Doxorubicin for Metastatic Breast Cancer: Time for a Change?

The chemotherapy of breast cancer is shifting to anthracyclines and to taxanes gradually rendering cyclophosphamide-based regimens to historical footnotes. In the adjuvant setting, doxorubicin, or epirubicin-based regimens have displaced CMF and its many variants. However, in the metastatic setting, the situation is more complex, because in palliative situations one must carefully weigh toxicity vs. the possibility of prolonging survival. When the Her2/neu protein is overexpressed, combined use of Herceptin with chemotherapy resulted in an impact on survival over chemotherapy alone, despite of crossover to subsequent Herceptin[[1]] for those in the chemotherapy alone arm. Recently, a combination of capecitabine + docetaxel showed a survival advantage over docetaxel treatment,[[2]] but the combined regimen's superiority over sequential treatment must be confirmed. The theme of seeking to improve results through combinations will dominate discussions on the treatment of metastatic breast cancer for some time, given the availability of a large number of additional drug classes with moderate activity: antimetabolites such as gemcitabine and folate antagonists, the vinca alkaloids, the topoisomerase I inhibitors, the alkylating agents, and the platinums. If one adds the new targeted agents and modulators, as well as endocrine therapies, the choice of regimens of interest are currently too numerous to incorporate into a logical treatment strategy.

Within this background, now enters the “sterically stabilized, pegylated liposomal doxorubicin.” The results with Lipo-Dox® studied by Chao et al.[[3]] in patients with metastatic breast cancer should be taken together with the more extensive data with Doxil®/Caekyx® that is similar in pharmacology and spectrum of toxicity. Although the Pegylated Liposomal Doxorubicin (PLD) has already found indications for the treatment of Kaposi's sarcoma and platinum pretreated ovarian cancer, its role in the treatment of metastatic breast cancer is slowly being defined.

Since chemotherapy was first used in hormone-refractory or independent metastatic breast cancer, the main disappointment has been the short duration of responses, measured in months, relative to hormonal therapies. This short duration likely reflects the rarity of complete responses even with combinations. A corollary to this shortcoming is the need for maintenance in responding patients, and all its adverse effect on patient tolerance. But the alternative of treatment interruptions had an even more negative impact on the patient's quality of life than continued treatment.[[4]] In recent randomized trials vs. free doxorubicin, the PLD yielded similar response rates or duration of response.[[5]] However, the contrast between PLD and free drug includes 1) the many drawbacks in maintaining treatment with free doxorubicin are likely to be overcome in patients who are responding to the PLD, 2) patients who have received prior adjuvant anthracyclines may still be safely treated with PLD, and 3) there is a potential for combinations with other drugs that differs from doxorubicin or epirubicin. As an example, the combination of PLD and docetaxel piloted by our group[[6]] and by Sparano et al.[[7]] is undergoing study by the Eastern Cooperative Oncology Group in patients with metastatic breast cancer, and in patients with Her2/neu overexpression it is combined with Herceptin. The prospective cardiac evaluation in this study will provide additional data on the cardiac safety of PLD, previously suggested by retrospective analysis[[8]] and by early data from the randomized trial vs. doxorubicin.[[5]]

The obvious question is: should PLD replace the free doxorubicin or epirubicin in the treatment of metastatic breast cancer? If used by itself, the undisputed advantage of PLD lies on its potential for avoiding cardiac toxicity. Other advantages for the patient may be predicted, as oncologists and nurses gain experience in avoiding occasionally distressing skin toxicities (that for a given patient, should only be a one-time occurrence in its severest form, leading to adjustment in treatment interval and dose). These advantages include 1) the practicality of intermittent administration up to doubling doxorubicin's 3-week interval[[9]]—key for patients with venous access problems, 2) obviating the need for many supportive measures such as antiemetics and cytokines, and 3) the near absence of alopecia. But beyond these advantages to specific patients, PLD-based drug combinations used to induce response, followed by PLD maintenance need to be tested for their impact on survival. Such strategy is appealing for minimizing the time on a toxic induction regimen and theoretically capitalizing on more uniform drug concentrations in smaller, responding tumors. Future areas of research should focus on pharmacodynamics of PLD (what affects its distribution in tumors?, and what leads it to release its payload?) given by itself or in combination. My opinion: use PLD now in first-line metastatic breast cancer unless the anthracycline-free interval has been less than 1 year. For those on the fence, stay tuned to additional developments as our knowledge expands on how these formulations perform in the laboratory and in the clinic.