The Lynx Group

Risk of Leukemia after Chemotherapy Small, but Real

March 2013, Highlights

Fewer than 0.5% of patients with breast cancer develop leukemia associated with chemotherapy, but this is 60% higher than the proportion documented in a previous analysis, according to a report based on the National Comprehensive Cancer Network (NCCN) database.

“Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of about 0.5%, which appears to be higher than previously reported,” said Antonio Wolff, MD, Professor of Oncology at the Sidney Kimmel Comprehensive Can­cer Center, Johns Hopkins Medicine, Baltimore, MD.

There have been concerns that chemotherapy may induce second malignancies. Ten years ago, the National Surgical Adjuvant Breast and Bowel Project (NSABP) found a 0.27% risk of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) occurring 8 years after treatment with doxorubicin plus cyclophosphamide. The greatest risk was seen among patients who received radiotherapy or growth factors.

In NSABP B-38, which was reported at the 2012 American Society of Clinical Oncology annual meeting, a 0.49% risk for patients with MDS and AML was found 5 years after treatment for breast cancer in patients who received growth factors.

To gauge the true risk, Dr Wolff and colleagues analyzed prospectively collected data on 20,533 patients with breast cancer who were followed for a median of 5.1 years. Patients had stage I to III breast cancer and received treatment at 8 NCCN cancer centers between 1997 and 2008. Women who developed a recurrence were excluded.

Hematologic Malignancies Developed

There were 51 cases of AML among the 20,533 patients, including 44 cases of myeloid leukemia and 7 cases of lymphoid leukemia.

“Leukemia risk was not limited to MDS and AML, and cases of high-risk lymphoid were observed,” Dr Wolff reported.

Because the hazard ratios (HRs) for the 2 types of malignancies were similar, these data sets were combined for final analysis. Most patients received 4 or 6 cycles of anthracycline and/or an alkylating agent, with or without a taxane.

Although many women today receive docetaxel plus cyclophosphamide and eliminate the anthracycline, this regimen was not well represented in this data set; therefore, its link to leukemia is unknown, he added.

The adjusted HR for the risk of leukemia was 1.29 for the receipt of radiation versus no radiation, but this increase did not reach statistical significance. The HR was 2.51 for any chemotherapy versus no chemotherapy (P = .007) and 1.59 for chemotherapy plus radiation versus one of these modalities alone (P = .127).

However, in a stratified analysis that included women treated only with surgery, a trend was observed for an increased risk with radiotherapy only (HR, 2.73; P = .194), and significant differences were seen for chemotherapy only (HR, 5.68; P = .037) and chemotherapy plus radiation (HR, 5.64; P = .028). The risk for the combined modality was not significantly higher than that seen with chemotherapy alone, Dr Wolff reported.

“Radiation alone appears to be a risk factor, but may not add much to patients already treated with chemotherapy,” Dr Wolff concluded.

The cumulative incidences of leukemia for all the patients were 0.25% at 5 years and 0.46% at 10 years, and for the chemotherapy plus radiotherapy cohort, they were 0.32% and 0.51%, respectively.

The baseline incidence of leukemia in women this age (ie, the risk for the general population) is not known, but Dr Wolff said the surgery-only cohort gives us an idea. Compared with surgery only, chemotherapy increased the risk, he noted, “but there are challenges in comparing this with baseline risk, because other factors, such as family history, could be in play.”

He further noted that because MDS was underreported until fairly recently, it may occur more frequently than suggested by this analysis, which did not find an increased risk.

More than 50% of the events emerged ?5 years after chemotherapy was given. The median time to an event was 3.3 years overall, although it extended to 8 years in some cases. Dr Wolff pointed out that although the latency period for anthracyclines is 1 to 3 years, it is much longer for cyclophosphamide. “Patients exposed to cyclophosphamide could be at risk at 10 years or more,” he estimated.

Eric P. Winer, MD, Professor of Medicine at Harvard Medical School, Boston, MA, emphasized that the risk of leukemia after chemotherapy is “quite small” and is actually less than 0.5%, considering that the general population has a baseline risk that is “greater than zero.”

Dr Winer indicated that when chemotherapy provides a benefit to the patient, the risk of leukemia is far less important than the risk of recurrence. But he noted that many patients are unnecessarily treated with chemotherapy, because they derive no benefit, and for these patients any degree of leukemia risk is of concern.

“We have to think carefully about treating women with a low risk of recurrence or with a biological subtype that is unlikely to benefit,” Dr Winer emphasized.

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