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Optimizing Efficacy and Manageable Toxicity in Metastatic Breast Cancer

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

33rd Congress of the European Society for Medical Oncology

Stockholm, Sweden / September 12-16, 2008

Despite substantial advances in early diagnosis and treatment of localized disease, large numbers of women will develop poor-prognosis metastatic breast cancer. In these patients, meaningful extensions of time to progression (TTP) and survival rather than cure constitute the most likely benefit from aggressive therapy. The clinical challenge is selecting a regimen that prolongs TTP and survival meaningful to the patient. New phase III data in advanced breast cancer have associated the anthracycline doxorubicin, an effective but toxic agent in its native form, with high degrees of efficacy and tolerability in a pegylated liposomal formulation. The results of the study define a regimen that has immediate relevance to management of metastatic disease.

“The main finding of this trial was the low toxicity profile of pegylated liposomal doxorubicin (PLD) at a dose of 40 mg/m2. This dose presented no grade 3/4 gastrointestinal toxicity and no grade IV alopecia. Grade IV adverse effects such as mucositis or hand-foot syndrome were lower than 5%. The treatment also presented no clinically relevant cardiotoxicity,” reported Dr. Emilio Alba, Chief, Medical Oncology Service, Hospital Universitario Vírgen de la Victoria, Málaga, Spain.

In this multicentre study, women with metastatic breast cancer and acceptable cardiac, renal and hepatic function were first treated with an induction therapy that consisted of conventional doxorubicin for three 21-day treatment cycles followed by three treatment cycles with docetaxel. Those who achieved a complete response (CR), partial response (PR) or stable disease (SD) were eligible for randomization to PLD at a dose of 40 mg/m2 administered once every 28 days for six cycles or to observation. The primary end point was TTP. Secondary end points included toxicity and overall survival (OS).

Study Findings

The median age of the 155 randomized patients was 57 years (range 30 to 74 years). Thirty per cent and 35% of patients randomized to PLD and observation, respectively, had received prior anthracycline therapy. At the time of randomization after the induction regimen, the disease status in the PLD vs. observation groups was CR 4% vs. 9%, PR 49% vs. 61%, and SD 47% vs. 31%. An overall distribution favoured observation but it did not differ significantly (P=0.077)

From the time of randomization, the median TTP was 8.32 months on PLD vs. 4.93 (P=0.0008) in the observation group. From the time of induction, the median TTP was 13.18 months on PLD compared with 10.06 months in the observation arm (P=0.0005). Survival at 12 months was 81% in the PLD arm vs. 66% (P=0.04) in the observation group. The median OS was not significantly different between the two groups but favoured PLD.

The outcome for PLD was characterized as meaningful because the rate and severity of adverse events was modest. Of the 78 patients randomized to PLD, only five had a drop in left ventricular ejection fraction (LVEF) of more than 10%, and the LVEF fell below 50% in only two women. There were no cases of symptomatic heart failure. In addition, grade 3/4 hand-foot syndrome, which is a dose-limiting toxicity of PLD, was uncommon in this study. Only three patients (4%) had grade 3 hand-foot syndrome and none had grade 4. Other grade 3/4 toxicities between treatment arms were unremarkable.

Controlled Toxicity in Modified Formulation

The low risk of adverse events, documented in previous trials with PLD, is attributed to the encapsulation of doxorubicin in liposomes with an outer coating of polyethylene glycol (PEG). The PEG liposome encapsulation increases the proportion of drug delivered to the tumour relative to normal tissues. This circumvents many of the toxicities that patients most fear from conventional chemotherapies.

“Many types of chemotherapy regimens increase TTP in metastatic breast cancer, but toxicity is the persistent obstacle,” Dr. Alba confirmed. “In this study, we saw a good relationship of benefit to risk. PLD provides an opportunity to improve survival in advanced disease with a good toxicity profile.”

It is notable that the increase in TTP in this trial is similar to that reported in similar populations using newer targeted therapies, such as trastuzumab or lapatinib. Dr. Alba characterized the three-month increase in TTP as an important threshold, noting that the majority of oncologists surveyed identified this increase as clinically meaningful.

The comparison of PLD to targeted therapies is relevant. Although targeted therapies are not without side effects, which frequently include rash and hypertension and may include hand-foot syndrome, mucositis and hypothyroidism, they are generally perceived to be better tolerated than cytotoxic agents, particularly anthracyclines.

Triple-negative Disease

However, anthracyclines are highly effective in a broad array of breast cancers including those in which targeted therapies have been poorly active. This issue has intensified with growing focus on “triple-negative” breast cancer. Triple negative refers to breast cancer patients whose malignancies are negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2).

“In patients with triple-negative disease, we are going to have to develop other types of targets and there are several which are showing promise. However, it is important to recognize that there are chemotherapy-sensitive breast cancer populations, and we do have data to show that these populations do very well,” declared Dr. Andrew Tutt, consultant clinical oncologist, Guy’s and St. Thomas Hospital, London, UK.

Among other data he cited, Dr. Tutt supported this conclusion with a recent analysis from the M.D. Anderson Cancer Center in Houston, Texas, that compared outcomes in 255 triple-negative breast cancer patients to 863 patients with one or more of the three receptor targets who received neoadjuvant chemotherapy (Liedtke et al. J Clin Oncol 2008; 26:1275-81). Although triple-negative women with residual disease did have a lower survival than receptor-positive women with residual disease after three years of follow-up (68% vs. 88%; P=0.0001), those who achieved a pathologic CR on chemotherapy had comparable survivals over this time frame (94% vs. 98%; P=0.24).

In those with residual disease, one issue is whether the triple-negative patients were receiving optimal therapy over the period of time that data were being collected (1985 to 2004). Although targeted therapies were not widely available in the early part of this time frame, many patients with advanced disease have been treated with targeted therapies on research protocols irrespective of their receptor status. While there is an increasing emphasis on documenting the presence of targets before initiating a targeted therapy, there have yet been no formal guidelines to mandate chemotherapies, such as anthracyclines, in breast cancer patients who are triple-negative. This is true despite evidence that these agents are highly active regardless of how breast cancer is subtyped.

“Maintenance therapy is a good option for almost everybody if we can design effective treatments that have an acceptable toxicity profile,” stated Dr. Alba, whose remarks are relevant to advanced disease whether or not patients do have triple-negative disease. “I think this goal is achieved in the case of PLD.”

Summary

A phase III study has demonstrated that maintenance therapy with six cycles of PLD significantly prolongs TTP and offers a survival benefit in women with metastatic breast cancer who have previously received an anthracycline and a taxane. The only remarkable grade 3 toxicity that occurred more commonly in the PLD group was hand-foot syndrome, which occurred in 4% of patients. The activity and tolerability of PLD is reassuring for prolonging survival in patients with metastatic breast cancer, and it is likely relevant to other breast cancer groups that depend on the activity of chemotherapy, such as those with triple-negative disease.

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