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PRIORITY PRESS - 45th Annual Meeting of the American Society of Clinical Oncology

Orlando, Florida / May 29-June 2, 2009

In breast cancer, the risks associated with adjunctive use of the most effective chemotherapies early include the potential for the same agents to be less effective, more toxic, or both if needed to control a relapse. While the risk of cumulative toxicity from some types of chemotherapy is well documented, the risk of diminished effect from prior use is not. New data demonstrate that effective rechallenges are possible, although the best evidence has been generated with pegylated liposomal doxorubicin (PLD), which employs a change in formulation to reduce the risk of toxicities while preserving potency.

Retrospective Data on Rechallenge

According to Dr. Jonathan Krell, Imperial College Healthcare NHS Trust, London, UK, “The current evidence base for rechallenging breast cancer patients with anthracyclines or taxanes in metastatic breast cancer has been limited. This has prevented a rational and objective approach to using what are otherwise very effective drugs in a patient population where maximum potency is likely important for response.”

In an initial effort to take a rational approach, Dr. Krell summarized 27 studies to extract the conclusion that reintroducing anthracyclines and taxanes is likely to be viable. Although he cautioned that the studies he reviewed, of which 20 evaluated the reintroduction of anthracyclines, were of varying quality, activity in the form of response rates, time to progression and even overall survival was on the order of these achieved in treatment-naive patients.

“There is evidence to support rechallenging breast cancer patients with either anthracyclines or taxanes,” Dr. Krell told delegates. Although he cautioned that the data regarding taxanes are limited to retrospective data, whereas two of the anthracycline studies were prospective, Dr. Krell suggested that more prospective studies of chemotherapy rechallenges with both agents would be helpful. He also called for more studies comparing anthracyclines to taxanes following adjuvant exposure to both agents, although he indicated that these agents should not necessarily be withheld from metastatic breast cancer patients on the basis of previous exposure alone.

A New Look at Anthracyclines

In the case of anthracyclines, however, the major concern is not only efficacy but increased risk of dose-limiting side effects, particularly cardiomyopathy. The potential to diminish these toxicities was the major impetus for the development of PLD. Initial studies confirmed that it is substantially better tolerated than conventional doxorubicin, a major advantage when patients with advanced disease have a low tolerance for significant side effects. However, a new meta-analysis using pooled data from four prospective trials specifically addressed activity of PLD in patients previously treated with anthracyclines. The trials individually and collectively demonstrated that PLD generates high rates of clinical benefit with relatively low adverse event rates even in patients with previous doxorubicin exposure.

“What many clinicians may find surprising is that the clinical benefit associated with PLD in this data set was also independent of previous anthracycline resistance,” reported Dr. Salah-Eddin Al-Batran, Oncology and Hematology Clinic, Krankenhaus Nordwest, Frankfurt am Main, Germany. In addition, response rates were found to be unaffected by the time to last treatment or by the cumulative dose of previous exposure to conventional anthracyclines.

This meta-analysis included four studies published between 2004 and 2008. Together, the prospective studies provided data on 935 patients treated with PLD for metastatic breast cancer. All patients in this analysis were heavily pretreated, but 274 had also been previously exposed to conventional anthracyclines. For the study population as a whole, the median number of previous chemotherapy regimens was four with a range of one to nine. Of those who had received previous conventional anthracyclines, 14% were exposed during an adjuvant regimen, 46% had been previously treated for metastatic disease and 40% received anthracyclines for both. The primary end point was a clinical benefit rate (CBR) >30%, where CBR was defined as an objective response or stable disease lasting six months.

The CBR for the overall population was 32%. The CBR for the subgroup with previous anthracycline exposure was 32.2% (95% CI, 26.7-37.8). Prior anthracycline exposure was not a factor in clinical response when measured in a variety of ways. For example, response rates were 33.3% in those who had received an anthracycline as an adjuvant, 34.4% in those who received the anthracycline for metastatic disease and 29.4% in those who had received both (P=0.71 for both vs. either adjuvant or metastatic treatment exposure). When response was assessed in those who had been defined as anthracycline-resistant according to the medical records, the response rate was almost identical to that of patients with no history of resistance (31.9% vs. 31.6%, respectively).

There was a higher rate of clinical benefit among those with a low vs. a high number of previous chemotherapy regimens, but Dr. Al-Batran attributed this to a better disease prognosis in this group. He also noted that patients who had been treated with a conventional anthracycline within the previous 12 months appeared to respond less well than those who had an interval of more than 12 months to last anthracycline dose, but the difference did not reach statistical significance (26.3% vs. 34.2%; P=0.21). Modestly greater survival times in PLD patients who had not been previously treated with a taxane also did not reach statistical significance.

Safety was not a part of this analysis, which was focused on sensitivity to PLD after previous anthracycline exposure, but Dr. Al-Batran cited previous evidence that PLD is associated with a substantially reduced risk of adverse events overall with a particularly strong advantage for avoiding grade 3 and 4 toxicities when compared to conventional doxorubicin. In prior studies, one of the most important advantages of PLD relative to conventional doxorubicin has been a relatively low risk of cumulative cardiotoxicity over multiple courses. Several studies within the meta-analysis did specifically evaluate evidence of cardiotoxicity, such as heart failure, without a significant association.

Corroborative Findings in the PELICAN Study

The same combination of potency and relative safety for PLD also has relevance to first-line therapy for metastatic breast cancer. The potential advantage of this agent over alternatives in this patient population is now being evaluated in PELICAN (Pegylated Liposomal Doxorubicin Versus Capecitabine as First-line Chemotherapy for Metastatic Breast Cancer), a large multicentre phase III study. In this study, conducted in Germany, 193 patients were randomized to PLD 50 mg/m² delivered intravenously once every 28 days or to capecitabine 1250 mg/m² b.i.d. delivered orally for 14 days in a 21-day cycle.

In the interim results reported here at ASCO, the tolerability has been similar even though types of adverse events have differed substantially. “Overall, the number of cycles delivered was similar between PLD and capecitabine, but there have been fewer grade 3 or 4 adverse events in the arm receiving PLD,” reported Dr. Al-Batran, who also presented these results.

The primary objective of PELICAN is time to disease progression, but efficacy results are not yet mature. Rather, this interim analysis was conducted to compare toxicities in two compounds that have been relatively well tolerated and are reasonable first-line choices for sequential single-agent chemotherapy in metastatic disease. “The most common toxicity of any grade has been hand-foot syndrome, which was seen in 35.1% of patients on PLD and 19.2% of those on capecitabine. Grade 3 or 4 diarrhea only occurred in patients on capecitabine [13.1%] and grade 3 or 4 thromboembolic events have been more common on capecitabine [9.1% vs. 1.5%],” Dr. Al-Batran stated.

Relative to conventional doxorubicin, the tolerability of PLD is a critical advantage for preserving a highly effective therapy in metastatic disease. In patients previously exposed to doxorubicin, the data validating the utility of PLD in anthracycline rechallenge is an important clinical finding due to limited options in patients who have been heavily pretreated. According to Dr. Krell, the evidence that rechallenges are viable provides a basis for revisiting the question of which is the optimal therapy in relapsed metastatic disease.

Summary

New data addressing the question of rechallenging breast cancer patients with chemotherapies to which they have been previously exposed suggest that at least some of these therapies retain activity and may have a role in recurrent metastatic disease. The best data, addressed by a meta-analysis of four studies, support the use of PLD, an anthracycline reformulation specifically for the goal of improved tolerability. The pooled data with PLD reinforced a larger analysis of 27 studies with anthracyclines and taxanes that provides a basis for concluding that rechallenges preserve highly active treatment options.