We performed a phase II trial of pegylated liposomal doxorubicin (30 mg/m2
) plus docetaxel (60 mg/m2
) every 3 weeks for up to eight treatment cycles in patients with metastatic breast cancer, used alone in HER2-negative disease or in combination with trastuzumab in HER2-positive disease. The rate of CHF was less than 3% in both arms, including the trastuzumab arm, indicating that the primary study endpoint (cardiac safety) was met. The objective response rate was approximately 45%, and median progression-free survival was approximately 11 months for both the HER2-negative and HER2-positive groups in our trial. Another trial that reported on the efficacy and safety of PLD (50 mg/m2 every 4 weeks) in combination with trastuzumab for HER2-positive metastatic cancer demonstrated comparable efficacy, a 30% rate of grade 3 hand-foot syndrome and no significant cardiotoxicity, which is very consistent with our findings [22
In a previous trial performed by the ECOG (E1193), 739 patients with metastatic breast cancer who had no prior adjuvant doxorubicin or prior chemotherapy for metastatic disease were randomized to receive doxorubicin (60 mg/m2
), paclitaxel (175 mg/m2
/24 h infusion), or the combination (50 and 150 mg/m2
/24 h plus granulocyte colony-stimulating factor) as first-line therapy [5
]. The response rates were 36, 34, and 47%, respectively, and median time to treatment failure was 5.8, 6, and 8 months, respectively (the definition of treatment failure corresponded to the progression-free survival endpoint used in this study). Although the difference favoring the combination was statistically significant for both end points, it was associated with more toxicity and did not improve median overall survival (18.9 vs. 22.2 vs. 22 months, respectively). Likewise, the PLD–docetaxel doublet evaluated in this trial in a similar patient population appears to be more effective when compared with other studies evaluating PLD alone (30% response and 6.9 month median PFS [17
]) or docetaxel alone (47% response rate and 6.1 month median time to progression [29
]) when used as first-line therapy.
Similar findings were confirmed in a subsequent phase III trial comparing the identical PLD–docetaxel doublet evaluated in our trial with single agent docetaxel (75 mg/m2
) in 751 patients with metastatic breast cancer [30
]. However, in contrast to our trial, which required no prior anthracycline exposure and central HER2 testing (which directed the use of concurrent trastuzumab), the subsequent phase III trial required relapse at least one or more years after prior adjuvant anthracycline therapy, did not include HER2 testing for all patients, nor include concurrent trastuzumab for known HER2-positive tumors. In that study, the PLD–docetaxel combination was associated with significantly improved median PFS (9.5 vs. 6.9 months, HR = 0.66, 95% CI 0.56–0.78; P
= 0.000001) and ORR (35 vs. 26%; P
= 0.0085), but no difference in median overall survival (20.5 vs. 20.6 months, HR = 1.02, 95% CI 0.86–1.22; P
= 0.81). Moreover, there was no difference in the incidence of grade ≥2 symptomatic cardiac events in the two arms (5 vs. 4%) or CHF (1% in both arms), providing unequivocal evidence of cardiac safety in patients who had prior adjuvant anthracycline exposure (median prior cumulative doxorubicin dose of 240 mg/m2
). On the other hand, the PLD–docetaxel combination was associated with higher rates of other toxicities, including grades 3 and 4 HFS (24 vs. 0%) and stomatitis (12 vs. 1%). Those higher rates of certain toxicities did not translate into differences in self reported patients outcomes as measured by the FACT-B instrument, which were similar in the two treatment arms. The results of our study, therefore, provide complementary information to the subsequent phase III trial, demonstrating similar toxicity profile and comparable efficacy for the PLD–docetaxel combination in patients with no prior anthracycline therapy confirmed to have HER2-negative tumors.
Other studies have also evaluated the cytotoxic doublet therapy compared with single agent cytotoxic therapy in patients with HER2-positive disease treated concurrently with trastuzumab. Robert et al. compared trastuzumab plus paclitaxel (175 mg/m2) with the same regimen plus carboplatin (AUC 6) every 3 weeks for six cycles; the addition of carboplatin produced a higher response rate (52 vs. 36%; P
= 0.04) and median PFS (10.7 vs. 7.1 months; P
= 0.03), but not overall survival (median 35.7 vs. 32.2 months) [31
]. Pegram et al. reported that when compared to trastuzumab plus docetaxel (100 mg/m2), the combination of trastuzumab plus docetaxel (75 mg/m2) and carboplatin (AUC 6) every 3 weeks for eight cycles was not associated with improved response rate (73% in both arms) or median time to disease progression (11.1 vs. 10.4 months; P
= 0.57) [32
]. Therefore, it is uncertain whether the addition of carboplatin to a taxane with trastuzumab offers a clinical benefit in HER2-positive disease, and this may depend on the taxane component of the doublet.
In our E3198 trial, the three-drug regimen of PLD–docetaxel plus trastuzumab was associated with excessive HFS despite the prophylactic use of high-dose pyridoxine, which had been shown to prevent HFS in a canine model [26
]. On the other hand, there was no increase in the risk of cardiac toxicity in the HER2-positive group (treated with trastuzumab) compared with the HER2-negative group (which did not receive trastuzumab), thereby serving as an internal control arm, a unique feature of our trial design. The cardiac safety profile observed in our trial (primary endpoint) confirms a previous report demonstrating the efficacy and cardiac safety trastuzumab plus PLD [22
The findings of the subsequent phase III trial comparing the PLD–docetaxel combination with docetaxel mono-therapy are consistent with many other studies comparing combination versus single agent cytotoxic therapy, demonstrating improved response and PFS without an impact on survival and more toxicity [33
]. Overall survival is generally not improved in such trials in part due to the availability of multiple agents that have activity when used as second or greater line therapy [34
]. Based upon these consistent observations, it is generally recommended that cytotoxic therapy be given as single agents sequentially rather than in combination [34
]. However, there are circumstances in which doublet cytotoxic therapy may be indicated and appropriate, such as patients with advanced, visceral disease, or substantial tumor-associated symptoms that require more rapid and effective palliation.
In conclusion, we found that the PLD–docetaxel combination to be an effective regimen for patients with metastatic breast cancer, whether used alone in HER2-negative disease or in combination with trastuzumab in HER2-positive disease. Of great interest, the addition of trast-uzumab to the doublet did not result in an increase in the risk of cardiac toxicity (study primary endpoint) but was associated with a higher risk of hand-foot syndrome. The results of our study provide complementary information to other trials demonstrating that PLD is in effective alternative to other cytotoxic agents for metastatic breast cancer, including doxorubicin as first-line therapy [17
], or vinorelbine as second or greater line therapy [18