ONCOLOGY Vol 18 No 14_Suppl_12

Primary systemic therapy (ie, preoperative or neoadjuvant) increasesthe possibility for breast-conserving surgery in patients with primarybreast cancer. Patients with pathologic complete response to primarysystemic therapy have improved survival compared with those with persistenttumors. Several phase II trials have evaluated gemcitabine-containingdoublet or triplet regimens as primary systemic therapy for breastcancer, results of which have shown promising clinical and pathologicresponse rates with manageable toxicity. Results of a phase I/II studyof gemcitabine (Gemzar)/epirubicin (Ellence)/docetaxel (Taxotere), orGEDoc, with prophylactic filgrastim (Neupogen), as primary systemictherapy in 77 evaluable patients with primary breast cancer are reportedherein. Dose-limiting toxicities were grade 3 febrile neutropenia(n = 1) and grade 3 diarrhea (n = 2) at the fourth dose level ofGEDoc tested (gemcitabine at 800 mg/m2 days 1 and 8, epirubicin at90 mg/ m2 day 1, and docetaxel at 75 mg/m2 day 1). As assessed byultrasound, 92% of patients responded overall (22% complete response),and 79% of patients could undergo breast-conserving surgery. Thepathologic complete response rate in resected breast tissue was 26%.

Use of the gemcitabine (Gemzar) plus docetaxel (Taxotere) combinationin metastatic breast cancer is motivated by the different mechanismsof action of the drugs, partially nonoverlapping toxicity profiles,and good single-agent activities of both drugs in treatment-naive andanthracycline-pretreated patients. In phase II trials, combinations ofgemcitabine at 900 or 1,000 mg/m2 on days 1 and 8 and docetaxel at 75to 100 mg/m2 on either day 1 or day 8 every 3 weeks, or gemcitabine at800 mg/m2 on days 1, 8, and 15 and docetaxel at 35 mg/m2 on days 1, 8,and 15 or 100 mg/m2 on day 1 every 4 weeks, have produced responserates of 36% to 79% in patients receiving primarily second-line treatment;response rates were greater than 50% in five of six studies. Inphase II trials using every-2-week regimens of gemcitabine at 1,500 or2,000 mg/m2 on day 1 and docetaxel at 50 or 65 mg/m2 on day 1 or 55mg/m2 on day 8, response rates were 50% in pretreated patients and66% in treatment-naive patients. Neutropenia is the primary toxicity ofthe combination; in phase II studies performed with or without growthfactor support, rates of grade 3/4 neutropenia ranged from 29% to 79%and rates of febrile neutropenia ranged from 0% to 18%. An ongoingphase III trial is comparing gemcitabine at 1,000 mg/m2 on days 1 and8 plus docetaxel at 75 mg/m2 on day 1 every 21 days, vs capecitabine at1,000 mg/m2 twice daily for 14 days plus docetaxel at 75 mg/m2 on day1 every 21 days in patients with metastatic breast cancer. Results of thistrial will help to determine optimal use of taxane-based combinationsin patients with advanced disease.

Although anthracyclines and the taxanes comprise the most activefirst-line cytotoxic treatments in patients with hormone-insensitive orlife-threatening metastatic breast cancer, many patients progress andrequire other chemotherapeutic agents. Development of new combinationsand/or agents is thus needed. Gemcitabine (Gemzar) and platinumcompounds have been employed as single agents, and the additionof gemcitabine to the platinums results in significant clinical benefitand response rates. Correlative biologic studies are expected fromseveral already-reported trials and may help elucidate predictive factorsfor both response and toxicity when combining gemcitabine andthe platinums. Trials incorporating these doublets in earlier stages ofbreast cancer or in the neoadjuvant setting may further elucidate theirrole in breast cancer treatment.

Gemcitabine (Gemzar) possesses meaningful antitumor activity inthe treatment of breast cancer, repeatedly demonstrating superior outcomeswithout the price of excessive toxicity in most patients. In combinationwith other agents, it has a potential for nonoverlapping toxicities,a novel mechanism of action, as well as a potential lack of completecross-resistance. Randomized phase III trials with gemcitabinehave yielded response rates that have translated into time to diseaseprogression and survival benefits. Thus, enthusiasm continues forgemcitabine, especially in combination with other cytotoxic agents. Theaugmentation of efficacy (ie, response rates, time to disease progression,overall survival) by the addition of gemcitabine to paclitaxel hasestablished this regimen as a first-line treatment option for patientswho might benefit from combination therapy. Gemcitabine now remainsunder active investigation for the treatment of early-stage breastcancer, with ongoing trials characterizing its role in the neoadjuvantsetting.

The tAnGo trial is a randomized, open-label, multicenter phase IIItrial examining adjuvant treatment with epirubicin (Ellence)/cyclophosphamide(Cytoxan, Neosar) for four cycles followed by paclitaxel aloneor combined with gemcitabine (Gemzar) for four cycles in patients withearly-stage breast cancer. In the Cancer and Leukemia Group B(CALGB) 9344 trial, addition of paclitaxel to anthracycline/cyclophosphamideadjuvant therapy resulted in increased time to recurrence andimproved survival. Because an unplanned subgroup analysis in CALGB9344 indicated a significant benefit of paclitaxel in patients with estrogenreceptor (ER)-negative disease but not ER-positive disease, the initialtAnGo trial design called for enrollment of patients with ER-negativedisease. The tAnGo trial entry criteria were recently amended toallow any ER status, given experience suggesting that clinical benefitof taxane-containing regimens in ER-positive disease may emerge overa time frame longer than that required to detect benefit in ER-negativedisease. Gemcitabine has been included as a partner for paclitaxel inthe tAnGo trial based on high response rates, including high completeresponse rates, observed in phase II trials of the combination in moreadvanced disease and based on the tolerability and safety of the combinationcompared with those of other taxane-containing two-drug combinations.The tAnGo trial is currently accruing patients and has atarget population of 3,000. Trial results should provide important informationon the role of gemcitabine in adjuvant therapy for breastcancer.

Trastuzumab (Herceptin) is an effective treatment in patients withHER2-overexpressing metastatic breast cancer. Risk of trastuzumabinducedcardiotoxicity raises concerns regarding combined use withanthracyclines or other potentially cardiotoxic agents followinganthracycline treatment. We characterized interactions betweentrastuzumab and gemcitabine (Gemzar) and the combination ofgemcitabine and cisplatin or carboplatin (Paraplatin) as such combinationsmight help reduce the risk of cardiotoxicity. Multiple drugeffect/combination index isobologram analysis was used to study theefficacy of chemotherapeutic drug plus trastuzumab combinations inHER2-overexpressing breast cancer cell lines. Combination index valueswere derived from parameters of the median effect plots, and statisticaltests were used to determine whether the mean combinationindex at multiple effect levels significantly differed from a combinationindex value of 1.0 (values < 1.0 indicate synergy; values > 1.0,antagonism; values equal to 1.0, additivity). At a wide range of clinicallyachievable drug concentrations, interactions between trastuzumaband gemcitabine were synergistic at low concentrations of gemcitabineand antagonistic at high concentrations. A consistent synergistic interactionwas observed with the three-drug combination of trastuzumabplus gemcitabine plus carboplatin or cisplatin. Available clinical dataon the use of trastuzumab plus gemcitabine, and trastuzumab plusgemcitabine/paclitaxel, as well as clinical data on the use ofgemcitabine/cisplatin in breast cancer, are discussed. These findingsindicate that trastuzumab plus gemcitabine and trastuzumab plusgemcitabine plus cisplatin or carboplatin are rational combinations toevaluate in clinical trials.

Gemcitabine (Gemzar) and paclitaxel are active drugs in the treatmentof metastatic breast cancer. Phase I clinical trials data have suggestedthat the gemcitabine plus paclitaxel combination is safe in breastcancer patients. Two doses/administration schedules have been preferredin subsequent phase II and III trials: gemcitabine on days 1 and8 plus a taxane on day 1, every 3 weeks; or gemcitabine plus a taxaneon days 1 and 14, every 4 weeks. In phase II trials, 114 of 221 patients(52%) responded to gemcitabine/paclitaxel therapy. Response rates werelower among patients who received previous chemotherapy for metastaticdisease (response rates: 45%, second line and 70%, first line).Toxicity of gemcitabine/paclitaxel regimens has generally been low, withfew cases of neutropenia or nonhematologic toxicity. Results of therandomized phase III registration trial show a clear advantage forgemcitabine plus paclitaxel over paclitaxel alone in time to disease progression,objective response, and overall survival. Triplet combinations,in which an anthracycline is added to gemcitabine/paclitaxel, are beingexplored in the metastatic and neoadjuvant settings.