Reports

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MEDICAL FRONTIERS - 32nd San Antonio Breast Cancer Symposium

San Antonio, Texas / December 10-13, 2009

Preoperative chemotherapy plays a role in the management of many patients with operable breast cancer. By shrinking the tumour, preoperative chemotherapy facilitates more complete excision. In some instances, the shrinkage allows a woman to undergo breast-conserving surgery when a mastectomy would have been required otherwise.

Anthracyclines have been used extensively in preoperative chemotherapy for breast cancer. The drug class offers the potential for complete pathologic remission and improved long-term outcomes in patients with locally advanced disease, stated Dr. Rosalba Torrisi, Vice-Director, Medical Senology Research Unit, European Institute of Oncology, Milan, Italy.

For patients with HER2-positive breast cancer, trastuzumab has been used to effect breast-tumour shrinkage prior to surgery. A trastuzumab/anthracycline combination would be attractive as preoperative therapy, but both agents are cardiotoxic, Dr. Torrisi continued.

“Pegylated liposomal doxorubicin [PLD] has been shown to have the same activity as conventional doxorubicin in breast cancer but with less toxicity,” she reported. “However, preoperative use of PLD with trastuzumab had not been evaluated in detail.”

To add to the information base about the PLD/trastuzumab combination, investigators at the Milan institute conducted a clinical trial involving patients with HER2-positive, locally advanced breast cancer. The preoperative chemotherapy regimen consisted of PLD 25 mg/m², cisplatin 60 mg/m² and fluorouracil 200 mg/m2/day, administered in 21-day cycles for a maximum of eight courses. Additionally, patients received a trastuzumab loading dose of 8 mg/kg followed by 8 mg/kg every 21 days. Patients with hormone receptor-positive breast cancer also received an aromatase inhibitor.

The primary outcomes were clinical response and pathologic complete response (CR), defined as the absence of invasive or measurable tumour in the breast or axillary lymph nodes, as well as the tolerability of the regimen. Investigators enrolled 32 patients whose median age was 47. Other baseline characteristics included hormone receptor-positive tumours in 15 patients, stage T4 disease in 15 patients and clinically positive lymph nodes in 26 women (86%).

Four patients attained a CR and 26 others a partial response (PR), resulting in an overall response rate of 94%. No patient progressed during preoperative therapy. Dr. Torrisi reported that 13 patients (41%) attained a pathologic CR. In addition, one had only isolated tumour cells remaining and two others had pathologic T1a residual disease. At surgery, 74% of patients had negative lymph nodes.

Dr. Torrisi reported that 21 patients completed all eight courses of the preoperative chemotherapy regimen. The remaining 11 patients stopped therapy early, even though only seven episodes of grade 3+ non-hematologic toxicity occurred, including three episodes in one patient. All patients had a left ventricular ejection fraction (LVEF) ³50% before preoperative chemotherapy and no patient had a decline to <50%.

“This regimen was very active and demonstrated activity similar to what has been observed with combinations of conventional anthracyclines and trastuzumab,” Dr. Torrisi told delegates. “Cardiac toxicity was negligible. We believe these results justify further evaluation of this preoperative regimen in patients with HER2-positive breast cancer.”

HER2-positive Breast Cancer

A second study reported here at the San Antonio meeting evaluated PLD in combination with paclitaxel and trastuzumab as preoperative therapy for patients with operable HER2-positive breast cancer. Dr. Petra Rietschel, Assistant Professor of Medicine, Division of Oncology, Albert Einstein College of Medicine, Bronx, New York, explained the rationale for studying the combination.

“Doxorubicin, paclitaxel and trastuzumab are all quite active in HER2-positive breast cancer,” she noted. “However, trastuzumab and doxorubicin are both cardiotoxic, and combining the two drugs increases the potential for significant cardiotoxicity. PLD is considerably less toxic to the heart compared with conventional doxorubicin, and the pegylated liposomal formulation appears to have substantial activity.”

Eligible patients had non-metastatic T1c-T4 breast cancer and no more than one positive lymph node. The preoperative regimen consisted of PLD 24 mg/m² every three weeks, paclitaxel 80 mg/m² weekly and trastuzumab started with a 4 mg/m² loading dose followed by 2 mg/m² weekly. Excessive skin toxicity necessitated lowering the starting dose of PLD to 20 mg/m², Dr. Rietschel added.

Investigators enrolled 24 patients whose median age was 55. Nine patients required paclitaxel dose reductions and 12 required reductions in the PLD dose. Five patients discontinued therapy early. One patient withdrew from the study during the first cycle of therapy and one patient died of causes unrelated to the treatment, leaving 22 patients evaluable for response.

The preoperative chemotherapy regimen led to pathologic CR in 13 patients (59%) and the remaining nine (41%) had PRs. One of the patients who did not complete the study had stable disease.

The most prominent treatment-related toxicity was grade 2-3 skin toxicity, observed in 18 of 22 patients (82%). Multiple-gated acquisition scans before and after preoperative chemotherapy showed no overt cardiotoxicity.

“The preoperative chemotherapy regimen of PLD, paclitaxel and trastuzumab appears to be highly active, and we observed no evidence of cardiotoxicity with the regimen,” remarked Dr. Rietschel. “Future evaluation of this regimen should focus on optimizing the regimen to reduce the skin toxicity.”

The two studies of PLD regimens were among several reports presented here at the SABCS that related to neoadjuvant chemotherapy for breast cancer.

• Austrian investigators reported that the neoadjuvant combination of epirubicin, docetaxel and capecitabine resulted in a higher rate of pathologic CR compared with epirubicin and docetaxel in patients with early breast cancer. The same group found that adding trastuzumab to either cytotoxic regimen resulted in a nonsignificant improvement in pathologic CR compared with chemotherapy alone in patients with HER2-positive early breast cancer.

• Investigators at Sunnybrook Health Sciences Centre and Princess Margaret Hospital in Toronto reported a conversion from positive to negative hormone receptor status between core biopsy and definitive surgery in 24% of patients who received neoadjuvant systemic therapy for locally advanced breast cancer. Most of the difference resulted from a loss of progesterone receptor. Further studies are planned to determine the possible prognostic significance.

• A study from China showed that a neoadjuvant regimen consisting of paclitaxel and carboplatin resulted in an overall response rate of 86%, CR rate of 32%, and pathologic CR in 19.4% of 127 patients with locally advanced breast cancer.

Adjuvant Therapy

Anthracyclines are also used extensively as adjuvant chemotherapy for breast cancer. As with preoperative therapy, adjuvant use of doxorubicin and other anthracycline agents poses a substantial risk of cardiotoxicity, one that has increased with the use of combination regimens that include doxorubicin and trastuzumab.

Investigators in a multinational randomized clinical trial compared the efficacy and safety of an adjuvant chemotherapy regimen containing standard doxorubicin with that of a regimen containing PLD. The trial involved patients who had curative surgery for locally advanced breast cancer or high-risk node-negative cancer.

Patients were randomized to one of two regimens:

•PLD 35 mg/m² plus cyclophosphamide 600 mg/m² every three weeks for four cycles, plus trastuzumab 4 mg/m² loading dose followed by 2 mg/m² weekly.

• Doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every three weeks for four cycles.

Patients in both groups finished adjuvant therapy with paclitaxel 80 mg/m² plus trastuzumab 2 mg/m² weekly for 12 weeks.

They had a MUGA scan or echocardiography at baseline, before cycle 5 and after cycle 8, and then every three months for a year, followed by assessments at six-month intervals for a second year.

Participants were randomized 2:1 to the PLD and doxorubicin arms. The primary objectives of the study related to the feasibility and cardiac safety of the regimens, stated Dr. Daniel Rayson, Associate Professor of Medicine, Dalhousie University, Halifax, Nova Scotia. Investigators sought to determine the incidence of level 1 (severe heart failure, cardiac death) and level 2 cardiotoxicity (asymptomatic or mildly symptomatic heart failure associated with a decline in LVEF).

Patients in the doxorubicin arm received a cumulative anthracycline dose of 233.3 mg/m² compared with 127.5 mg/m² in the PLD arm. LVEF in the doxorubicin group averaged 66% at baseline, 63% before cycle 5 (13 weeks) and 60.3% after cycle 8 (P=0.017). In the PLD group the mean LVEF was 65% at baseline, 62% before cycle 5 and 61.6% after cycle 8 (P=0.058).

“The overall incidence of cardiac toxicity was zero in both groups, and no patient in either group was unable to receive trastuzumab because of changes in LVEF,” observed Dr. Rayson.

Principal toxicities (all grades) in the doxorubicin arm were alopecia (76.6%), fatigue (73.0%) and nausea (63.3%). In the PLD group, alopecia (52.5%), fatigue (52.5%), hand-foot syndrome (59.3%) and nausea (54.2%) were most common. Grade 3-4 toxicity occurred infrequently in both treatment groups.

The data reported here in San Antonio constituted an interim analysis. Investigators anticipate the final analysis will be available by mid-2010.

Other reports involving adjuvant systemic therapy for breast cancer included the following:

• A multicentre French study showed no improvement in disease-free survival or overall survival (OS) with adjuvant fluorouracil and docetaxel in patients with locally advanced inflammatory breast cancer treated preoperatively with epirubicin and cyclophosphamide.

• Preliminary data from a multicentre US trial showed no increase in cardiotoxicity from adding lapatinib to paclitaxel/trastuzumab adjuvant systemic therapy.

• A retrospective analysis of outcomes with several adjuvant chemotherapy regimens showed that six cycles of fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy led to a higher incidence of amenorrhea compared with three cycles of FEC followed by three cycles of docetaxel or four cycles of FEC followed by four cycles of docetaxel.

Prior Anthracycline Exposure

At the 2008 San Antonio meeting, Dr. Joseph Sparano, Professor of Medicine, Division of Oncology, Albert Einstein College of Medicine, had reported findings from a study of PLD and docetaxel in patients with advanced breast cancer in relapse after prior adjuvant or neoadjuvant anthracycline therapy. The data had shown that PLD plus docetaxel improved time to progression without an increased risk of cardiotoxicity compared with docetaxel alone (Sparano et al. Cancer Res 2008;68(suppl):Abstract 60).

Here at the 2009 meeting, Dr. Sparano and colleagues presented a new analysis of the study, examining the relationship between the anthracycline-free interval (time from completion of therapy to relapse) and outcome.

The data emerged from a randomized clinical trial involving 751 patients with advanced breast cancer that had relapsed at least one year after adjuvant or neoadjuvant anthracycline therapy. The patients were randomized to docetaxel 75 mg/m² or to PLD 30 mg/m² followed by docetaxel 60 mg/m². The primary end point was time to progression. Secondary outcomes of interest included OS, progression-free survival (PFS), objective response rate and safety.

In the current analysis, patients were grouped according to their anthracycline-free interval. One group comprised 306 patients who had an anthracycline-free interval of 1 to 2 years, and the other group included 442 patients with an interval exceeding two years.

Among patients with the briefer anthracycline-free interval, those treated with docetaxel alone had a time to progression of 5.7 months compared with 7.8 months in the PLD/docetaxel group (P=0.002). A similar advantage was observed in patients who had an anthracycline-free interval >2 years: time to progression 7.7 months with docetaxel alone vs. 10.6 months with PLD plus docetaxel (P<0.001).

PFS also favoured the PLD arm in patients with anthracycline-free intervals of 1 to 2 years (7.7 vs. 5.5 months with docetaxel alone, P=0.002) and with anthracycline-free intervals lasting beyond two years (10.0 vs. 7.7 months, P<0.001). OS and overall response rate did not differ between treatment groups, regardless of the anthracycline-free interval.

Overall, the longer anthracycline-free interval significantly improved time to progression (8.9 vs. 6.6 months, P=0.001), OS (23.4 vs. 17.2 months, P<0.001) and PFS (8.7 vs. 6.5 months, P<0.001).

The incidence of heart failure was about 1% and did not differ significantly between treatment groups, noted researcher Dr. Preeta Kanojia, Horsham, Pennsylvania, on behalf of the study group. Hand-foot syndrome and stomatitis occurred more often in patients treated with PLD. Most cases of hand-foot syndrome responded to a reduction in the PLD dose or a delay in the treatment cycle. However, 20% of patients treated with PLD discontinued because of hand-foot syndrome. Rates of hand-foot syndrome seen with PLD/docetaxel were similar to those seen in a study of a capecitabine regimen for metastatic breast cancer.

According to investigators, an anthracycline-free interval greater than two years improved time to progression, OS and PFS, regardless of treatment. Similar to results of the overall study, treatment with the combination of PLD/docetaxel resulted in statistically significant improvement in time to progression and PFS compared with docetaxel among patients with advanced breast cancer, regardless of the anthracycline-free interval. The addition of PLD to a docetaxel-based regimen is an active option for patients with advanced breast cancer previously treated with adjuvant anthracycline regimens.