Lissoni et al. (2009): A Randomized Study of Chemotherapy versus Biochemotherapy with Chemotherapy plus Aloe arborescens in Patients with Metastatic Cancer

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Title	A Randomized Study of Chemotherapy versus Biochemotherapy with Chemotherapy plus Aloe arborescens in Patients with Metastatic Cancer
Topic	Aloe vera
Author	Lissoni, P, Rovelli, F, Brivio, F, Zago, R, Colciago, M, Messina, G, Mora, A, Porro, G
Year	2009
Journal	In Vivo
DOI	https://iv.iiarjournals.org/content/23/1/171.short

Brief summary

Aloe has been shown to have an anti-cancer effect. Researchers tested a mixture of aloe with honey and alcohol on the effectiveness of chemotherapy. Patients with metastasising cancer were divided into two arms. All patients underwent chemotherapy, and one arm took 10ml of the aloe mixture three times a day. Compared to patients without aloe, those with aloe were more likely to respond to tumour treatment and still had a higher survival rate after three years.

Aloe hat nachweislich eine krebshemmende Wirkung. Forscher testeten eine Mixtur aus Aloe mit Honig und Alkohol auf die Wirksamkeit der Chemotherapie. Patienten mit metastasierenden Krebserkrankungen wurden in zwei Gruppen eingeteilt. Alle Patienten unterzogen sich einer Chemotherapie, und eine Gruppe nahm dreimal täglich 10ml der Aloe Mixtur ein. Im Vergleich zu Patienten ohne Aloe hatten diejenigen mit Aloe eine größere Wahrscheinlichkeit, auf die Tumorbehandlung anzusprechen, und hatte auch nach drei Jahren noch eine größere Überlebensrate.

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 metastatic cancer; histological diagnosis of lung cancer or gastrointestinal tumour; measurable lesions
Exclusion criteria	Previous chemotherapy; brain metastasis; double tumour; lack of tolerance to polychemotherapy due to performance status, age or comorbidities
N randomized	240
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	Italy
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: weekly End of study unclear

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	Lung Cancer, Gastrointestinal Cancers, Colorectal Cancer, Gastrointestinal Cancers - Gastric (Stomach) Cancer, Gastrointestinal Cancers - Pancreatic 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	Advanced Stage
Specifications on cancer stages	Dominant metastasis sites per arm: Soft tissues: Aloe arm = 7; Control arm = 6 Bone: Aloe arm =20; Control arm = 16 Lung: Aloe arm =26; Control arm = 25 Liver: Aloe arm =37; Control arm = 35 Liver + lung: Aloe arm =24; Control arm = 25 Liver + peritoneum: Aloe arm =7; Control arm = 12
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Chemotherapy: Non-small cell lung cancer: Chemotherapy consisted of cisplatin (CDDP) plus etoposide (VP16) or weekly vinorelbine (VNR) Small cell lung cancer: Chemotherapy consisted of cisplatin (CDDP) plus etoposide (VP16) Colorectal cancer: low-dose oxaliplatin (OXA) plus 5-fluorouracil (5-FU) Gastric cancer: weekly 5-fluorouracil Pancreatic adenocarcinoma: weekly gemcitabine (GEM)
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Gender per arm: Aloe arm: male = 67; female = 54 Control arm: male = 65; female = 54
Age groups	Adults (18+)
Age groups specification	Median age (range) per arm: Aloe arm: 64 (61-77) years Control arm: 65 (58-79) years

Arms

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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	119
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
Dosage and regime	Aloe aborescens (300g fresh aloe leaves in 500g honey and 40ml 40% alcohol) was given orally at a dose of 10 ml thrice daily every day without interruption, either during or after chemotherapy, until the progression of disease, starting 6 days prior to the onset of chemotherapy. + all patients: chemotherapy
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.	60
Side effects / Interactions	Aloe was well tolerated in all patients and no metabolic undesirable effects were observed. In addition, no aloe-related toxicity occurred, including vomiting and diarrhoea.

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	121
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: chemotherapy
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.	60
Side effects / Interactions	NA

Outcomes

Tumor response

Outcome type As specificed by the authors	Primary
Outcome specification	The clinical response and toxicity were assessed according to WHO criteria. The clinical responses were radiologically evaluated after at least three cycles of chemotherapy by repeating the same radiological investigation used prior to the onset of chemotherapy, including CT scan, NMR and PET. Gradations: Complete response Partial response Stable disease Disease control Progressive disease
Type of measurement	Observation, Physical examination
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".	The percentages of complete responses and partial responses achieved in patients concomitantly treated with aloe were significantly higher than in those who received chemotherapy alone: Aloe arm = 40/119 (34%) vs. Control arm = 23/121 (19%), p<0.01.
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 36 months The percentage of 3-year survival obtained in patients concomitantly treated with aloe was significantly higher than that found in the control arm (p<0.01).

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	?

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Toxicity was assessed according to WHO criteria. Patients were monitored weekly by routine laboratory tests. The evaluation of subjective symptoms, such as fatigue and asthenia, was assessed by an individual report.
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".	Chemotherapy was substantially better tolerated in patients concomitantly treated with aloe. In particular, the occurrence of asthenia and/or fatigue was significantly less frequent in patients concomitantly treated with aloe than in those who received chemotherapy alone: Aloe arm = 31/119 (26% ) vs. Control arm = 56/121 (46%), p<0.01. VNR-induced constipation was significantly less frequent in the aloe arm than in the control arm: 3/17 (18%) vs. 12/17 (71% ), p<0.01. OXA-induced neurotoxicity, with paresthesic disturbances, was less frequent in patients who received aloe with respect to those treated with chemotherapy alone, but without statistically significant differences.
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	?
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