Optimizing Cytotoxic Chemotherapy: New Insights

Progress continues in the investigation of cytotoxicchemotherapy for breast cancer, and recentdata have yielded important new insights.Among the many approaches understudy are dose-dense anthracyline-taxaneand cyclophosphamide regimens inpatients with high-risk early disease; AC/taxane combinations incorporatinggemcitabine (Gemzar) or capecitabine(Xeloda); taxanes combined with antiangiogenesisagents such as bevacizumab(Avastin); regimens for patients with inflammatoryor HER2-positive breast cancer,including a taxane plus a targetedagent, for example trastuzumab(Herceptin) or the small-molecule tyrosinekinase inhibitor lapatinib (Tykerb); andnovel taxane formulations such as albumin-bound or nab-paclitaxel (Abraxane),which was approved in January 2005 forpatients with metastatic breast cancer notresponsive to combination therapy, andwhich has demonstrated in randomizedtrials efficacy and tolerability superior toconventional taxanes in first-line therapy.

Studies reported in this issue of"Hot Topics" were presented at the 29thannual San Antonio Breast Cancer Symposium(SABCS). Some are remarkablefor their efficacy and tolerability outcomes;others hint at potential future changes inthe treatment of women with both earlyand advanced disease.

The benefit of dose-dense AC/taxanechemotherapy in high-risk early-stagebreast cancer was confirmed by the GermanAGO Group, in a randomized phaseIII trial of nearly 1,300 patients with amedian of 8 positive axillary lymph nodes(abstract 53). Dr. Volker J. Moebus reportedthat dose-dense therapy withepirubicin (Ellence)–paclitaxel (Taxol)and cyclophosphamide was superior to standard therapy in both relapse-free survival(70% vs 62%, P = .00079) and overallsurvival (82% vs 77%, P = .029). Resultsof a mature 70-patient cardiac safetystudy have led Dr. Chau T. Dang andcolleagues to conclude that dose-denseAC (with doxorubicin) followed by Taxolwith trastuzumab for 52 weeks in HER2-positive patients is feasible, with one reportedcase of CHF (congestive heartfailure) and no significant declines inLVEF (left ventricular ejection fraction)at month 2 MUGA.

A second interim efficacy analysis ofthe BCIRG 006 trial in 3,200 HER2-positive women, presented by Dr. Dennis J.Slamon, found trastuzumab plusdocetaxel with carboplatin produced acomparable survival benefit but had significantlylower toxicity vs trastuzumabplus an AC regimen using doxorubicin(abstract 52). During a median followupof 3 years, patients randomized to theanthracycline-containing experimentalregimen experienced higher cardiactoxcity and there was one case of ACrelatedleukemia.

Trials comparing different taxanes andcombinations were also informative: Ina planned interim analysis of a phase IIhead-to-head trial of first-line nabpaclitaxelvs docetaxel in chemonaivestage IV breast cancer, our group foundwomen who received nab-paclitaxel hadlonger progression-free survival (abstract46). Notably, weekly nab-paclitaxel (at100 or 150 mg/m2) increased tumor responserate by more than 60% vsdocetaxel, and was better tolerated. In aphase II open-label study reported byDr. Barry C. Mirtsching, weekly firstlinenab-paclitaxel was well tolerated andeffective in patients with taxane-refractorymetastatic or locally advanced breastcancer (LABC), with a response rate approaching75% (abstract 6073).

Early results from a phase II trial offirst-line nab-paclitaxel and capecitabinein metastatic breast cancer by Dr. Lee S.Schwartzberg et al showed an ORR of53% (with survival data not yet mature)and good tolerability, with a 10% incidenceof neuropathy and hand-foot syndrome(abstract 1096).

In a small retrospective analysis of anab-paclitaxel/bevacizumab combinationin 27 consecutive patients withheavily pretreated metastatic disease, Dr.John S. Link reported an ORR of 59%,with durable reponses and no grade 3 neuropathy (abstract 1095).

In a phase II study in LABC, Dr. AndrRobidoux noted weekly nab-paclitaxelat 100 mg/m² for 12 consecutive weeksfollowed by an anthracycline was welltolerated and produced a clinical CR rateof 32% (abstract 3068). After therapywith nab-paclitaxel followed by FEC, theclinical CR rate was 57%; all patientswere able to undergo resection and onethirdhad surgery for breast conservation.In another phase II study of LABC,Dr. Denise A. Yardley reported that atriplet of biweekly neoadjuvantgemcitabine, epirubicin, and nabpaclitaxelyielded a 94% overall pathologicresponse rate and was well tolerated,with no febrile neutropenia and nograde 3/4 neuropathy (abstract 3069).

Dr. Yardley and coinvestigators alsowill analyze tumor levels of SPARC todetermine if these correlate with clinicalreponse to nab-paclitaxel; SPARC hasbeen shown to specifically bind to albumin,so there may be increased localizationof nab-paclitaxel at the tumor site.

In an early trial in newly diagnosedHER2-positive IBC, Dr. MassimoCristofanilli reported adjuvant therapywith paclitaxel plus lapatinib produced aclinical response in 77% of patients (CR10%, PR 67%), with stable disease seenin an additional 10%; side effects weremanageable and included grade 3 diarrhea,asthenia, and fatigue (abstract 1).

Taken together, recent and ongoingclinical studies clearly have yieldedadvances and a new understanding ofcytotoxic-based treatment strategies forbreast cancer, with important data thatwill point the way toward better plansfor rational, optimized therapy in 2007and beyond.

Disclosures:

Dr. William J. Gradishar hasno significant financial interest or other relationshipwith the manufacturers of any products or providersof any service mentioned in this educational activity.