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MS drug mitoxantrone may increase colorectal cancer risk
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Patients with multiple sclerosis treated with mitoxantrone may face an increased risk for colorectal cancer, according to the results of a retrospective cohort study.
Colonoscopy should be advised for these patients after mitoxantrone therapy if the association is confirmed, according to the researchers.
“A number of observational studies demonstrated an increased incidence of acute myeloid leukemia in patients with multiple sclerosis [MS] treated with mitoxantrone,” Mathias Buttmann, MD, senior neurology consultant at University of Würzburg in Germany, told HemOnc Today. “Most of these studies focused on leukemia, but did not study the incidence of other types of malignancies.”
Buttmann and colleagues retrospectively reviewed 676 patients (median age, 41 years; interquartile range [IQR], 33-47; 67.2% women) with MS treated at their institution between 1994 and 2007.
The researchers collected information on confirmed malignancies in these patients, as well as life status and cause of death through the year 2010. They calculated standardized incidence ratios based on comparison with the German general population. Malignancy rates were compared with the German national cancer registry and matched for age, sex and year of occurrence.
Median follow-up was 8.7 years (IQR, 6.8-11.2), representing 6,220 person-years.
The cohort had a median cumulative mitoxantrone dose of 79 mg/m2 (IQR, 50.8-102.4).
Thirty-seven patients (5.5%) developed a malignancy after initiation (SIR = 1.5; 95% CI, 1.05-2.08). Malignancies that developed after treatment included breast cancer (n = 9), colorectal cancer (n = 7), AML (n = 4), and two cases each of glioblastoma multiforme, lung cancer, pancreatic cancer and prostate cancer. Nine other unspecified malignancies also developed.
All patients diagnosed with AML achieved full remission and remained alive at the end of follow-up.
The median age for patients diagnosed with colorectal cancer was 58 years (range, 53-73); these patients had a cumulative mitoxantrone dose of 61 mg/m2 (range, 36-115).
All but one patient received their diagnoses at tumor stage pT3, with the remaining patient diagnosed at tumor stage pT4. Six patients presented with local lymph node metastases; four had distant metastases.
Three patients with colorectal cancer died of their disease during follow-up. In the overall cohort, 55 patients (8.1%) died. Twelve deaths were attributed to malignancy.
The researchers calculated increased SIRs for colorectal cancer (SIR = 2.98; 95% CI, 1.2-6.14) and AML (SIR = 10.44; 95% CI, 3.39-24.36). They did not observe significant increases for other malignancies, including breast cancer.
Multivariate analyses identified older age at treatment initiation as a risk factor for malignancy. Cumulative dose (> 75 mg/m2 vs. 75 mg/m2), treatment with other immunosuppressive agents, and sex did not appear to be risk factors.
The researchers acknowledged study limitations, including the small cohort size and the potential exclusion of improperly diagnosed malignancies. They further noted that additional malignancies may have been diagnosed with a longer follow-up period.
“Seven cases of colorectal cancer represent a threefold increase compared to the general population when matched for age, sex and year of occurrence,” Buttmann said. “Although this represented a statistically significant increase, the number of observed cases is too low to firmly conclude that mitoxantrone increases the risk for colorectal cancer in MS patients. Further observational studies in other cohorts, specifically studying the incidence of colorectal cancer in mitoxantrone-treated MS patients, are needed before we can be sure that this is a true adverse effect of mitoxantrone and did not occur by chance in our cohort.”
Due to the paucity of approved therapies for secondary progressive MS, mitoxantrone should continue to be prescribed in carefully selected cases, according to Buttmann.
“I am aware that neurologists who have not used a lot of mitoxantrone in the past might be further deterred by our study to use it in their patients, while physicians with a lot of clinical experience in using this drug will continue using it in selected patients due to its strong therapeutic potential,” Buttmann said. “Should our finding be confirmed, post-therapy colonoscopy might help to improve the safety of this still important drug.” – by Cameron Kelsall
For more information:
Mathias Buttmann , MD, can be reached at m.buttmann@ukw.de.
Disclosure: Buttmann reports grants for clinical research related to multiple sclerosis biomarkers from Merck Serono and Novartis; consultant roles with Roche and Teva Pharma; speaking fees from Biogen; and travel expenses from Bayer HealthCare Pharmaceuticals, Genzyme and Novartis. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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