Tag Archives: Cancer

Yet Another Null Result on Vitamin D and Calcium Supplementation in Older Women

Hard on the heels of the results of a systematic review in a recent blog,[1] yet another RCT of calcium and vitamin D in healthy people.[2] This time the end-point is cancer, and again the result is null. The authors call for yet more research but, again, one wonders whether this topic should not just be put to bed. It is true, of course, that exposure to sunlight is associated with lower risk of cancer, but this might not be a causal relationship, and even if it is, sunlight and oral vitamin D are not the same thing, just as oral and ovarian oestrogen are not equivalent.

— Richard Lilford, CLAHRC WM Director


  1. Lilford RJ. Effects of Vitamin D Supplementation. NIHR CLAHRC West Midlands News Blog. 24 March 2017.
  2. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women. A Randomized Clinical Trial. JAMA. 2017; 317(12): 1234-43.

Three Hits Hypothesis

Quite a lot of diseases are brought about by the conflation of two factors. Mice infected with certain herpes viruses suffer no ill-effect unless a helminth infestation supervenes. Oral allergy syndrome arises when a certain pollen interacts with certain foods (usually raw fruits, vegetables and nuts). The hygiene hypothesis says that lack of exposure to certain gut bacteria sensitises the body to allergic reactions to a range of environmental allergens. The pathway for disease involves three hits:

Genetically predisposed person –> Exposure 1 –> Exposure 2 –> Disease.

An intriguing example of a three-hit condition is the severe disease of children – Burkitt’s lymphoma. This cancer arises in germinal centres of lymph nodes in the neck. It is known that Epstein-Barr (EB) virus infection is necessary for endemic Burkitt’s lymphoma to develop because it prevents apoptosis (cell death) when certain mutations occur in the cell. But endemic Burkitt’s lymphoma only occurs in the malaria belt, and why this is so has been a mystery until the last few years. Now we know that the malaria parasite Plasmodium falciparum ‘upregulates’ an enzyme that causes mutations in DNA in lymph cells. These mutations are a normal part of antibody production since rearrangements of chromosome segments is necessary for antibody specificity. But in people with falciparum malaria, the effect ‘spills over’ to cause mutations of cancer genes. The double hit of EB plus malaria sets the scene for carcinogenesis.[1] Why in the neck – perhaps because lymph cells in the necks of children work particularly hard eradicating throat and ear infections, in which case there is a ‘four hits’ hypothesis!

— Richard Lilford, CLAHRC WM Director


  1. Thorley-Lawson D, Deitsch KW, Duca KA, Torgbor C. The Link between Plasmodium falciparum Malaria and Endemic Burkitt’s Lymphoma—New Insight into a 50-Year-Old Enigma. PLoS Pathog. 2016; 12(1): e1005331.

Can Thinking Make It So?

When we think of risk factors for mortality we properly think behaviours (e.g. smoking / obesity) or genetics (e.g. family history). What about psychological factors – can unhappiness increase your risk of risk of cancer? Well, Batty and colleagues [1] have tackled this problem as follows:

  1. They assembled 16 prospective cohort studies where behaviours and psychological state had been measured and in which participants were followed up to see if cancer developed.
  2. They obtained the raw data and obtained an individual patient meta-analysis.
  3. They adjusted for the usual things known to increase risk of cancer (obesity, smoking, etc).
  4. They calculated relative risk of cancer according to antecedent psychological state.

They found a positive correlation between psychological distress and risk of cancer. But causality might have run the other way – (occult) cancers may have been the cause of psychological distress, not the other way round. So:

  1. They ‘left censored’ the data, thereby widening the gap between the point in time where the psychological state was measured and the point where cancer supervened.

The association between psychological state and cancer death persisted, even when they were separated by many years. What is the explanation?

  1. Failure to fully control for all behaviours (although behaviour could be the mechanism through which the cancer risk is increased in people with depression, in which case they ‘over-controlled’).
  2. Reduced natural killer cell function.
  3. Increased steroid levels, which can apparently affect DNA repair in some way.
  4. Some mechanism yet to be discovered.

In any event, the findings are intriguing, for all that practical implications may be limited.

— Richard Lilford, CLAHRC WM Director


  1. Batty GD, Russ TC, Stamatakis E, Kivimäki M. Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies. BMJ. 2017; 356: j108.

Thyroid Cancer: Another Indolent Tumour Prone to Massive Over Diagnosis

Park and colleagues, writing in the BMJ, document a massive (80 times) rise in the incidence of thyroid cancer in South Korea over the past two decades.[1] What is going on here? An epidemic of thyroid cancer in South Korea? No, the mortality from cancer of the thyroid has remained absolutely flat over the study period. The rise in the incidence of cancer is due entirely to screening uncovering cancers that would have otherwise remained occult. It turns out that the great majority of thyroid cancers are entirely innocent. As with prostate cancer and intraductal breast cancer, thyroid cancer tends to have a very long lead time, such that the patient is most likely to die with, rather than from, the disease.

— Richard Lilford, CLAHRC WM Director


  1. Park S, Oh C-M, Cho H, et al. Association between screening and the thyroid cancer “epidemic” in South Korea: evidence from a nationwide study. BMJ. 2016; 355: i5745.

Using Meta-Analysis to Answer Questions That Could Never Be Answered in a Single Trial

An example based on surgical technique for excision of cervical pre-cancer

It is well known that cervical pre-cancer is associated with increased risk of pre-term birth (with all that this entails), and that cervical treatment adds to the risk. A recent extensive meta-analysis of 70 observational studies with a control group of some sort showed that the more radical the procedure (in terms of tissue destroyed or removed), the greater the risk.[1] This is important information for women who must balance the putative benefit of deeper margins against the documented risks to a subsequent pregnancy. Where possible (i.e. milder grade lesions) it may be advisable to delay treatment until after bearing children and, indeed, not to delay having children.

— Richard Lilford, CLAHRC WM Director


  1. Kyrgiou M, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ. 2016; 354: i3633.

Abnormal Glandular Cells on a Smear Test: What Do They Mean?

When a woman has a smear test, two types of cell are sampled – squamous cells from the ectocervix, and glandular cells from the endocervix:

054 DC - Abnormal Glandular Cells

When abnormal cells are found they are mostly squamous cells from the ectocervix. But about one time in twenty they are glandular cells from the endo-cervix. The squamous cells, meanwhile, can have either a high-grade or a low-grade abnormality.

A recent Swedish study followed up over three million women who had had a cervical smear.[1] Over 15 years, over 3% of women with high-grade squamous cell abnormality and nearly 1% with low-grade squamous cells abnormality developed invasive cancer – almost always squamous cell cancer. But what about the much smaller population of women with abnormal glandular cells? Here about 2.5% developed cancer over the follow-up period – usually adenocarcinoma. The risk is greatest over the first few months, thereafter accumulating very gradually. The high risk post-smear is, of course, because the smear is the trigger for the biopsy. The very slow progression rate over subsequent years should be highly reassuring for any woman who has had an abnormal smear result. As cone biopsy is associated with worse pregnancy outcomes, the CLAHRC WM Director would advise women with abnormal glandular cells to have regular smear test and complete their families as soon as possible. Testing for different types of papilloma virus may help determine whether the risk is higher or lower than the above risk of 2.5%. This study shows the value of long-term registry data of the sort Sweden is famous for.

— Richard Lilford, CLAHRC WM Director


  1. Wang J, Andrae B, Sundström K, et al. Risk of invasive cervical cancer after atypical glandular cells in cervical screening: nationwide cohort study. BMJ. 2016; 352: i276.

An Article We All Had Better Read

Oh dear – the CLAHRC WM Director would so like to think that disease-specific mortality is the appropriate outcome for cancer screening trials, rather than all-cause mortality. But Black and colleagues have published a very sobering article.[1] They found 12 trials of cancer screening (yes, only 12) where both cancer-specific mortality and all-cause mortality are reported. The effect size (in relative risk terms) is bigger for cancer-specific than for all-cause mortality in seven trials, about the same in four, and the other way in one. This suggests that the benefit is greater, even relatively, for cancer-specific than for all deaths. There are two explanations for this – one that the CLAHRC WM Director had thought of, and the other that was new to him.

  1. Investigation and treatment of false positives (including cancers that would never had presented) may increase risk of death as a result of iatrogenesis and heightened anxiety. There is some evidence for this.
  2. According to the ‘sticky diagnosis theory’, once a diagnostic label has been assigned, then a subsequent death is systematically more likely to be attributed to that diagnosis than if that diagnosis had not been made. There is some evidence for this hypothesis too.

And here is the thing – in screening trials a very small proportion of people in either arm of the study die from the index disease. The corollary is that a small mortality increase among the majority not destined to die has a relatively large effect.

So we have done many expensive trials, and implemented large, expensive screening programmes, yet our effects might have been nugatory. And there is a reason why so few trials have all-cause mortality outcomes – the trials have to be long and potential effects on this end-point are small and liable to be lost in the noise. Somewhere there is a ‘horizon of science’ where precision is hard to find, and where tiny biases can swamp treatment effects. At the risk of sounding nihilistic, the CLAHRC WM Director wonders whether cancer screening is such a topic.

— Richard Lilford, CLAHRC WM Director


  1. Black WC, Haggstrom DA, Welch HG. All-Cause Mortality in Randomized Trials of Cancer Screening. J Nat Cancer Instit. 2002; 94(3): 167-73.

More on Whole Genome / Whole Exon Germline Sequencing – This Time in Children Who Get Cancer

News Blog readers may remember a previous post on germline mutations in children with autism spectrum disorder (with and without congenital anomalies). Now germline mutations have been compared in children with cancer and controls.[1] Among 1,120 affected children, 8.5% had predisposing germline gene mutations. This was an underestimate because it included only genes that were identified in advance, on the grounds of established relevance to carcinogenesis. The real value may be 50% higher. Only 40% of patients with likely pathogenic mutations had any family history. The CLAHRC WM Director suspects that children with germline mutations are at risk of second primary cancers, and that some second primary cancers previously attributed to treatment of the primary cancer are in fact caused by germline mutations. The CLAHRC WM Director proposes a study to examine the incidence of such mutations in children with secondary cancers.

— Richard Lilford, CLAHRC WM Director


  1. CZhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015; 373:2336-46.

Q. When Can Evidence-Based Care do More Harm than Good?

A. When People Mistake no Evidence of Effect for Evidence of no Effect.

Imagine that you have malignant melanoma on your forearm. You can select wide margin excision or a narrow margin. The latter is obviously less disfiguring.

Results from six RCTs (n=4,233) have been consolidated in a meta-analysis.[1] In keeping with individual trials and with previous meta-analyses, the result is null for numerous outcomes. However, the point estimates all favour wider margins and the confidence limits are close to the (arbitrary) 0.5% significance level. For example, the hazard ratio for overall survival favouring wide margins is 1.09 (0.98-1.22). The authors state that the study shows “a 33% probability that [overall survival] is more than 10% worse” when a narrow margin excision is used. It should be added that this assumes an uninformative prior. If the prior probability estimate favoured better survival with wider excision margins, then the evidence in favour of a wider margin excision is stronger still. Moreover, the authors quote results showing that patients do not trade even small survival gains for improved cosmetic outcome. Despite loose statistical language (conflating the probability of survival given the data with the probability of the data if there was no difference in outcome), the authors have done science and practice a great service. This paper should be quoted in the context of surgical treatment of cancer, not just melanoma excision. For example, is sentinel biopsy really preferred to axillary dissection in breast cancer surgery?

— Richard Lilford, CLAHRC WM Director


  1. Wheatley K, Wilson JS, Gaunt P, Marsden JR. Surgical excision margins in primary cutaneous melanoma: A meta-analysis and Bayesian probability evaluation. Cancer Treat Rev. 2015. [ePub].

Smokeless Tobacco

News blog readers will have seen our recent blog post on the dangerous areca nut that is often chewed with tobacco. Siddiqi and colleagues have carried out a massive survey of the use of “smokeless tobacco” worldwide, yielding data from 113 countries.[1] Smokeless tobacco is heavily consumed in South and South East Asia, and some African and Nordic countries. The authors conducted an extensive meta-analysis of the effects of oral tobacco – a task made complex by the many different preparations. For example, versions used in Nordic countries, South Africa and North America seem innocuous, whereas versions used in Asia are highly carcinogenic, even after controlling for alcohol and smoking. Of course, much of the toxicity may come not from the tobacco, but from the areca nut that often accompanies it and which releases large amounts of cancer and fibrosis-inducing copper.

— Richard Lilford, CLAHRC WM Director


  1. Siddiqi K, Shah A, Abbas SM, Vidyasagaran A, Jawad M, Dogar O, Sheikh A. Global burden of disease due to smokeless tobacco consumption in adults: analysis of data from 113 countries. BMC Medicine. 2015. 13:194.