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Doxil Maintenance of Ovarian Cancer Remission
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: There is emerging evidence that maintenance chemotherapy is of value for ovarian cancer patients after surgery and remission-induction chemotherapy. Paclitaxel remains effective in this capacity but has cumulative toxicity. In this report, experience with long-term pegylated doxorubicin (Doxil®) administered monthly for up to 5 years is reported in 16 patients. In general, treatment was well tolerated, without cumulative myelotoxicity or cardiotoxicity (with one exception). Thus, Doxil® may prove a useful agent for maintaining ovarian cancer remission.
Source: Andrepoulou E, et al. Pegylated liposomal doxorubicin HCL (PLD; Caelyx/Doxil®): Experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer. Ann Oncology. 2007;18:716-721.
Pegylated liposomal doxorubicin (Doxil) has significant antitumor activity when administered to ovarian cancer patients.1,2 In the current report, a retrospective review, Andreopoulou and colleagues from New York University examined the role for this drug in long-term maintenance after initial treatment with a platinum-based regimen. Their experience with 16 patients who received Doxil for greater than one year for either ovarian (n = 14) or fallopian tube (n = 2) cancer is described. All 16 patients had either stable disease or objective tumor regression with prior doublet treatment either as initial or secondary therapy. Doxil (30 to 40 mg/m2) was administered every four to eight weeks, indefinitely. This analysis was primarily to assess the safety and tolerance of such an approach.
In this regard, the investigators noted a lack of evidence for cumulative myelosuppression and, with one exception, cardiac toxicity. One patient required hospitalization for cardiogenic shock, which occurred during a period of neutropenic sepsis associated with topotecan treatment 10 months after the Doxil maintenance had been discontinued. The other 15 patients did not have any evidence of acquired cardiac dysfunction. Seven of the 16 patients continued to receive Doxil maintenance therapy with a median cumulative dose of 1680 mg/m2 (range 1180 to 2460 mg/m2). Of the seven, four had tumor relapse after three to six years of maintenance therapy, but this occurred during a time when the interval had been stretched typically because of cutaneous toxicity. In these patients, maintenance Doxil was reinstituted after "reinduction" with a platinum-based regimen.
Some level of skin toxicity was evident in all treated patients. However, rarely did it exceed a low level (grade 1). Most commonly observed was the well-described palmar-plantar erythrodysesthesia. In addition, some patients experienced rash elsewhere while others developed increased pigmentation. If skin toxicity exceeded grade 1, dosing interval was increased by one week. The analysis revealed that during the second year and in subsequent years, the dosing intervals were adjusted, primarily on the basis of patients' convenience but did not exceed eight-weeks.
It is notable that patients did not require antiemetic or steroid premedication during treatment. Thus, during the maintenance phase, Doxil monotherapy was well tolerated with no grade 4 toxicity, two grade 3 neutropenias, one grade 3 mucositis, and one grade 3 diarrhea. As noted, there was no observable change in cardiac function in 15 of the 16 patients.
Induction chemotherapy with platinum-based regimens results in a high response rate, but unfortunately, the majority of patients relapse within two years. Impetus for sustained treatment in patients with ovarian cancer has recently been gained by the Southwest Oncology Group/Gynecologic Oncology Group (SWOG-GOG) study demonstrating 12 cycles of intravenous paclitaxel administered every 28 days after achieving a clinical remission resulted in a seven-month improvement in median progression-free survival compared with those received only three cycles of paclitaxel.3 In fact, further analysis reveals that those who achieve the lowest CA125 level after induction chemotherapy may be precisely the ones who benefit most from sustained treatment.4 Paclitaxel, however, over the long term is associated with a cumulative toxicity, most notably neurotoxicity. Doxil, on the other hand, may be particularly suitable for long-term maintenance therapy inasmuch as it may be administered at longer intervals and is less likely to be associated with cumulative myelosuppression or other toxicities. Cardiac safety of course is of concern for any anthracycline. However, preclinical and clinical investigations have indicated the safety of the pegylated formulation. For example, data from a series of patients with AIDS-related Kaposi's sarcoma indicated some patients may tolerate cumulative Doxil doses up to 2360 mg/m2 over a five-year period with no decrement in cardiac function.5 When compared to doxorubicin, Doxil was found to be less cardiotoxic when treating breast cancer.6
In this study, long-term monthly doses of Doxil proved well tolerated and safe. Although this was an observational study and not a clinical trial, the data is encouraging in that years (rather than months) of therapy were described. Certainly, there would seem enough here to warrant a clinical trial in which pegylated liposomal doxorubicin, administered indefinitely, is compared to a limited paclitaxel maintenance schedule for patients in complete remission after induction chemotherapy for ovarian cancer.
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2. Muggia FM, et al. J Clin Oncol. 1997;15:987-993.
3. Markman M, et al. J Clin Oncol. 2003;21:2460-2465.
4. Riedinger JM, et al. Ann Oncol. 2006;17:1234-1238.
5. Mustafa M. Proc Am Soc Clin Oncol. 2001;20:2915a.
6. O'Brien ME, et al. Ann Oncol. 2004;15:440-44.