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Alert Number 177

Doxorubicin: the Gift that Keeps on Giving

Date: July 22, 2006

Doxorubicin (a well-known example of a class of drugs known as anthracyclines) is a drug that some of us may have to face one day as part of the famous "CHOP" regimen. CHOP is used a lot more frequently in treating lymphoma patients but I have seen it used for SLL patients as well. By the way, CHOP stands for Cyclophosphamide, Doxorubicin (also called hydrochloro-adriamycin), Vincristine (also called Oncovin) and prednisolone. Another more recent anthracycline drug is Mitoxantrone: featured in the FCR + Mitoxantrone trial at M. D. Anderson that we reviewed several months ago (Mitoxantrone plus FCR). All anthracycline drugs are well known to be unfriendly to the heart. In fact, that was the cause of the flap in our review of the FCR + M clinical trial protocol. In its original version the protocol did not include cardiac screening of the subjects or warn them about potential cardiac toxicity, something that was mandated by the FDA. I am glad to report that after our ever-so-gentle nudging M. D. Anderson has since modified their protocol to include cardiac screening. Here is a link to our review if you missed all the excitement back then: Mitoxantrone plus FCR.

The reason for this Topics Alert is that the news gets worse about anthracyclines. As the Medscape article below reports, the cardiac damage done by these drugs (doxorubicin and presumably its sister drugs belonging to the anthracycline family, such as mitoxantrone) does not stop when the drug use is stopped — the damage may continue for years afterwards. The recommendation now is that these patients are at life-long risk of cardiac problems as a result of their exposure to anthracycline drugs, and need to be monitored. Bummer!

But as the researcher correctly points out, this does not mean good old "Dox" should never be used. It is a very potent chemotherapy drug and there are times when its use is the correct choice. Once again, the mantra is the same — weigh the risks and rewards involved in therapy decisions. If I was looking for first line treatment for CLL and I had family history of cardiac problems, would I choose a therapy containing mitoxantrone or doxorubicin? Not on your life! But let’s say I have been around the block more than a couple of times and by now I have massively bulky lymph nodes. Just suppose I am looking to get as clean a remission as I can before going in for a stem cell transplant. R + CHOP may well be the optimum choice in that scenario. It is all a question of not taking on toxicity that can be avoided and at the same time not hiding your head in the sand when tough decisions have to be made.

Be well,


News Report

Medscape Medical News 2006. © 2006 Medscape

Cardiac Damage From Anthracyclines May Continue for Years

Zosia Chustecka

July 21, 2006 — Doxorubicin and other anthracyclines are known to be cardiotoxic, but a study that has been following patients after treatment for up to 27 years suggests that cardiac function continues to deteriorate. The findings were published online July 20 in the Annals of Oncology.

The study involved 22 long-term survivors who had been treated with doxorubicin for a malignant bone tumor. They had received a median cumulative dose of 360 mg/m2 (range, 225-550 mg/m2).

The median follow-up was 22 years (range, 15-27 years), considerably longer than the 13 years of most other studies carried out to date in these patient populations. "Our prospective study on treatment-related cardiac toxicity is probably one of those with the most prolonged follow-up," lead author Inge Brouwer, MD, from the pediatric oncology subdivison at the University of Hroningen Medical Center in the Netherlands, commented to Medscape.

Significant Increase in Dysfunction Since Last Follow-up

Only 1 of the 22 patients had cardiac symptoms; she had dyspnea and was being treated with captopril for left ventricular dysfunction. Eight other patients (36%) had hypertension.

Assessment by echocardiography (ECC) found a high rate of dysfunction, the researchers write. Of 22 patients, 6 (27%) had decreased systolic function and 10 patients (45%) had impaired diastolic function.

This group of patients has been monitored regularly since receiving doxorubixin, with follow-up examinations at a median of 7 and 14 years posttreatment. However, this latest follow-up at 22 years found that the number of patients with systolic dysfunction had increased significantly — in fact, this was a novel finding in 5 of 6 of the patients diagnosed.

All 6 patients with impaired systolic function also displayed cardiac wall motion abnormalities, which suggest ischemic heart disease. This was confirmed in one case by positron emission tomography.

"Our results suggest that after treatment with anthracyclines there is an ongoing deterioration of cardiac function, and no extinction is anticipated," the researchers conclude. "It is possible that this deterioration will continue, although we don't know if and when there will be further progression," Dr. Brouwer added. For this reason, anthracycline-treated cancer survivors should be considered for life-long cardiac surveillance, and regular ECG seems important, she said.

"By now, most oncological centers perform ECG in order to anticipate [early] cardiac problems during anthracycline treatment," Dr. Brouwer told Medscape. She advises clinicians to continue follow-up (cardiac follow-up but also general follow-up), even if the cancer treatment was administered decades ago.

"Most doxorubicin-treated survivors with cardiac abnormalities that show up on ECC have no cardiac complaints. We need to keep checking them and be ready to start medication to stabilize their heart function in order to prevent further cardiac deterioration and development of cardiac complaints," Dr. Brouwer commented. "It is important to be ready to treat cardiovascular risk factors — for example, high blood pressure or cholesterol — and to encourage patients to make helpful lifestyle changes such as stopping smoking, reducing their weight if necessary, and taking exercise."

Despite this adverse effect of cardiac toxicity, doxorubicin is a highly effective treatment and the cure of cancer is still the first priority, Dr. Brouwer emphasized. Also, in recent years lower doses have been used, and ways to protect the heart — for example, with the experimental drug dexrazoxane — are being explored, she said.

Ann Oncol. Published online July 20, 2006.

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