rovelli, F
Year	1998
Journal	Natural Immunity
DOI	https://doi.org/10.1159/000069427

Brief summary

Melatonin is a brain hormone that stimulates the defence system against cancer cells. The anti-cancer properties of aloe have also been proven. In this study, researchers investigated the effect of melatonin or melatonin + aloe on the progression of cancer and the survival rate in cancer patients with a life expectancy of <6 months. The patients were divided into two arms: Melatonin 20mg per day or melatonin (same dose) plus 1ml twice daily of an aloe tincture (aloe + alcohol). Patients who took the aloe tincture tended to have a more favourable disease course and a better 1-year survival rate than those who took melatonin alone. Some patients had diarrhoea when they started taking the aloe tincture, but this subsided after the first few days.

Melatonin ist ein Hirnhormon, welches das Abwehrsystem gegen Krebszellen anregt. Auch die krebshemmenden Eigenschaften der Aloe wurden nachgewiesen. In dieser Studie untersuchten Forscher die Wirkung von Melatonin oder Melatonin + Aloe auf das Fortschreiten von Krebs und die Überlebensrate bei Krebspatienten mit einer Lebenserwartung von <6 Monaten. Die Patienten wurden in zwei Gruppen eingeteilt: Melatonin 20mg pro Tag oder Melatonin (gleiche Dosis) plus 1ml zweimal täglich einer Aloe-Tinktur (Aloe + Alkohol). Patienten, die die Aloe-Tinktur einnahmen, hatten tendenziell einen positiveren Krankheitsverlauf und eine bessere 1-Jahres-Überlebensrate als diejenigen, die nur Melatonin einnahmen. Einige Patienten hatten Durchfall, als sie mit der Einnahme der Aloe-Tinktur begannen, dieser lies jedoch nach den ersten Tagen nach.

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	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	Histologically proven advanced lung cancer, gastrointestinal tract tumor, breast cancer or brain glioblastoma; measurable neoplastic lesions; progression on classical chemotherapy, radiotherapy or endocrine therapy or poor clinical conditions precluding chemotherapy; patients were eligible after at least 1 month from the last chemotherapy course; life expectancy <6 months
Exclusion criteria	Double tumour; other concomitant immunomodulatory therapy
N randomized	50
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. Chi-square-test; Student’s t test and an analysis of variance; survival curves were plotted according to the Kaplan-Meier method; the differences between curves were evaluated by the log-rank test.
Countries of data collection	Italy
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: baseline T1: 2-month-intervals until progression of diasease Follow-up: after 1 year

Characteristics of participants

Stratification according to tumor histotype

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	Lung Cancer, Gastrointestinal Cancers, Breast Cancer, Brain and Central Nervous System (CNS) Cancers - Glioblastoma
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	Advanced Stage
Specifications on cancer stages	Patients with untreatable locally advanced or metastatic solid tumors and a life expectancy <6 months Tumor histotype: Non-small cell lung cancer: Control arm = 11; Aloe arm = 12 Gastrointestinal tract tumors: Control arm = 9; Aloe arm = 7 Breast cancer: Control arm = 4; Aloe arm = 3 Brain glioblastoma: Control arm = 2; Aloe arm = 2
Comorbidities	NI
Current cancer therapies	No therapy
Specifications on cancer therapies	Patients, for whom no other effective standard therapy was available, because of lack of response to previous chemotherapies or a poor clinical status precluding chemotherapy. Previous chemotherapy (patients were eligible after at least 1 month from the last chemotherapy course): Aloe arm: 20/24 Control arm: 21/26
Previous cancer therapies	Chemotherapy, Radiation therapy, Hormone therapy
Gender	Mixed
Gender specifications	Gender per arm: Aloe arm: female = 37.5% Control arm: female= 38.5%
Age groups	Adults (18+)
Age groups specification	Mean age (range) per arm: Aloe arm: 63 (48-80) years Placebo arm: 61 (46-79) years

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	24
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	Aloe vera
Dosage and regime	Aloe vera was administered as a tincture (Aloe vera leaves: 10%; 40% alcohol: 90%) at a dose of 1 ml twice/day (morning and evening), every day until disease progression. All patients: During the dark period of the day, Melatonin was administered orally at a dose of 20 mg/day, every day until disease progression.
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.	365
Side effects / Interactions	Some patients had diarrhoea when they started taking the aloe tincture, but this subsided after the first few days. Melatonin was well tolerated, no related toxicities.

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	26
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	No additional treatment
Dosage and regime	All patients: During the dark period of the day, Melatonin was administered orally at a dose of 20 mg/day, every day until disease progression.
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.	365
Side effects / Interactions	Melatonin was well tolerated, no related toxicities.

Outcomes

Tumor response

Outcome type As specificed by the authors	Primary
Outcome specification	The clinical response was evaluated according to WHO criteria, by repeating the radiological examinations at 2-month intervals. WHO Gradiations: Complete response Partial response Stable disease Disease control Progressive disease
Type of measurement	WHO-Scale (World Health Organisation)
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 objective tumor regression was achieved in the control arm. In contrast, 2/24 (8%) patients of the aloe arm had partial response. Stable disease was obtained in 12/24 (50%) patients of the aloe arm and in only 7/26 (27%) patients of the control arm. There were significantly fewer patients with non-progressive disease in the aloe arm (14/24) compared to control arm (7/26), p<0.05. 7/24 (42%) patients of the aloe arm and 19/26 (73%) patients of the control arm had progressive disease.
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".	Survival rate after 12 months The percent 1-year survival achieved in patients of the aloe arm was also significantly higher than that seen in the control arm: Aloe arm = 9/24 (37%); Control arm = 4/26 (15%) (p<0.05).

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	NI
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	?

Additional Notes

PRO/CONTRA