ETHICAL DILEMMA WITH CAELYX DOSAGE

July 9, 2010 — Pegylated liposomal doxorubicin (PLD) — an established standard treatment regimen in the management of platinum-resistant ovarian cancer — is the source of a "serious ethical dilemma" in ovarian cancer chemotherapy trials, according to a letter appearing in the July 1 issue of the Journal of Clinical Oncology.

The dilemma stems from the fact that the 40 mg/m2 dose (every 28 days) of the drug is "overwhelmingly" the "community standard," but the drug continues to be used as a control group in clinical trials at a dose of 50 mg/m2, writes Maurie Markman, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, in his letter. Dr. Markman has an oncology videoblog on Medscape Medical News.

The lower dose is favored by practicing oncologists because it largely averts "substantial and clinically relevant toxicity" associated with the higher dose but still provides "equivalent efficacy," says Dr. Markman.

The toxicities include palmar-plantar erythrodysesthesia or hand-foot syndrome (HFS) — a "most distressing symptom complex" that involves skin changes and pain, notes Dr. Markman.

Dr. Markman explains that the higher dose was the dose approved by the US Food and Drug Administration (FDA), so pharmaceutical and biotechnology companies that investigate new agents in ovarian cancer use this dose in the control group of their trial because "apparently, the rules require" it, he says.

If there is no change in the situation, "it is appropriate to call on all institutional review boards . . . to very seriously consider rejecting their site's participation" in any study involving PLD unless the dose is reduced, declares Dr. Markman.

Dr. Markman also appeals to individual investigators and asks them what dose of PLD they use with patients. "If the truthful answer is 40 mg/m2 (or any dose <50 mg/m2), what possible acceptable ethical justification can they provide for agreeing to treat patients on this trial at the higher, more toxic dose level?"

Not All Clinical Trials Are Using the Higher Dose

In a response to Dr. Markman's letter, another oncologist presents a different picture of the current state of affairs in ovarian cancer clinical trials with a PLD control group.

"Time has already come for this change," Gabriella Ferrandina, MD, from the Catholic University of Campobasso in Italy, writes in a response.

In a review of randomized clinical trials using PLD as a control group (at www.clinicaltrials.gov), she found that 4 (NCT00976911, NCT00913835, NCT00635193, and NCT00657878) of 7 ongoing studies are already using 40 mg/m2 instead of 50 mg/m2.

Notably, Dr. Ferrandina does not address the ethics of the 3 trials that were found to be using the 50 mg/m2 dose.

Dr. Ferrandina points out that there has not been a direct comparison in a trial of the doses in question. Instead, various studies have examined either the 40 mg/m2 or 50 mg/m2 dose and, thus, provide an indirect comparison of the 2 doses. "We have to recognize that this does not really represent level 1 evidence," she notes. Nevertheless, Dr. Ferrandina helped design and participated in a clinical trial of PLD that elected to use the lower, less toxic dose.

"We deeply and seriously discussed this issue [of dose] when designing the Multicenter Italian Trials in Ovarian Cancer 3 randomized phase 3 study comparing PLD and gemcitabine in patients with ovarian cancer progressing or recurring within 12 months of the completion of primary treatment," she writes.

Dr. Ferrandina provides some insight into the Italian team's thinking.

They noted that HFS and mucositis/stomatitis documented at the 40 mg/m2 dose were "quite [a bit] lower" (grade 3/4 HFS, 5%; grade 3/4 mucositis/stomatitis, 3%) (Gynecol Oncol. 2000;78:369-372) than had been seen in previously published results (grade 3/4 HFS, 25%; grade 3/4 mucositis/stomatitis, 8%) at the 50 mg/m2 dose (J Clin Oncol. 2001;19:3312-3322).

What Is to Be Done?

Neither Dr. Markman nor Dr. Ferrandina believe a clinical trial comparing the 2 doses is a practical solution to the problem at hand because, in part, some patients would be randomized to the higher dose.

Dr. Markman suggests that institutions might need to get involved and formally reject participation in any clinical trial involving PLD at 50 mg/m2, whereas Dr. Ferrandina is of a different mind.

"I think that there will be no need for institutional review boards of community-based centers or universities to take up a formal position in this context," she writes.

Dr. Ferrandina sees community influence as the most powerful agent of change.

"I think that the more and more diffuse use in the clinical practice of PLD 40 mg/m2 will be, in and of itself, stronger than any regulatory rules, and that the lower and safer PLD dose level will tacitly replace the [FDA]-approved dosage in clinical trials," she writes.

Dr. Ferrandina also suggests that the conscience of individual clinicians will be at play.

"Any physician would be undoubtedly embarrassed to administer to his/her own patients a PLD dose of 50 mg/m2, despite being the control arm of a clinical trial," she writes.

Dr. Ferrandina thinks that clinical trial designers run the risk that clinicians will decline to participate or only enroll select patients in trials using 50 mg/m2.

Dr. Markman, in his letter, introduces another agent of potential change in the PLD dilemma: patients.

If institutional review boards will not get involved and reject participation in clinical trials involving PLD at a 50 mg/m2 dose, Dr. Markman suggests that they ought to at least provide patients with "adequate informed consent."

"How adequate can that consent possibly be if individuals are not provided clear and full disclosure of the documented efficacy [and] toxicity data associated with the 50 vs 40 mg/m2 dose of PLD in the treatment of platinum-resistant ovarian cancer?" he writes.

Dr. Markman and Dr. Ferrandina have disclosed no relevant financial relationships.

J Clin Oncol. 2010.28:319-320, 321-322.