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These are the excellent presentations from the Children with Cancer UK sponsored childhood cancer session organised by Professor Denis Henshaw for the 8th Princess Chulabhorn International Scientific Congress held in Thailand in November 2016.

The melatonin debate

During our conference we called for the introduction of melatonin as an adjunct therapy in the treatment of cancer in children and in teenagers and young adults. The Children's Cancer and Leukaemia Group (a Charity), based at the Leicester Royal Infirmary and which has many paediatric oncologist members, posted a caution about the use of melatonin on their website stating that they do not support our call, and emailed it to all their members.

This has resulted in questions from parents, patients and health workers asking for more information. Here is our short response.

Re: CCLG Public Statement: Behind the headlines: Melatonin and childhood cancer

Children with Cancer UK, as a Charity with a remit to find causes, to help prevent cancer and to help improve treatment in children and young people aged 0 to 24, needs to keep a wide over-view of developing scientific knowledge around these issues. Two of our registered Aims are:

  • To understand the long-term health implications of paediatric and young person cancer and its treatment
  • To promote the dissemination of research findings to achieve maximum impact – for treatment and for prevention of new cases

The people who wrote and approved the unsigned CCLG statement for publication seem to be unaware of the extensive scientific literature on melatonin and recent advances in scientific and medical knowledge regarding melatonin and cancer.

The CCLG statement simply describes melatonin as "a hormone that plays a role in sleep". Pineal melatonin does indeed circulate in the blood like a hormone and does play an important role in controlling a healthy circadian rhythm. Such a simplistic description can be found all over the internet. The role of melatonin in circadian rhythm ("sleep") is tiny compared with its bio-protective role inside every living cell in our body.

More correctly, melatonin is an idoleamine, a monoamine neurotransmitter chemical that is produced in large amounts in the mitochondria of every living cell. Total melatonin in a healthy person is tens of thousands of times higher than that derived from pineal melatonin. Its protective properties are far greater than the pineal melatonin that circulates nightly in the blood and helps to control sleep patterns.

Here are some relatively brief comments from us:

1. Children with Cancer UK have been repeatedly suggesting that the use of melatonin be considered in the treatment of paediatric and young person cancer since our first International Conference on Childhood Leukaemia in 2004. The scientific facts have been reported over recent years in the scientific literature on how melatonin protects foetal development and stimulates protective immunomodulation in infants. Melatonin is well-known as a powerful natural anti-oxidant and an anti-cancer agent with multiple actions many of which are receptor mediated.

At our 2018 conference, Professor Cathy Vaillancourt of the University of Quebec gave an authoritative state of knowledge Presentation entitled "Melatonin as a Protective Agent in utero: Role in Foetal programming". It is available on the Day Two video of our conference (starting at 5 hr 36 min).

She showed healthy maternal and placental melatonin levels and how they increase over the duration of pregnancy. After birth, the infant only receives melatonin through breast milk and cannot make its own until about three months of age. The UK has one of the lowest levels of breast feeding in the world. This is not intended to 'blame' mothers, but melatonin supplementation in some early compound milk Formulas should be considered.

Also on the Day Two video (starting at 6 hr 8 min) Professor Richard Stevens (well known for his seminal 1987 paper: "Electric power use and breast cancer: a hypothesis", Am.J.Epidem. 125(4): 556–561) gave a Presentation on how our lifestyles and environment are reducing our endogenous circadian melatonin levels, including in 3 to 5 year-olds. This is likely to adversely affect their health.

On Day Three (starting at 2 hr 39 min) Professor Russel Reiter, probably the most pre-eminent expert on melatonin in the world, gave a very detailed 40 minute scientific and medical Presentation entitled: "The Utility of Melatonin in the Treatment of Childhood Cancer".

He showed in detail how melatonin, inhibits metastasis, reduces chemotherapeutic resistance including in cancerous stem cells. He also demonstrates how melatonin, with its context specificity, protects healthy cells by scavenging free radicals that commonly used chemotherapeutic agents generate in both cancer cells and healthy cells and which are responsible for most of the long-term toxic effects of chemotherapy.

Professor Reiter pointed the extreme safety of melatonin. He reminded the audience that you cannot kill an animal with melatonin, though you can with aspirin - just as you can with radiotherapy and chemotherapy drugs.


2. The CCLG posting states that our press release does not include any links or references to evidence that backs up what we are saying.

In our experience, a press release is not the place to cite extensive references, indeed we note that the CCLG statement is unsigned and contains no references at all. Our press release cited comments from three of our key speakers and sought to encourage the attendance at Childhood Cancer 2018 where the scientific evidence was extensively discussed and cited. As written above, the platform presentations are now freely available for all to watch on You Tube.

We welcome detailed scientific and medical comments on all of our conference presentations. The raison d'être of our conferences is to stimulate proper professional debate and thereby move medical knowledge forward and reduce the burden of cancer on children, young people and their families. As above, professional comment submitted to the peer-reviewed journals where the wide-ranging conference material was previously published would also be appropriate.


3. CCLG state that "the contribution of melatonin to improved survival in trials in which other drugs are studied is unclear".

Based on the published evidence, we hold a rather different view.
We note a 2012 review by Seely et al, (Integr Cancer Ther 2012 11: 293) of 21 clinical trials of the use of melatonin as an adjunct treatment in cancer therapy for solid tumours. They do not include children but are relevant to us at Children with Cancer UK in view of our remit to include teenagers and young adults up to age 24. The overall results show a doubling in 1-year survival and significant reduction in a wide range of adverse health side-effects.

Melatonin has been used for a number of years to treat children with sleeping difficulties and was subject to a 2009 review by Hoebert et al ("Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia" J. Pineal Res. 2009; 47:1–7).

Indications are that at the doses employed, up to 6 mg per day, melatonin is entirely safe, Hoebert et al state: "We conclude that melatonin remains an effective therapy on the long term for the treatment of CSOI in children with ADHD and has no safety concerns regarding serious adverse events or treatment related co-morbidity."


4. CCLG state:"The improvement in survival for children with cancer has been achieved over recent decades as a result of carefully designed clinical trials, which are the 'gold standard' in testing new treatments. Through these trials, the benefits have been identified and their safety confirmed".

The CCLG do not specify to which new treatments they are referring, but we doubt whether existing treatments can possibly be considered safe, as both radiotherapy and many specific chemotherapy drugs are known to cause secondary cancers. Also, the latest advanced CAR-T cell based immunotherapy treatments are showing some really concerning adverse effects. We are not against the development of such advanced treatments – indeed we are a substantial co-funder of such treatment being developed.

At the Children with Cancer UK Brain Tumour workshop in February 2016, we were repeatedly reminded that radiotherapy actually promotes the growth of new brain tumours months or years after initial treatment. The phenomenon has been demonstrated quantitatively in a mouse model by Duan et al 2018 (Rad Oncol; DOI: 10.1016/j.ijrobp.2018.08.033): "Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth".

Our concerns about the effects of ionising radiation extend to medium doses such as those used in paediatric CT scans. Evidence suggests that the use of CT scans as a diagnostic in otherwise healthy children leads to a measurable increased risk of leukaemia, brain tumours and other cancers (see for example Pearce et al 2012 [The Lancet; DOI:10.1016/S0140-6736(12)60815-0], and Matthews et al [BMJ 2013;346:f2360 doi: 10.1136/bmj.f2360].

Through its funding, Children with Cancer were pioneers (via LRF / Bloodwise) of the introduction of Minimal Residual Disease (MRD) in the UK via the ALL trials. MRD has of course been extremely successful in the treatment of childhood leukaemia. Even so, long-term health issues with childhood leukaemia survivors remain and we cannot see how MRD could be described as "safe". 40% to 50% of childhood cancer survivors develop an endocrine disorder over their lifetime due to a late toxic effect of their chemotherapy.


5. CCLG state: "we are striving to make treatments for children kinder and more effective, but these need to be based on robust evidence of likely benefit. This evidence does not exist for melatonin at the moment."

The evidence supports the opposite view! In fact, with more than 30,000 peer-reviewed publications, far more is known about melatonin than any specific cancer treatment drug.

The mechanistic evidence underlying existing clinical trials is underpinned by a number of reviews – see for example Reiter et al 2017 (Int. J. Mol. Sci. 2017, 18, 843 [47 pages]; doi:10.3390/ijms18040843): "Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis".

Despite the CCLG claims, the ONS data for England shows that recent overall improvement in 5 and 10-year survival from diagnosis of paediatric cancer has effectively stalled (see figure). In the period 2007 – 2017, the annual percentage rise in 10-year survival was only 0.18%. The MRD ALL trials probably caused the rise in improvement from 2004-2007, but since then improvement in long-term overall survival after paediatric cancer is minimal.


6. CCLG state: "Until such evidence is available, our expert view is that calling for the NHS to add an untested supplement to 'standard treatment' is not justified."

There seems to be a misunderstanding here. It is taken as read that any specific introduction of melatonin as part of paediatric and young-person cancer treatment therapy would, of course, have to begin with an appropriate clinical trial.

As indicated above a number of those on older people have already been carried out with great success and impressive results. The use of safe use of melatonin in children with sleep disorders has also been established and accepted by NICE and the NHS in the UK.

Given the properties of melatonin, which is naturally produced in the body, its use in cancer treatment should be seen as a form of immunotherapy.


7. CCLG mention side effects of taking melatonin, but none of these can be considered serious. Melatonin regulates sleep and resets circadian rhythms. If taken in the daytime, it may induce drowsiness as prolonged-release melatonin may do so in elderly inform people who need to get up at night leading to falls.


8. The way forward

We propose to commission a Melatonin Report and then run a ‘Melatonin as an Adjunct’ workshop meeting. As indicated above, there are decent trials published that indicate melatonin’s effectiveness in improving survival and decreased unwanted toxic side effects.

Signed

Professor Denis Henshaw, Scientific Director,   and   Alasdair Philips, Trustee, Children with Cancer UK.

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