Tag Archives: Cancer

Oh Dear – Evidence Against Alcohol Accumulates

Yes, more research [1] [2] on alcohol – increases in cancers of mouth, throat and oesophagus. Not good places to have cancer. Direct contact of C2-H5-OH with the membrane is the likely causal mechanism. So here is an hypothesis – the more dilute a given amount of alcohol, the better. So I think beer > wine > spirits, ceteris paribus. I guess this has been tested? But next week I may have some more reassuring news for us oenophiles.

— Richard Lilford, CLAHRC WM Director

References:

  1. LoConte NK, Brewster AM, Kaur JS, Merrill JK, Alberg AJ. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. J Clin Oncol. 2017; 35: 1-11.
  2. The Lancet. Alcohol and cancer. Lancet. 2017. 390: 2215.
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Calling All Men – Screening for Prostate Cancer Probably Does Save a Few Prostate Cancer Deaths

Two large randomised trials with 12 years follow-up.[1] [2] One shows reduction in prostate cancer deaths, the other produced a null result. But science cannot prove a null, and point estimates were favourable in both trials. Moreover, there were many differences in implementation of screening across the two large trials. So the authors of a recent study [3] amalgamated the individual research from each individual study and analysed the consolidated dataset to adjust for differences in screening intensity using a measure of the average time by which diagnosis is advanced by screening compared to not screening. This was calculated in different ways, but the results do suggest a screening effect on prostate cancer deaths of about 8%. Whether this translates into all-cause mortality is uncertain, as per a previous News Blog on this issue.[4] I was attracted to this paper, not only because prostate screening is a controversial and important public health issue, but also because it deals with a common scenario in contemporary clinical research – apparently contradictory trial results where one trial provides a null result and the other provides a positive result.

— Richard Lilford, CLAHRC WM Director

References:

  1. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014; 384: 2027-35.
  2. Pinsky PF, Prorok PC, Yu K, et al. Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years. Cancer. 2017; 123: 592-9.
  3. Tsodikov A, Gulati R, Heijnsdijk AEM, et al. Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials. Ann Intern Med. 2017; 164: 449-55.
  4. Lilford RJ. Thyroid Cancer: Another Indolent Tumour Prone to Massive Over Diagnosis. NIHR CLAHRC West Midlands News Blog. 24 March 2017.

How Many Mutations for Cancer?

During our lifetime our somatic cells (non-reproductive cells) constantly accumulate mutations – in some cases these mutations lead to uncontrolled proliferation and allow the cells to invade other tissues and spread to other organs – i.e. become cancerous. Most of the mutations in cancerous cells are unimportant – it is only a few that are ‘drivers’ of cancer and dictate the way the cell behaves. However, we do not know how many mutations are actually required to cause cancer, or whether this number varies across cancer types.

Researchers working for the Wellcome Trust looked at over 7,500 tumours of 29 cancer types using methods adapted from molecular evolution to see which mutations were more common in cancerous than in non-cancerous cells.[1] They found that, on average, cancerous cells have around four coding substitutions (where a DNA nucleobase is exchanged for another, such as switching from adenine to guanine) that are ‘driver mutations’. This ranged from around one mutation per tumour in thyroid and testicular cancer, four in breast and liver cancer, to more than ten in endometrial and colorectal cancer. Of these ‘driver mutations’ around half occur in cancer genes that have yet to be discovered.

In the long-term these findings could help advance the development of precision cancer treatment, allowing drugs to be specifically targeted at the appropriate mutation(s).

— Peter Chilton, Research Fellow

Reference:

  1. Matrincorena I, Raine KM, Gerstung M, Dawson KJ, Haase K, Van Loo P, Davies H, Stratton MR, Campbell PJ. Universal Patterns of Selection in Cancer and Somatic Tissues. Cell. 2017.

Alternative Therapies for Cancer

We often read of cancer patients who forgo or delay traditional conventional options, such as chemotherapy, and instead opt for alternative therapies, such as spiritual healing or herbal remedies given by non-medical personnel. Unfortunately this can have serious survival implications for the patient – in many cases the treatment fails to stop the cancer. However, there is a paucity of actual clinical evidence on the use and effectiveness of alternative therapies. Step in Johnson and colleagues who examined the United States Cancer Database to compare the survival outcomes of patients who underwent alternative therapies with those who received conventional therapies for four cancer types (breast, prostate, lung and colorectal).[1] Although rare, they found 281 patients who had chosen alternative therapies exclusive of any other treatment – these patients were more likely to be younger, female, have a lower comorbidity score, higher income, higher education, and a more advanced cancer stage. When matched with patients who received conventional treatments (on cancer type, age, clinical stage, etc.), they found that alternative therapies were associated with significantly lower five-year survival overall – 78.3% of patients who underwent conventional therapies survived, compared to 54.7% of those who had alternative therapies only (hazard ratio 2.21, 95% CI 1.72-2.83). When looked at by cancer type increased hazard ratios were found for breast (HR 5.68, 95% CI 3.22-10.04), lung (HR 2.17, 95% CI 1.42-3.32) and colorectal cancer (HR 4.57, 1.66-12.61), but there was no significant difference for prostate cancer (HR1.68, 95% CI 0.68-4.17) – the authors suggest this may be because of the long natural history of prostate cancer and the short follow-up of the study.

By itself, undergoing alternative therapies isn’t likely to be harmful, but it should be taken in combination with conventional therapy, and health practitioners need to ensure that patients are fully aware of the impact of their decisions regarding cancer treatment.

— Peter Chilton, Research Fellow
Reference:

  1. Johnson SB, Park HS, Gross CP, Yu JB. Use of Alternative Medicine for Cancer and Its Impact on Survival. J Natl Cancer Inst. 2017.

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

References:

  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

References:

  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

Reference:

  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

Reference:

  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

Reference:

  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

Reference:

  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.