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EDITORIALS |
From the Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
Correspondence: Address correspondence to: Clifford Hudis, MD, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 206, New York, NY 10021; Fax: 212-717-3764; E-mail: hudisc{at}mskcc.org
Adjuvant systemic treatment with cytotoxic chemotherapy is one of the most important public health advances of modern medical oncology. Because of the prevalence of early-stage breast cancer in the United States, treatment with only a 1% to 3% absolute benefit in disease-free overall survival over 5 to 10 years of follow-up can have a profound impact on society.1 It is this public health benefit that motivates the broad use of these treatments in lower-risk patients with tumors lacking hormone receptors, as well as in higher-risk and younger patients even when hormone receptors are present.
Every medical therapy has a price and all of life consists of choices made by weighing risks and benefits, but adjuvant chemotherapy for breast cancer is not a big gamble. Administered as per guidelines and in appropriate patients it is effective and worth the risks. These include the usual acute toxicities, such as nausea, vomiting, alopecia, neutropenia, and mucositis, all of which can be more or less ameliorated by modern supportive measures, as well as longer-term toxicities. In their review, Weldon et al. focus our attention on one rare but important consequence of chemotherapy: the risks of secondary leukemia and myelodysplasia.2 Their case discussion clearly highlights a typical course for this toxicity, as well as its rarity. In addition, they carefully catalogue the specific chromosomal abnormalities that may be detected, the usual time course, and the refractory nature of these malignancies. It is clear that for each of the commonly used cytotoxic agents, one or several subsequent leukemias have been described in the literature, and this complication is among the most feared for many patients and clinicians. Unfortunately, it is equally clear that early detection is neither likely nor likely to be effective leaving clinicians worried and helpless.
Thankfully, acute leukemia and myelodysplasia after adjuvant chemotherapy for breast cancer is rare. Although it may occur in as many as 1 in 100 treated patients using currently available standard regimens the incidence may be higher or lower depending on the exact regimen used. Radiotherapy may contribute risk as well.3 In terms of chemotherapy regimens, the incidence may be a bit higher with longer anthracycline-containing regimens, but in many cases it is these more toxic approaches that are associated with superior outcomes.4–6 It is also clear that some regimens, such as those requiring autologous stem-cell support, are possibly even more toxic in terms of secondary leukemia, but these approaches are not widely used at present.
In considering the issue of secondary malignancies it is important for us to remember that event-free and overall survival, as generally reported in all randomized trials, includes leukemia and other second malignancies as events, but many studies appropriately include secondary cancers as events even when calculating disease-free survival. Hence, when we tell our patients, for example, that cyclophosphamide, epirubicin, and fluorouracil offers a 10% advantage in disease-free survival over cyclophosphamide, methotrexate, and 5-fluorouracil at 5 years, we are already including (and discounting) the negative impact of leukemia and any other related (or unrelated) secondary malignancy.7 The point is that although it is important to convey the risks of many specific toxicities, it is perhaps more important to emphasize the overall impact of treatment not only in terms of disease-specific outcome but also overall survival. This can provide the best and most accurate reassurance to our patients that their treatment is worthwhile.
At the same time, we have an obligation to continue to improve treatment by increasing its effectiveness and decreasing its toxicity. It is not or at least should not be necessary to have secondary malignancies as a consequence of effective treatment. We can and should strive to do better. Current efforts to demonstrate the effectiveness of safer hormone therapies (considering the adenocarcinomas and even rarer sarcomas associated with tamoxifen) are one example.8–12 Another is the develop- ment of newer effective targeted therapies. To date, secondary malignancies have not been attributed to trastuzumab or any of the small molecule signal transduction inhibitors currently in clinical trial.13–16 This safety profile is an important aspect of our current push toward targeted therapies and it is expected to the degree that these agents effectively select the malignant cells and leave normal stem cells unperturbed.
Given that we have recognized for many years the potential harm associated with current adjuvant chemotherapy regimens, how does the Weldon article help? For investigators it suggests that we continue to focus our research agenda on safer and more effective treatments, for clinicians it reassures us that we are doing more good than harm with currently available tools, and for patients it provides a clearer definition of the risks and benefits so that they can make the most informed choices possible.
Received for publication June 11, 2002. Accepted for publication June 20, 2002.
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