Mitoxantrone and Colorectal Cancer: Is There an Increased Risk?

Mitoxantrone is an anthracycline derivative used in multiple indications. The drug works by intercalating into DNA, causing breaks in the DNA strand, as well as binding type II topoisomerase, which disrupts DNA replication.¹ Both patients with cancer (prostate, acute non-lymphocytic leukemia, lymphoma) and non-cancerous (multiple sclerosis [MS]) conditions are treated with mitoxantrone.

The effects of mitoxantrone are seen both on proliferating and non-proliferating cells, leading to a significant side effect profile. The most common adverse events include cardiac, dermatologic, gastrointestinal, endocrine, hematologic, and central nervous system toxicities.

Although significantly less common than the preceding toxicities, mitoxantrone carries a black box warning for increased risk of secondary acute myelogenous leukemia (AML). This risk is reported as being between 0.25% and 1.6% at 5 to 10 years post-treatment, though there is a paucity of data evaluating this risk. Prior studies report possible risk factors as a higher cumulative dose and concomitant chemotherapy.

Based on the black box warning and concern that mitoxantrone may predispose patients to additional malignancies because of its pharmacologic mechanism of action, a recent retrospective cohort study was published in Neurology.²

Nearly 700 patients with MS at a single center in Germany were evaluated for a median follow-up time of 8.7 years. Thirty-seven patients (5.5%) were diagnosed with a malignancy after starting mitoxantrone: breast cancer (9), colorectal cancer (CRC, 7), AML (4) and miscellaneous (17). The only 2 malignancies that had statistically significantly increased standardized incidence ratios were colorectal cancer (2.98, 95% CI 1.20-6.14) and AML (10.44, 95% CI 3.39-24.36). Contrasting with previous studies, however, the increased risk of malignancy was not associated with cumulative dose or concurrent chemotherapy.

Of the 7 patients diagnosed with CRC, the median age at diagnosis was 58 years old and median time to CRC diagnosis was 74 months. At the time of diagnosis, all of the patients had either local lymph node involvement or distant metastases.