Patients with immune-mediated diseases and a history of malignancy had similar rates of cancer recurrence whether or not they were receiving immunosuppressive treatments, shows a newly published systematic review and meta-analysis that covered approximately 24,000 patients and 86,000 person-years of follow-up.

The findings could “help guide clinical decision making,” providing “reassurance that it remains safe to use conventional immunomodulators, anti-TNF [tumor necrosis factor] agents, or newer biologics in individuals with [immune-mediated diseases] with a prior malignancy consistent with recent guidelines,” Akshita Gupta, MD, of Massachusetts General Hospital, Boston, and coinvestigators wrote in Clinical Gastroenterology and Hepatology.

And because a stratification of studies by the timing of immunosuppression therapy initiation found no increased risk when treatment was started within 5 years of a cancer diagnosis compared to later on, the meta-analysis could “potentially reduce the time to initiation of immunosuppressive treatment,” the authors wrote, noting a continued need for individualized decision-making.

Ustekinumab, a monoclonal antibody targeting interleukin-12 and IL-23, and vedolizumab, a monoclonal antibody that binds to alpha4beta₇ integrin, were covered in the meta-analysis, but investigators found no studies on the use of upadacitinib or other Janus kinase (JAK) inhibitors, or the use of S1P modulators, in patients with prior malignancies.

The analysis included 31 observational studies, 17 of which involved patients with inflammatory bowel disease (IBD). (Of the other studies, 14 involved patients with rheumatoid arthritis, 2 covered psoriasis, and 1 covered ankylosing spondylitis.)

Similar levels of risk

The incidence rate of new or recurrent cancers among individuals not receiving any immunosuppressive therapy for IBD or other immune-mediated diseases after an index cancer was 35 per 1,000 patient-years (95% confidence interval, 27-43 per 1,000 patient-years; 1,627 incident cancers among 12,238 patients, 43,765 patient-years), and the rate among anti-TNF users was similar at 32 per 1,000 patient-years (95% CI, 25-38 per 1,000 patient-years; 571 cancers among 3,939 patients, 17,772 patient-years).

Among patients on conventional immunomodulator therapy (thiopurines, methotrexate), the incidence rate was numerically higher at 46 per 1,000 patient-years (95% CI, 31-61; 1,104 incident cancers among 5,930 patients; 17,018 patient-years), but was not statistically different from anti-TNF (P = .92) or no immunosuppression (P = .98).

Patients on combination immunosuppression also had numerically higher rates of new or recurrent cancers at 56 per 1,000 patient-years (95% CI, 31-81; 179 incident cancers, 2,659 patient-years), but these rates were not statistically different from immunomodulator use alone (P = .19), anti-TNF alone (P = .06) or no immunosuppressive therapy (P = .14).

Patients on ustekinumab and vedolizumab similarly had numerically lower rates of cancer recurrence, compared with other treatment groups: 21 per 1,000 patient-years (95% CI, 0-44; 5 cancers among 41 patients, 213 patient-years) and 16 per 1,000 patient-years (95% CI, 5-26; 37 cancers among 281 patients, 1,951 patient-years). However, the difference was statistically significant only for vedolizumab (P = .03 vs. immunomodulators and P = .04 vs. anti-TNF agents).

Subgroup analyses for new primary cancers, recurrence of a prior cancer, and type of index cancer (skin cancer vs. other cancers) similarly found no statistically significant differences between treatment arms. Results were similar in patients with IBD and RA.

Timing of therapy

The new meta-analysis confirms and expands a previous meta-analysis published in Gastroenterology in 2016 that showed no impact of treatment – primarily IMM or anti-TNF treatment – on cancer recurrence in patients with immune-mediated diseases, Dr. Gupta and coauthors wrote.

The 2016 meta-analysis reported similar cancer recurrence rates with IMMs and anti-TNFs when immunosuppression was introduced before or after 6 years of cancer diagnosis. In the new meta-analysis – with twice the number of patients, a longer duration of follow-up, and the inclusion of other biologic therapies – a stratification of results at the median interval of therapy initiation similarly found no increased risk before 5 years, compared with after 5 years.

“Although several existing guidelines recommend avoiding immunosuppression for 5 years after the index cancer, our results indicate that it may be safe to initiate these agents earlier than 5 years, at least in some patients,” Dr. Gupta and coauthors wrote, mentioning the possible impact of selection bias and surveillance bias in the study. Ongoing registries “may help answer this question more definitively with prospectively collected data, but inherently may suffer from this selection bias as well.”

Assessment of the newer biologics ustekinumab and vedolizumab is limited by the low number of studies (four and five, respectively) and by limited duration of follow-up. “Longer-term evaluation after these treatments is essential but it is reassuring that in the early analysis we did not observe an increase and in fact noted numerically lower rates of cancers,” they wrote.

It is also “critically important” to generate more data on JAK inhibitors, and to further study the safety of combining systemic chemotherapy and the continuation of IBD therapy in the setting of a new cancer diagnosis, they wrote.

The study was funded in part by grants from the Crohn’s and Colitis Foundation, and the Chleck Family Foundation. Dr. Gupta disclosed no conflicts. One coauthor disclosed consulting for Abbvie, Amgen, Biogen, and other companies, and receiving grants from several companies. Another coauthor disclosed serving on the scientific advisory boards for AbbVie and other companies, and receiving research support from Pfizer.

Veronica Hackethal, MD, MSc

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