Barts-MS rose-tinted-odometer: ★★
Guilty as accused!
I did a very one-sided post this weekend on the pros of oral cladribine as a treatment for MS during the COVID-19 pandemic. One commentator asked ‘what about the cons?’. As with all immunosuppressive therapies, there is a risk of secondary malignancies. In fact, both the EMA and FDA labels mention secondary malignancies as a complication of cladribine therapy. We think the short-term cancer risk, i.e. within the first 2 years, was driven by the very low numbers of cases in the placebo arms of phase 3 trials. The cancer rate in the cladribine-exposed subjects was in keeping with the expected background rates compared to subjects on other DMTs and people from the general population from data in an international population-based cancer registry (GLOBOCAN). So I am not convinced that cladribine is associated with a short term cancer risk. However, the jury is out in relation to the intermediate to longterm risk. However, the safety data from the extension and post-marketing surveillance studies look very promising and based on the biology and mode-of-action of cladribine I think this risk is likely to be low.
Although cladribine works via DNA mechanisms it is not a mutagen; i.e. it does not cause mutations in DNA. When cladribine is incorporated into DNA it inhibits DNA polymerases, the enzymes that extend the DNA chain. The cell then senses this as a problem and this triggers apoptosis the biological process that causes the cell to trigger a suicide programme called ‘programmed cell death’. The reason why cladribine is so selective for lymphocytes is that the enzyme that activates cladribine is only found in high concentrations in lymphocytes and the other cells that don’t express this enzyme are resistant to cladribine’s effects.
Saying this secondary malignancy is a complication with all immunosuppressive therapies regardless of their mode of action. The reason is that we rely on peripheral tumour immune surveillance, i.e. our immune system find early cancers and attacks and destroys them. Suppress the immune system intensely enough and for long enough and certain cancers will develop. For example, fingolimod, and I suspect the whole S1P modulator class, is associated with skin cancer (basal and squamous), lymphoma and potentially other cancers, e..g. Kaposi’s sarcoma. Anti-CD20 therapies may be linked to breast cancer. Natalizumab, CNS lymphoma. Alemtuzumab, cervical cancer and possibly thyroid cancer, although one could argue the thyroid cancer risks with alemtuzumab may be due to ascertain bias from the high rate of thyroid screening due to thyroid secondary autoimmunity. The only DMTs not associated with secondary malignancies are the immunomodulators, i.e. interferon-beta, glatiramer acetate and teriflunomide.
Is there anything you can do about the immunosuppressive cancer risk? Yes, there is. You need to enrol and stick to your country’s cancer screening programmes. In the UK there are three national programmes; cervical, breast and colon. Breast cancer screening starts at the age of 50 and stops at the age of 70. Colon cancer screening starts at the age of 50 or 60, which depends on where you live in the UK. Cervical cancer screening is for women between 25 and 64 years of age. However, there is a push to extend cervical cancer screening beyond 64 now that cervical smear screening is being replaced with vaginal swabs, which are self-administered, and use PCR testing to detect HPV, the virus that causes cervical cancer. HPV testing is so much more pleasant for women and more reliable and reproducible than looking for abnormal cells under a microscope.
In the UK the prostate cancer screening programme is available on request, i.e. you can request a PSA (prostate-specific antigen) test. National PSA prostate cancer screening was dropped as the PSA assay was too unreliable. It generated too many false positives or detected very small cancers that were unlikely to cause any problems. In comparison, some of the treatments for prostate cancer cause more harm. In fact, most men who die in old age have asymptomatic prostate cancer at post-mortem; if something else rather than the cancer was going to kill these men why bother about detecting cancer? Please note the dropping of the national prostate cancer screening programme has been controversial and some people think it was a mistake. In many countries, PSA screening is still being done at a national level.
In some parts of the UK, there are pilot lung cancer screening programmes with high-resolution spiral chest CT scans being offered. The early results are very impressive in targeted groups at high-risk of lung cancer such as heavy smokers or ex-smokers. I am convinced that lung cancer screening is likely to become routine in the UK in smokers in the not too distant future.
Other groups for cancer screening include high-risk subjects for example patients with dysplastic naevus syndrome of the skin, who are at risk of melanoma, those with well-defined genetic conditions associated with specific cancers, patients with a very strong family history of specific cancers, patients with inflammatory bowel disease, anal cancer screening in HPV and HIV postive men-who-have-sex-with-men, oesophageal cancer screening in patients with Barrett’s oesophagus, etc.
A few years ago I asked our renal transplant team for advice about their cancer screening programme for their transplant patients. In short, they don’t do anything that is outside of the national cancer screening programme. The reason they gave is that when you start screening a younger population than that defined by the national screening programmes you are likely to detect more false positives cancers, which leads to unnecessary intervention that cause more harm. You also create cancer anxiety syndrome; i.e. patients start to worry excessively about developing cancer. I have a few patients on DMTs who suffer from this condition; so it is real.
However, there are some self-screening programmes that you can engage in, for example, self-examination of your breasts and testes for woman and men, respectively, and the regular examination of worrisome skin lesions. The following are just three YouTube videos on how to do breast, testes and skin lesion self-examinations.
As MS HCPs we are meant to prompt you to make sure you are registered with your GP and are enrolled in the screening programmes. Outside of HPV screening in women about to start an immunosuppressive therapy, I tend to forget to do this. This is another example to have proformas of standardised checklists to make sure we don’t forget this important task.
I would be interested to know what your experience has been with regard to your awareness about cancer risk on immunosuppressive therapies, cancer screening and self-examination. In this study below despite the vast majority of the woman being aware of breast self-examination, a large minority didn’t examine their breasts every month. Does this apply to you?
Watanabe et al. Awareness of Self-Examination, Screening, and Risk Factors for Breast Cancer Among Women Awaiting Care at the Outpatient Clinic of a Mastology Unit. J Cancer Educ. 2020 Oct 9. doi: 10.1007/s13187-020-01892-1.
This study aimed to evaluate the awareness and practice of breast self-examination (BSE) and the awareness of screening and risk factors for breast cancer among patients from a mastology clinic and to associate such findings with sociodemographic factors of that population. A total of 202 randomly selected patients from the outpatient clinic of the Mastology Unit of São Paulo School of Medicine were interviewed. A structured questionnaire was used and included questions regarding sociodemographic variables, questions to assess the knowledge and practice of BSE, and knowledge of mammographic screening and risk factors for breast cancer. The vast majority of patients were aware of the existence of BSE (93.1%). BSE was performed by most patients (64.9%), although only 20.3% performed it adequately. Only 21.8% of respondents showed awareness of the best screening method for breast cancer. Furthermore, 17.3% of patients showed adequate awareness of risk factors for breast cancer. The analysis of sociodemographic variables showed that older, postmenopausal, and less-educated women showed better practice of BSE. Overall, the patients had no adequate awareness of BSE, mammographic screening, and risk factors for breast cancer, and the majority failed to practice BSE adequately, particularly the group of patients with the higher level of education. These data show that educational measures regarding the practice of BSE and, especially, mammograms should be emphasized, regardless of education level or family income of the patient.
PS (4-Mar-2021): In response to a request from one of the comments in the survey: “…you could you please comment on cancer risk for anti CD20+ treatments, as well as cancer-related topics for younger pwMS”. I have therefore added the presentation from Professor Hauser from the MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting, from September 2020. As you can see the rate of malignancies and female breast cancer in ocrelizumab-treated patients remained broadly within the range reported in the general population from epidemiological data. Please note these patients have been followed for over 7 years. I hope this helps.