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43rd Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2007

Metastatic breast cancer (MBC) demonstrates substantial sensitivity to anthracyclines, typically administered in combination or sequentially with a taxane. The development of pegylated liposomal doxorubicin (PLD) has permitted a series of clinical trials in MBC, as well as other anthracycline-sensitive cancers, to test whether outcomes can be improved while reducing toxicities. The most significant of the new data in MBC is a multicentre phase III study testing a maintenance regimen following standard chemotherapy. The prolongation of time to progression (TTP) with an acceptable level of adverse events has been identified as a step forward and a potential new standard of care for this disease.

“As a first-line approach to MBC, maintenance therapy with PLD significantly delays the TTP without significant clinical toxicity,” reported Dr. Emilio Alba, Medical Oncology Service, Hospital Clínico Universitario Vírgen de la Victoria, Málaga, Spain. Speaking on behalf of the Spanish Breast Cancer Research Group (GEICAM), he stated, “Based on these results, this maintenance regimen will be our standard arm for future studies.”

The randomized maintenance trial was conducted with 155 MBC patients who had completed an induction regimen of doxorubicin and docetaxel delivered sequentially. The same group of investigators had previously found sequential delivery to be better tolerated and equally as effective as concomitant delivery when measured by response rates, TTP and overall survival (Alba et al. J Clin Oncol 2004;22: 2587-93). In this sequential induction regimen, patients received doxorubicin 75 mg/m2 every 21 days for three cycles followed by docetaxel 100 mg/m2 every 21 days for three cycles (six cycles total). A complete response (CR), partial response (PR) or stable disease (SD) on the induction regimen were the eligibility criteria for entry into the maintenance study (Figure 1). Patients also had to have a good performance status (grade 2 or better), no radiation within the previous four weeks, and no symptomatic brain metastases.

Figure 1. Study Design

In the maintenance study, for which the primary end point was TTP, there were 78 patients randomized to receive 40 mg/m2 PLD every four weeks for six cycles and 77 patients randomized to observation. All clinically relevant disease characteristics such as median age, ECOG performance status, hormonal status and site of disease were equally balanced between the two groups.

Study Findings

On induction therapy, a CR was achieved in less than 10% in either group. Although the observation group had a higher rate of PR (61% vs. 49%) and a lower rate of SD (30% vs. 47%), these differences did not reach statistical significance.

At the end of 24 months of follow-up from the time to randomization, the TTP was 8.38 months for those receiving maintenance therapy vs. 5.06 months for those in the observation group (P=0.0006). This produced a hazard ratio (HR) of 0.54 or a 46% reduction favouring PLD (Figure 2).

Figure
n from Randomization

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When TTP was calculated from the start of induction therapy, the median interval for patients randomized to PLD was 13.22 months vs. 10.16 months for patients randomized to observation (P=0.0005). This produced an HR of 0.53 favo

Figure 3. Time to Progression from Initial Induction Treatment

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The advantage of maintenance PLD for TTP was achieved with relatively little toxicity. The most significant adverse event was neutropenia in 32%, but only 12% of patients had neutropenia of grade 3 or 4. Moreover, it was experienced by 9% of the observation group, indicating that these events were not entirely PLD-related. There was no grade 3 or 4 anemia in either group. While 35% of the PLD group did have grade 1 or 2 anemia, the rate was 12% in the observation group.

Grade 3 or 4 non-hematological toxicities were also uncommon on maintenance PLD with none occurring in more than 5% of patients. These included mucositis, palmar-plantar erythema, and fatigue. There was one grade 3 infusion reaction. While grade 1 or 2 nausea or vomiting was reported in 21% of the patients on PLD, it was also reported in 4% of observation patients. Similarly, grade 1 or 2 fatigue and alopecia was observed in 32% and 29%, respectively, of PLD patients but also occurred in 8% and 4%, respectively, of observation patients. The effect of maintenance PLD on cardiotoxicity was negligible. The median left ventricular ejection fraction (LVEF) was 61% in the PLD group and 60% in the observation group when both were measured after the PLD group finished the maintenance therapy. A decrease in LVEF of 10% or greater was observed in 6% of PLD patients but also in 1% of observation patients. At last measurement, two patients who received PLD had LVEF <50% vs. no patients in the observation group, but there was no congestive heart failure detected in either group.

“Overall, the toxicity has been modest and manageable, while the cardiotoxicity has not been relevant,” Dr. Alba told listeners.

Discussion

He emphasized that while the median 3.3-month increase in TTP was highly statistically significant, the on-treatment results were yet more encouraging. Most progressions were avoided while the patients were on therapy with PLD, and its relative advantage over observation would have been greater if patients had received a longer course of therapy. Emphasizing that this study demonstrates that maintenance PLD therapy is a therapeutic option in responding patients with MBC after first-line chemotherapy, Dr. Alba noted that these data build on the previous trials. “While standard chemotherapy has proven effective for patients with MBC, the response is short-lived,” he remarked. “This is an approach to extending survival without unacceptable toxicity.”

Other Strategies to Avoid Toxicity in Metastatic Breast Cancer

Another strategy has been to introduce monoclonal antibodies into the treatment of MBC. Relative to chemotherapy, these drugs have been well tolerated, even though a previous phase III trial of conventional doxorubicin and trastuzumab demonstrated a high degree of activity but unacceptable cardiotoxicity in Her2-positive MBC patients. To circumvent this risk, one group of investigators tested trastuzumab with PLD while another evaluated trastuzumab with capecitabine. Both yielded encouraging results.

In the study led by Dr. Elmar Stickeler, University of Freiburg, Germany, 16 patients were evaluated on a combination of trastuzumab (4 mg/kg loading dose on day 2 followed by a weekly 2 mg/kg dose) and PLD (40 mg/m2 administered every 28 days). Although the number of patients in this study was small, no serious cardiotoxicity was detected.

“Half of the patients developed minor changes on electrocardiogram,” Dr. Stickeler reported, but he cautioned that the study was not controlled, so modest electrocardiogram changes in non-treated patients may also occur. However, as in the previous study of conventional doxorubicin and trastuzumab, this combination was also active. Overall, 43% of this population of advanced MBC patients were judged to have derived a clinical benefit from the combination based on a favourable change in tumour burden from baseline. In the absence of serious cardiotoxicity, Dr. Stickeler characterized this regimen as “safe and feasible.”

The results of the German study are consistent with those previously reported by a team of Canadian investigators led by Dr. Stephen Chia, British Columbia Cancer Agency, Vancouver. In a study published last year (Chia et al. J Clin Oncol 2006;24:2773-8), 30 women with Her2-positive MBC were treated with the same dose and schedule of trastuzumab used in the German trial plus PLD 50 mg/m2 every four weeks for six cycles. Again, there was a favourable level of activity but no clinically significant cardiotoxicity.

Other studies at a much earlier stage of clinical investigation have associated PLD and other targeted monoclonal antibodies with an acceptable safety profile. In a phase I study of PLD and lapatinib, a selective inhibitor of the ErbB1 and ErbB2 tyrosine kinases, dose-limiting toxicity was not reached in patients receiving up to 45 mg/m2 of PLD on an every-28-day cycle when combined with lapatinib 1500 mg taken daily. In initial data provided on seven patients by Dr. Mary Cianfrocca, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, there has been no grade 3 or 4 adverse event of any kind. Although one patient did experience a substantial drop in LVEF from baseline, it was accompanied by pericardial effusion and judged to be secondary to progressive disease.

“The combination of conventional doxorubicin and trastuzumab, while effective, led to an unacceptable risk of cardiac toxicity in a phase III study,” Dr. Cianfrocca noted. “While PLD was developed to improve the therapeutic index and overall benefit of the anthracyclines, this is one of the first studies to evaluate the effect with lapatinib. Although more data are needed, the combination appears to be active with reasonable tolerability.”

In the study of trastuzumab plus capecitabine, 40 consecutive women with advanced breast cancer and prior exposure to anthracyclines and at least one anti-microtubule agent, such as taxane or vinorelbine, were given capecitabine 2500 mg every day for two weeks out of a three-week cycle along with a daily dose of trastuzumab 8 mg/kg (after a loading dose of 6 mg/kg). Dose reductions of any kind were only necessary in 22.5% of patients and the activity was substantial. Although TTP was only eight months, 2.9% achieved a CR and 20% achieved a PR. SD was achieved in 48.6%.

“The combination of trastuzumab and capecitabine appears to be an effective and safe option as salvage therapy in a heavily pretreated population. TTP and response rates are similar to results with capecitabine and lapatinib,” reported Dr. Rupert Bartsch, Medical University of Vienna, Austria.

Risk Prediction Model

One non-pharmacologic approach to risk management has been the development of a risk prediction model in order to modify therapies only as necessary. This approach optimizes dose intensity while reducing risk of adverse events. In a study of one such model developed to predict neutropenic events, the approach appeared to be valid for application prior to each cycle of chemotherapy. Based on the relative risk for neutropenic complications as revealed by this system, doses could be delayed, growth factor support could be introduced, or the patient could be switched to a less toxic regimen. The model was specifically studied in patients receiving anthracycline therapy.

“The prediction model was developed for cycle-based risk prediction during chemotherapy,” explained Dr. Gregory Reardon, Informagenics, Worthington, Ohio. The prediction model was tested using data generated from the phase III trial which demonstrated that PLD had fewer side effects than conventional doxorubicin, including cardiotoxicity, alopecia, nausea and vomiting, and myelosuppression (O’Brien et al. Ann Oncol 2004;15:440-9). Over 500 MBC patients (N=509) were randomized to PLD 50 mg/m2 every four weeks or 60 mg/m2 of conventional doxorubicin every three weeks. The rates of cardiotoxicity and alopecia were three times higher, the rate of neutropenia was more than two times higher and the rate of vomiting was increased by 50% on conventional doxorubicin when compared to PLD.

Working only with neutropenia from the 509-patient data in that comparative trial, the prediction model was developed by looking at 22 variables. Only those variables that remained significant in a logistic regression analysis were selected for weighted risk scores, which were based on their relative predictive specificity and sensitivity. By adding risk scores, an estimate of anthracycline-induced neutropenic complications was calculated.

“The risk prediction tool demonstrated good internal validity and may be applied by the clinician prior to a cycle of chemotherapy,” Dr. Reardon stated. “Patient care could be enhanced by targeting the use of prophylactic granulocyte colony-stimulating factor, or by using safer alternatives such as PLD in place of doxorubicin in high-risk patients,” he concluded.

Summary

Anthracyclines have potent anti-tumour effects that can be limited by numerous toxicities, including ventricular dysfunction, nausea and vomiting, and neutropenia. Several comparative studies have confirmed that the risks of doxorubicin in MBC, where it has been a mainstay of treatment, can be modified by substituting doxorubicin in a pegylated liposomal formulation, which retains anti-tumour activity but reduces systemic adverse effects. The data support this strategy in providing a better benefit:risk ratio in MBC therapy.