Roxanne Nelson

June 10, 2011

June 10, 2011 (Chicago, Illinois) — Pegylated liposomal doxorubicin (PLD), used alone or in combination with other agents, is part of the treatment regimen for both platinum-sensitive and platinum-resistant recurrent epithelial ovarian cancer. However, the long-term use of PLD might carry a risk for secondary cancer of the oral cavity, according to data presented here at the American Society of Clinical Oncology 2011 Annual Meeting.

Although the numbers are small, the data are nevertheless compelling, explained first author Timothy Cannon, MD, a hematology/oncology fellow at the New York University (NYU) Cancer Institute in New York City.

"Most patients who receive doxorubicin only get it for 6 cycles, and oral cancers have not been observed in those patients," he told Medscape Medical News. The study patients "are from NYU and are part of a series in which they received it for 30 months. Among these patients, there obviously is a very high incidence of oral cancers."

Four patients who received long-term PLD for advanced-stage ovarian cancer developed malignant and/or premalignant lesions of the tongue and/or oral cavity. Dr. Cannon points out that there were only about 16 patients who received PLD for an extended period of time, "so 4 out of 16 patients is quite high."

All 4 of the patients had received maintenance therapy with PLD for at least 3 years. Of this group, 3 women were subsequently diagnosed with squamous cell carcinoma (SCC) of the tongue and/or oral cavity, and 1 patient was diagnosed with sublingual mucosa high-grade dysplasia. All 3 cases of SCCs were negative for human papillomavirus.

Of note, said Dr. Cannon, was a patient who presented with 3 separate lesions of SCC of the oral cavity.

"I don't think this is a coincidence, that 4 of 16 patients receiving this treatment developed oral cancers," he said. "If this treatment for ovarian cancer becomes more popular, then this is something that should become known. Early dental screening would need to be initiated, and the treatment may need to be stopped after a certain time period."

It is relatively uncommon for ovarian cancer patients to receive PLD for this length of time, but among the NYU patients, the regimen has been very successful. "Of the patients who developed oral cancer, all had been free of ovarian cancer for a long time," Dr. Cannon explained. "Obviously, we had this serious and unanticipated adverse event."

PLD Effective and Less Toxic

A number of studies have reported the benefit of PLD in recurrent ovarian cancer. As previously reported by Medscape Medical News, one study found that replacing paclitaxel with PLD in a carboplatin chemotherapy regimen in a population of patients with advanced ovarian cancer in late relapse significantly reduced adverse events without affecting survival. The use of PLD significantly decreased the incidence of alopecia and neurotoxicity, compared with the standard paclitaxel regimen.

Another trial, published last year in the Journal of Clinical Oncology (2010;28:3323-3329), reported that the combination of PLD and carboplatin was a "more effective, less toxic alternative to the current standard" of carboplatin and paclitaxel in patients with platinum-sensitive relapsed/recurrent ovarian cancer. The combination of carboplatin and PLD was associated with a statistically significant improvement in progression-free survival (hazard ratio, 0.82; P = .005) and a reduction in severe toxicities.

The most data on doxorubicin and secondary malignancies come from studies of Kaposi's sarcoma, where it is commonly used. However, the majority of secondary cancers in this setting are lymphomas. "They were also in AIDS patients, so we are looking at an entirely different population," Dr. Cannon noted. "Basically, there are not a lot of data out there about long-term use with this drug."

None of the 4 patients were former smokers, but of note is the fact that 3 of the patients had deleterious BRCA mutations, which might have played a role. Immunohistochemical staining for p16 was negative in all of the SCC specimens.

Ovarian Cancer Patients Who Developed Secondary Oral Cancers

Diagnosis Duration of PLD treatment (mo) Cumulative PLD dose (mg/m2) Age at diagnosis: ovarian cancer (y) Age at diagnosis: oral cancer (y) Outcome
T1N0M0 SCC of the tongue 96 1800 65 76 Died of cardiogenic shock
Sublingual dysplasia 132 2320 55 67 Alive; currently no evidence of cancer
T2N0 SCC of the tongue 32 2116 67 71 Alive; currently no evidence of cancer
Multifocal oral SCC with 3 separate T1N0 lesions 80 3000 43 52 Partial response to chemotherapy for oral SCC refractory to treatment; no evidence of ovarian cancer recurrence


At NYU, long-term PLD is still being used, but patients are being screened more closely and treating physicians might be stopping it earlier, Dr. Cannon said.

"This is an interesting observation, but should certainly not change the manner in which this important antineoplastic agent is used in the management of ovarian cancer," said Maurie Markman, MD, an ovarian cancer expert who is vice president of patient oncology services and national director of medical oncology at the Cancer Treatment Centers of America in Philadelphia, Pennsylvania.

"It will be important for other gynecologic cancer investigators to review their own experience with this agent to determine if oral cavity cancers have been observed," added Dr. Markman.

Dr. Cannon has disclosed no relevant financial relationships. Coauthor Franco Muggia, MD, from the NYU Cancer Institute, reports serving as a consultant/advisor for Johnson & Johnson.

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract 5557. Presented June 5, 2011.

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