Optimizing Cytotoxic Chemotherapy: New Insights

March 1, 2007

Progress continues in the investigation of cytotoxicchemotherapy for breast cancer, and recentdata have yielded important 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.