What is the cancer risk with MS Disease-modifying treatments?

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This question comes up time and again with MS treatments and probably is one of the most important negative selection choices secondary to PML for DMTs in MS. Every time a new drug is presented to the clinical community, the cancer stats are heavily scrutinised. For example, with ocrelizumab the greater number of breast cancers in the treated arm versus placebo impacted on who ultimately received the drug i.e. not someone with a family history of breast cancer.

A review of 42 randomized controlled trials between 1991-2021, however tells a different story. In a pooled analysis of 10,638 placebo participants and 16,360 active drug participants there was no difference in the incidence rates of tumours in either arm (560 cancers in placebo and 430 cases in active treatment per 100,000 person-years). This is lower than what is reported in the MS population outside of clinical trials.

They also observed that the incidence of tumours increased with time, particularly after 2011 (see Figure below). This is in line with the use of more potent immunosuppressants over the past decade or so, but of course other factors such as environment (e.g. pollution), co-morbidities (e.g. obesity, smoking), cancer screening and diagnosis, and lifestyle changes may also be responsible for this observation. In their discussion on this point the authors have written the following:

The statistically significant effect of the sequestrating and depletive mechanism of action on the risk of neoplasms in both the placebo and the active-treatment groups of DMTs but not on the neoplasm incidence rate ratio between active and placebo groups indicates that the apparent effect modification may not be a direct one but a result of confounding. The modifier effect of sequestrating and depleting agents on cancer incidence may reflect the fact that these agents are commonly used as second line treatments and in older pwMS.

And, of course the last sentence with the effect of age is a different dilemma to ponder over altogether!

However, on balance I think looking at active and placebo arms of clinical trials for cancer rates isn’t that useful, as it’s looking at only a snapshot of what is the lead time for the development of cancer (which amounts to 30-50 years in a majority of cases), and also rarely is data on lifestyle factors collected in clinical trials. Nonetheless, this analysis does provide interesting data and probably it is worth collecting long-term data on immunosuppressive and immune sequestering agents to know truly if there is something there.

Figure: Bubble plot of log-incidence rate of neoplasms vs. year of study publication. There is a statistically signifcant direct relationship between the log-incidence rate of neoplasms in placebo (β=0.0805, P<0.0001, n=38) (A) and active arm of MS trials (β=0.0693, P=0.0118, n=35) (B) and the year of trial publication

Abstract

Neurol. 2022 Jan 23. doi: 10.1007/s00415-021-10932-9. Online ahead of print.

Disease-modifying treatments for multiple sclerosis have not affected the incidence of neoplasms in clinical trials over 3 decades: a meta-analysis with meta-regression

Dimitrios Papadopoulos Panagiotis GklinosGiorgos Psarros  Konstantina Drellia Eumorphia Maria Delicha Tim Friede Dimos D Mitsikostas Richard S Nicholas 

Objective: Our study aimed to estimate the incidence of neoplasms in clinical trials of DMTs for MS and to test the hypothesis that DMTs increase the risk of neoplasms in the duration of MS randomized controlled trials (RCTs).

Methods: Data were extracted from 42 RCTs of DMTs published between 1991 and 2020. The incidence rate (IR) of neoplasms was estimated by pooling the neoplasms in the active and placebo-treatment arm per patient-year. The neoplasm incidence rate ratio (IRR) of active over placebo-treatment arms was used as measure of the effect of DMTs on the risk of developing neoplasms.

Results: The meta-analysis included 10,638 placebo and 16,360 active-treatment arm patients. A non-significant pooled neoplasm incidence rate ratio (IRR: 1.0797; 95% CI: 0.8281 to 1.4077; P = 0.5711) with no heterogeneity (I2 = 0%) was observed in active over placebo-treatment groups from 1991 to 2020. We found a significant association between the incidence of neoplasms and the year of publication in both active and placebo arms of RCTs. Trials of sequestrating and depletive DMTs were associated with significantly higher incidence of neoplasms in both active and placebo-treated arms compared to immunomodulatory treatment trials.

Conclusions: Our study indicates that treatment with DMTs has not modified the risk of neoplasms in MS clinical trials from 1991 to 2020, which may reflect a low carcinogenic potential of DMTs and/or that the neoplasia latencies far exceed the typical MS trial observation periods.

Keywords: Cancer; Disease-modifying treatments; Multiple sclerosis; Neoplasm; Randomized clinical trials.

About the author

Neuro Doc Gnanapavan

4 comments

  • One big confounding factor is that exercise may help reduce the risk of cancer.
    There are papers being published about this at the moment.
    It’s confounding because MS, left to its own devices, increases disability and therefore decreases the levels of exercise possible. Therefore pwMS untreated would be expected to have higher cancer rates as we don’t exercise as much. Do we know if this is the case – are those who opt to forego treatment at greater risk of cancer than the background population?

    The more potent DMTs allow us to have more active lives for longer. If exercise = lower cancer risk then we should see

    more activity = lower cancer risk.

    So if a DMT increases cancer risk but the extra exercise decreases cancer risk, is exercise fully cancelling out the additional DMT risk? And which DMTs carry higher risk vs efficacy and the ability to continue exercising and its capacity to reduce cancer risk?

    For example aHSCT might carry a ridiculously high cancer risk BUT because it means the patient is effectively “reset” and lives an active life from then on – how much does that “active life” and the exercise done in that life mitigate the risks from the treatment?

    There is also a role to be played by GPs here. It’s all very well for Summaries of Product Characteristics to warn of a possible increase in cancer risk. But if family doctors keep dismissing the well-founded concerns of patients asking for cancer screening “early” or where they might otherwise not be considered a risk – then that risk of cancer becomes not only a reality but a reality resulting untreated and potentially deadly tumours.

    The cancer risk depends on how seriously patients and doctors take the slow but inevitable brain damage from MS – whether the benefit of aggressive treatment is worth the risk of potential cancer.

    But it is also dependent on how vigilant first-line practitioners are. As an MS patient I would be happy to take the risk of potentially developing cancer if I know we are monitoring vigilantly and will treat it aggressively. As it stands I can not have that confidence because I know my GP will just fob me off as hypochondriac.

    • 👍🏻

      True, so True.

      [Off topic, but answer to Simon Brown]

      Out of my own experience and of relatives.

      We just kept annoying the first line docters and in a later stage also my first neuro.

      I know me better than everyone else. So if I say that something is wrong I’m a pitbull.
      Most people who are not hospital regulars let them being send home. Oh, the doctor said that it’s probably nothing.

      My newest neuro and my ms nurse always take my info with care and handle accordingly.

      My sister had the same when they found a tumor of 7 by 5 cm. She had to keep pushing! OMG

      Just keep pushing if you are send back home!

      You know you!

      Thanks for all your topics NDG. I always enjoy reading them. (And Google translate doesn’t make a mess of it like with MD1)🧐

      Sorry MD1 🤐

    • Hi Simon,
      It’s in fact the socioeconomic determinants that play an even bigger role (I suspect some of this is delayed diagnosis) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073199/
      And then you have individual risk such as older age, smoking, red meat, salt (stomach cancer), alcohol excess etc.
      The exercise is probably linked to many of these factors and difficult to separate out.
      In population terms MS patients have a lower risk than the population average for cancer, but we don’t know if long-term use of DMTs increases this risk in a small way.

  • I always looked at it this way: cancer is a Disease I MIGHT have someday, or not. MS is the disease I definitely DO have. I’m going to treat the disease I definitely do have as aggressively as possible and not worry about other hypothetical diseases.

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