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Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Laetrile treatment for cancer

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Versión publicada: 19 octubre 2005 Historial de versiones

https://doi.org/10.1002/14651858.CD005476

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The aim of this review is to assess the effectiveness of Laetrile, as a sole or an adjunctive cancer therapy. Our primary question is 'does Laetrile prolong life or recurrences in patients with any type of cancer?'.

Our secondary questions are:

  • Does Laetrile reduce tumor burden?

  • Does it improve patients' quality of life (QOL)?

  • Does it provide pain relief?

  • Does it affect the efficacy of concomitant standard interventions?

  • Compared to a standard intervention, does Laetrile have less severe side effects?

  • Does Laetrile reduce tumor burden in cancer patients that, before Laetrile treatment, have not been treated with other interventions such as chemotherapy, radiotherapy, surgery or other cytotoxic drugs?

Background

According to the most recent World Health Organization (WHO) report from 2003, 12.6% of all deaths are caused by cancer (WHO 2003). This makes cancer the second most frequent cause of death after cardiovascular diseases in developed countries. It has been estimated that 22 million people are currently living with cancer and by 2020, 15 million people may have been diagnosed with cancer (WHO 2003). Cancer incidence has also increased in children. In European countries it is estimated that 1 in 500 children are diagnosed with cancer before the age of 15 (WHO website).

Many surveys have reported that increasing numbers of patients suffering from cancer turn towards so called alternative cancer cures, hoping for an effective therapy. However, few alternative cancer therapies seem to be backed up by encouraging evidence. Some of them are associated with high‐risks (Gibbs 2004), and the quality of information about complementary and alternative medicine (CAM) for cancer treatment has the potential to seriously mislead patients (Schmidt 2004). Many websites suggest a variety of alternative cancer cures and most of them advertise and sell such products even when they are illegal (Quackwatch website).

Laetrile has been one of the most popular non‐conventional remedies used by cancer patients since the 1970s (Holland 1982; Moss 2005). Laetrile's proponents consider it to be a natural cancer cure; by contrast Laetrile's opponents consider it a toxic and ineffective drug.

Currently Laetrile is variously described as amygdalin, mandelonitrile beta‐glucuronide (Fenselau 1977), vitamin B17, bitter almond (Curezone website), mandelonitrile, apricot kernels, Xing Ren, amygdaloside, Prunus armeniaca (TCM Canadian website), nitriloside, Prunus persica seeds (Fukuda 2003), Prunus amygdalus (cureforcancer web),Tao Ren or semen persica (Herbasin website), and prunasin (MSKCC website).

Considerable confusion exists concerning the relationship between the structure and nomenclature of Laetrile and amygdalin. They are often used interchangeably, but they are not the same product. Amygdalin (Fig.1) is a cyanogenic glycoside plant compound (Bruneton 1999) found in the pits of many fruits and in numerous plants belonging to the Rosaceae family such as Prunus persica (peach), Prunus armeniaca (apricot), Prunus amygdalus (almond); it has also been found in the barks of Prunus africana (pygeum) (Gurib‐Fakim 2004), which is also erronously known as bitter almond. Naturally it has got a dextrorotatory (R) configuration, which is considered to be the active form (Kwon 2003). Additional terminology is associated with amygdalin. Neo‐amygdalin is the inactive S isomer, which does not occur naturally. Isoamygdalin (Fig.2) is the name of the mixture of the two epimers R‐amygdalin and neo‐amygdalin (S‐amygdalin) (Turczan 1978).

The term Laetrile (Fig.3) is an acronym from laevorotatory and mandelonitrile used to describe a purified form of amygdalin (Fenselau 1977; Fukuda 2003; Howard‐Ruben 1984). The chemical composition of the US‐patented Laetrile (D‐mandelonitrile‐ß‐glucuronide), a semisynthetic derivative of amygdalin, is different from the Laetrile/amygdalin produced in Mexico (D‐mandelonitrile‐ß‐gentiobioside) (Fig.4), which is made from crushed apricot pits (Dorr 1978, Fenselau 1977).

Several commercial Laetrile preparations contain only mandelonitrile glucuronide or various concentrations of amygdalin and isoamygdalin. Many of them may contain no glucuronide at all (Fenselau 1977). Laetrile treatments can also include an additional metabolic therapy program consisting of diet, enzymes and vitamins (Moertel 1982).

Beta‐glucosidases enzymes, found in intestinal bacteria (Carter 1980) and in some commonly eaten plants, break down amygdalin to benzaldehyde, glucose and cyanide (HCN) (Dorr 1978; Newmark 1981), which is thought to be the active compound in Laetrile products (Miller 1981). Cyanide is a constituent of mandelonitrile (Fig.5), which is a structural component of both amygdalin and Laetrile products.

Four different rationales have been proposed to explain the anticancer activity of Laetrile, but so far none of them seem to be supported by sound scientific evidence (NCI website). Amygdalin was isolated by two French chemists Robiquet and Boutron and in 1837 it was named emulsin by Liebig and Wöhler (Dorr 1978; Pasteur Inst website). In the 1950s, a purportedly non‐toxic intravenous form of amygdalin was patented as Laetrile. The results of an analysis conducted by the National Cancer Institute (NCI) in order to prove the purity of both oral and injectable amygdalin products, manufactured by Cyto Pharma of Mexico, indicated that these amygdalin products were substandard by US criteria for manufactured pharmaceutical products (Davignon 1978). Other studies also showed the presence of contaminants in both injectable and oral supplements of Laetrile (Dorr 1978). In 1979 Shaffer reported that the Food and Drug Administration (FDA) retained that Laetrile products were toxic and ineffective and Laetrile was consequently banned from US‐interstate transportation. However, in 1980 the Associated Press reported that 23 US States legalised the use of the substance within their boundaries and with certain restriction for terminal cancer patients (Curran 1980) and during 1970s at least 70,000 Americans had used Laetrile (Ellison 1978).

The NCI investigated the effectiveness of Laetrile, but the results of their study did not support the anticancer activity of Laetrile: out of the 22 suitable cases, only six patients experienced a positive response (Ellison 1978). In the 1980s two clinical trials were sponsored by the NCI with the approval of the FDA. Their results did not show the efficacy of Laetrile. Many case reports of the effectiveness, either as an anticancer agent or as a palliative treatment, have been published in the literature. Such anecdotal data are not appropriate for demonstrating efficacy.

Several laboratories studies have shown positive results (Bhatti 1981; Biaglow 1978; Fukuda 2003; Kwon 2003; Manner 1978) regarding the anti‐cancer effect of amygdalin. Furthermore the use of amygdalin and other cyanogenetic glucosides have been discussed as anticancer prodrugs (Kousparou 2002; Syrigos 1998).
To date no reviews of the efficacy of Laetrile have been performed.

At the moment Laetrile is banned by the FDA and also by the European Community (Meijer 2001). Nevertheless it continues to be manufactured and administered as an anticancer therapy, primarily in Mexico (ACS 1991). In recent years many websites have started promoting and selling Laetrile (Quackwatch website). Some claim that the FDA has ruled Laetrile illegal in order to protect the profits of the pharmaceutical industry and permit testing on Laetrile only by its opponents (ACTIC website; U‐Magazine website).

Objectives

The aim of this review is to assess the effectiveness of Laetrile, as a sole or an adjunctive cancer therapy. Our primary question is 'does Laetrile prolong life or recurrences in patients with any type of cancer?'.

Our secondary questions are:

  • Does Laetrile reduce tumor burden?

  • Does it improve patients' quality of life (QOL)?

  • Does it provide pain relief?

  • Does it affect the efficacy of concomitant standard interventions?

  • Compared to a standard intervention, does Laetrile have less severe side effects?

  • Does Laetrile reduce tumor burden in cancer patients that, before Laetrile treatment, have not been treated with other interventions such as chemotherapy, radiotherapy, surgery or other cytotoxic drugs?

Methods

Criteria for considering studies for this review

Types of studies

For this systematic review only randomised controlled trials (RCTs) and non RCTs will be included. Non RCTs will be restricted to studies with concurrent controls.

Types of participants

Any cancer patients at various stages of their illness will be included.

Types of interventions

In this study the reviewers will include oral supplements or parenteral (intravenous or intramuscular) administrations of Laetrile, sometimes also labeled as amygdalin, mandelonitrile, mandelonitrile beta‐glucuronide, vitamin B17, bitter almond, apricot kernels, Prunus persica semen or seeds or Keishi‐bukuryo‐gan (KBG), that contains Prunus persica seeds, Prunus amygdalus semen or seeds, Prunus armeniaca semen or seeds or Xing REN, Tao Ren or semen persica, amygdaloside, nitriloside and prunasin.

The reviewers will also consider treatments which use Laetrile in combinations with other therapies, such as metabolic therapy. The intervention, in any dose, preparation or time schedule compared with standard care only or placebo will be identified.

Types of outcome measures

Primary outcome measures

  • Survival

  • Recurrences

Secondary outcome measures

  • QOL: change in weight, stress, anxiety and depression, effect on adverse effects from conventional cancer treatments (Morrone 1962)

  • Level of pain (Navarro 1964)

  • Tumor response: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) (Moertel 1982)

  • Blood cyanide level > 3 µg/ml (Moertel 1981)

  • Significant urine cyanide changes (Ames 1981)

  • Toxic reactions linked to cyanide poisoning and other adverse events (Moertel 1982)

All of the above mentioned data will be tabulated and the methodological quality of each trial will be assessed by using the Cochrane scale of methodological quality (Cochrane Handbook). The heterogeneity concerning the various ways in which survival, tumor response and QOL are measured will be discussed.

Search methods for identification of studies

Search strategy for identification of studies
The following databases will be searched:
The Cochrane Central Register of Controlled Trials (CENTRAL)
MEDLINE (from 1951)
EMBASE (from 1980)
Allied and Complementary Medicine (AMED)
Scirus
CancerLit
CINAHL (all from 1982)
CAMbase (from 1998).

For ongoing trials the MetaRegister at http://www.controlled‐trials.com/ and the National Research Register at http://www.update‐software.com/national/ will be searched. In addition, the bibliographies of all located studies will be scanned and unpublished or on‐going trials will be identified through correspondence with experts in the field. Finally, our own files will be hand searched for further studies. No language restrictions are imposed.

Search terms for searching PubMed
A. To identify the intervention(s) evaluated:
1. "Laetrile"/ all MeSH
2. (((((Laetrile or laetril) or letril) or letrile) or lactrile) or laetrile).ti.ab.sh.tw.rn.
3. "amygdalin"/all MeSH
4. (((((amygdalin or Neoamygdalin) or Amygdaloside) or isoamygdalin) or amygdaloside).ti.ab.sh.tw.
5. ((((((mandelonitrile or mandelonitrile) or mandelonitrile (+‐)‐isomer) or mandelonitrile beta‐glucuronide) or Mandelonitrile‐beta‐Gentiobioside) or Mandelonitrile beta Gentiobioside) or Mandelonitrile Beta Glucuronic Acid).ti.ab.sh.tw.
6. (((mandelonitrile‐beta‐glucoside or prunasine) or prulaurasin) or prunasin (R)‐isomer)
7. Vitamin B 17
8. Prunus /all MeSH
9. (((bitter almond or Prunus amygdalus) or Prunus amygdalus (semen or seeds)) or almond seeds)
10. (((Prunus armeniaca (semen or seeds) or Apricot (seeds or kernels)) or Xing Ren) or Semen Armeniacae amarum)
11. ((((((Prunus persica (semen or seeds)) or Peach (semen or seeds)) or peach kernel) or semen (persica or pesicae)) or Tao Ren) or tonin) or tounin),
12. ((keishi‐bukuryo‐gan or keishibukuryogan) or TJ‐25)
13. nitriloside
14. sarcacinase
15. C20‐H27‐N‐O11(amygdalin)
16. C14‐H15‐N‐O7 (laetrile )
17. OR/ 1‐16
B. Search terms used to identify cancer patients:
18. (neoplas* or antineoplas*) ti, ab, rw, sh.
19. cancer*. ti, ab, rw, sh.
20. carcin*. ti, ab, rw, sh.
21. oncol*. ti, ab, rw, sh.
22. sarcoma ti, ab, rw, sh.
23. tumor/ all MeSH
24. ((leucaemia or leukaemia) or leukemia)
25. (adenoma or adenopathy)
26. malignant. ti, ab, rw, sh.
27. Lymphoma. ti, ab, rw, sh.
28. OR/18‐27
C. Search terms to identify for the types of study design to be included:
29. clinical trial.pt.
30. controlled clinical trial. pt
31. randomised controlled trial.pt.
32. random*.tw
33. (double adj blind*).tw.
34. placebo*tw.
35. control*.tw.
36. control* stud*. pt, tw.
37. cohort stud*. pt, tw.
38. case‐control stud*. pt, tw.
39. human stud*. pt, tw.
40. comparative study. pt, tw.
41. follow‐up stud*. pt, tw.
42. clinical stud*. pt, tw.
43. OR/29‐42
D. Strategy to locate the studies
44. 17 AND 28 AND 43

Search terms for NHS Dialog
NHS Dialog is a portal that provides databases such as AMED, CINHAL, EMBASE and MEDLINE. All the above terms will be searched in the same way in the NHS Dialog portal, apart from the truncation symbol *, that has been replaced by $. In order to limit truncation and avoid the possibility of overflow, a number of characters after the wildcard were also specified.

Search terms for CAMbase
CAMbase is a virtual search engine with modern XML‐based retrieval‐technology, which enables the user to easily find relevant literature of Complementary and Alternative Medicine (CAM) in different resources. The use of CAMbase is optimized in a way that the user can type in his request as a naturally spoken phrase. It is helpful to complete the sentence.
We used the following sentences:

  • Laetrile for cancer

  • Vitamin B17 for cancer

  • Amygdalin and cancer

  • Prunus and cancer

Data collection and analysis

Study selection
All titles and abstracts retrieved by electronic searching will be downloaded to a reference management database (e.g. Reference Manager or Endnote), duplicates will be removed and the remaining references will be examined by two reviewers (SM, SL) independently. Those studies which clearly do not meet the inclusion criteria will be excluded. Copies of the full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed by two reviewers (SM, SL) independently. Data on characteristics of patients and interventions, study quality and endpoints will be abstracted independently by two reviewers onto a data abstraction form specially developed for the review. Differences between reviewers will be resolved by discussion or by appeal to a third reviewer if necessary.

Assessment of methodological quality of included studies
Methodological quality of included RCTs will be assessed using the following criteria:
Blinding
We will code the blinding of patients, treatment providers and outcome assessors as:

  • yes

  • no

  • unclear

Randomisation
We will code the randomisation of participants to intervention groups as:

  • adequate e.g. a computer‐generated random sequence or a table of random numbers

  • inadequate e.g. date of birth, clinic id‐number or surname

  • unclear e.g. not reported

Allocation concealment
We will code the concealment of allocation sequence from treatment providers and participants as:

  • adequate e.g. where the allocation sequence could not be foretold (A)

  • unclear e.g. not reported (B)

  • inadequate e.g. the computer‐generated random sequence was displayed so treatment providers could see which arm of the trial the next participant was assigned to, or kept in a sealed opaque envelope (C)

Loss to follow‐up
We will record the number of participants in each intervention arm whose outcomes were not reported at the end of the study; we will note if loss to follow‐up was not reported.
Intention‐to‐treat
We will note whether reported data allow an intention‐to‐treat analyses:

  • Yes

  • No

  • Unclear

Methodological quality of non‐randomised controlled trials will be assessed as above and additionally assessed on the basis of:
Comparability of treatment groups at baseline

  • yes

  • no

  • unclear

Adjustment for potential confounders

  • yes

  • no

  • unclear

Data abstraction of outcome data from each trial
For time to event data (overall and disease free survival) we will abstract the hazard ratio (HR) and its variance from trial reports. If these are not presented, we will abstract the data required to estimate them using Parmar's methods (Parmar 1998), e.g. number of events in each arm and log‐rank p‐value comparing the relevant outcomes in each arm. If it is not possible to estimate the HR, we will abstract the number of patients in each treatment arm who experienced the outcome of interest, in order to estimate a relative risk (RR).

For dichotomous outcomes (e.g. adverse events) we will abstract the number of patients in each treatment arm who experienced the outcome of interest, in order to estimate a RR.

For continuous outcomes (e.g. QOL measures) the final value of the outcome of interest in each treatment arms at the end of follow‐up will be abstracted for each study.

Where possible, all data abstracted will be those relevant to an intention to treat (ITT) analysis.

Statistical methods
For time to event data HR will be pooled using the generic inverse variance facility of RevMan 4.2.

For any dichotomous outcomes (e.g. adverse events, and numbers of patients who relapse or die, if it is not possible to treat these outcomes as time‐to‐event data), the RR and its 95% confidence interval (CI) will be calculated for each study. Statistics from each study will be pooled.

For continuous outcomes (e.g. QOL measures, psychiatric scales) the mean difference between the treatment arms at the end of follow‐up will be calculated for each study. These will be pooled using the mean difference method if all trials have measured the outcome on the same scale, or using the standardised mean difference (SMD) method otherwise.

Random effects models will be used for all meta‐analyses (DerSimonian 1986).

Heterogeneity between studies will be assessed both by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003) and by a formal statistical test of the significance of the heterogeneity (Egger 2001). If there is evidence of substantial heterogeneity, the possible reasons for this will be investigated and reported.

A sensitivity analysis will consider the effects of excluding poor quality studies.

A sub‐group analysis will be performed restricted to cancer patients who, before Laetrile treatment, have not been treated with chemotherapy, radiotherapy, surgery or other cytotoxic drugs. This is in order to assess the effectiveness of Laetrile as a sole therapy.