Multiple sclerosis drug mitoxantrone may be linked to increased risk of colorectal cancer

In continuation of my update on Mitoxantrone

Mitoxantrone is used for aggressive types of relapsing-remitting or progressive MS that do not respond to other MS drugs. But its use is limited because previous studies have shown an increased risk of leukemia and heart damage.

 Mitoxantrone

The current study examined whether the drug increases the risk of other types of cancer. For the study, German researchers looked at all people with MS who were treated with mitoxantrone from 1994 to 2007 and followed them until 2010.

Of the 676 people, 37 people, or 5.5 percent, were diagnosed with cancer after taking the drug, including nine people with breast cancer, seven with colorectal cancer and four with acute myeloid leukemia, which has been associated with mitoxantrone.

The rate of leukemia was 10 times higher in the people treated with mitoxantrone than in the general population in Germany. The rate of colorectal cancer, which is cancer of the colon and rectum, was three times higher than that of the general population. For breast cancer and all other types of cancer, people who had taken mitoxantrone were no more likely to develop the diseases than those in the general population.

Of the seven people with colorectal cancer, three died from the cancer during the study. The four people with leukemia all went into remission after treatment and were alive at the end of the study.

The researchers also looked at whether factors such as how much of the drug people had received cumulatively and whether they also received other immunosuppressant drugs affected their risk of developing cancer. The only factor related to a higher risk of cancer was being older when starting to take the drug.

"Despite an increased risk of acute myeloid leukemia and colorectal cancer, the overall rate of cancer was low enough to justify still using this drug for people severely affected by MS if no better treatment is available," said study author Mathias Buttmann, MD, of the University of Würzburg in Würzburg, Germany. "Mitoxantrone is the only approved treatment for people with secondary progressive MS without relapses and should be considered in people where the disease is evolving quickly. Also, many of the new and highly effective MS drugs are not available to people in a number of countries for economic reasons, so mitoxantrone is being used for people with very active relapsing forms of the disease."

Buttmann noted that the study was relatively small and needs to be confirmed. If the results are confirmed, he said that colonoscopies should be given after treatment with the drug to screen for colorectal cancer, which can be treated more effectively when diagnosed earlier.

Ref : http://dx.doi.org/10.1212/WNL.0000000000002745

Mitoxantrone for MS linked to colorectal cancer risk

In continuation of my update on mitoxantrone 

Treatment with mitoxantrone for multiple sclerosis (MS) carries only a mildly increased risk of malignancy overall, but the risk of colorectal cancer and leukaemia is heightened, researchers have found.

They report a threefold increased incidence of colorectal cancer and a 10-fold increased incidence of acute myeloid leukaemia (AML) among 37 of 676 MS patients who were diagnosed with a malignancy over a median 8.7 years after starting mitoxantrone treatment.

The team, led by Mathias Buttmann (University of Würzburg, Germany), notes that colorectal cancer appeared to be the more life-threatening adverse effect, with three of seven affected patients dying from the tumour, whereas all four patients with AML experienced full remission after treatment.

"[P]osttreatment colonoscopy might improve the risk-benefit ratio of this highly active immunosuppressive drug", they recommend in Neurology

Among the 5.5% of patients diagnosed with a malignancy, nine developed breast cancer, seven colorectal cancer and four AML, and there were also two cases each of glioblastoma multiforme, lung, pancreatic and prostate cancer, and one case each of nine other types of cancer.

The overall standardised incidence ratio for any type of malignancy was 1.5 compared with the general population, and other than colorectal cancer and AML no other specific cancer type was associated with a significantly increased risk.

For the majority of patients, mitoxantrone was administered at a dose of 12 mg/m2every 3 months, while 152 patients received induction therapy with three monthly cycles of 12 mg/m2 followed by maintenance infusions of 5 mg/m2 every 3 months once clinical stabilisation had occurred.

Neither cumulative mitoxantrone dose (>75 vs ≤75 mg/m2) nor treatment with other immunosuppressive drugs increased the risk of malignancy. There was also no association with gender. But the risk did increase 1.55-fold with every 5-year increase in age at treatment initiation.

Among the 55 patients who died over the 6220 person-years of follow-up, 12 did so from a malignancy and 43 from other causes.

Buttmann and colleagues note that "[m]itoxantrone is currently the only approved treatment for patients with secondary progressive MS without superimposed relapses and should be considered in patients with rapidly evolving disabling disease."

The overall incidence of all malignancies "appears acceptably low to justify mitoxantrone treatment in severely affected patients with MS if no better therapeutic alternative is available", they conclude.

Old FDA-approved drugs may hold promise for treatment of rare, drug-resistant cancer

After studying how samples of GIST responded to various concentrations of the 89 drugs in the laboratory, Dr. Duensing and her colleagues identified 37 compounds that showed some anticancer activity in at least one of the concentrations tested. Importantly, they noted that the most promising candidates all belonged to only two major drug classes: inhibitors of gene transcription and so-called topoisomerase II inhibitors. Based on these findings, the research team selected the two most promising compounds for further testing - gene transcription inhibitor mithramycin A (left structure below) , which is in clinical trials to treat Ewing sarcoma, and topoisomerase II inhibitor mitoxantrone (beow right structure), which is used in metastatic breast cancer and leukemia.

Both drugs were highly effective in fighting GIST in laboratory tests. Moreover, the mechanism of action of each drug was linked to the specific underlying biology of these tumors.

"These are very encouraging results," said Dr. Duensing. "The next step will be moving our findings to clinical exploration to see if the results we found in the lab hold up in patients."

Old FDA-approved drugs may hold promise for treatment of rare, drug-resistant cancer

Ref : http://www.upmc.com/media/NewsReleases/2014/Pages/upci-scientists-detect-therapy-for-drug-resistant-cancer.aspx