Several clinical trials have explored the efficacy of docetaxel (Taxotere) as primary chemotherapy for breast cancer. Docetaxel has been evaluated as single-agent therapy, sequentially as a single agent following anthracycline-containing regimens, and in combination with anthracyclines, cisplatin, and trastuzumab (Herceptin) in patients with high-risk early breast cancer.
ABSTRACT: Several clinical trials have explored the efficacy of docetaxel (Taxotere) as primary chemotherapy for breast cancer. Docetaxel has been evaluated as single-agent therapy, sequentially as a single agent following anthracycline-containing regimens, and in combination with anthracyclines, cisplatin, and trastuzumab (Herceptin) in patients with high-risk early breast cancer. Two large, randomized phase III trials have demonstrated significant improvements in clinical and pathologic response rates with the sequential addition of docetaxel to an anthracycline-containing preoperative regimen. A trial conducted in the United Kingdom demonstrated that docetaxel sequential to CVAP (cyclophosphamide [Cytoxan, Neosar], vincristine, doxorubicin [Adriamycin], prednisolone) produced a higher overall clinical response rate (94% vs 66%, P = .001) and pathologic complete response rate (34% vs 18%) compared to additional cycles of CVAP as primary chemotherapy. This translated into a survival advantage for docetaxel-treated patients, whose 3-year disease-free and overall survival were significantly improved (97% vs 84%; 90% vs 77%, P = .03). The results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-27 demonstrated that primary doxorubicin/cyclophosphamide followed by docetaxel significantly increased the clinical complete response (65% vs 40%, P Breast cancer is a major public health problemworldwide. An estimated 40,800 women died of the disease in 2001, making breastcancer second only to lung cancer as the leading cause of cancer death in womenin the United States. However, over the last decade, breast cancer mortalityrates decreased approximately 1.5% per year in the United States and UnitedKingdom. This is due in part to the widespread use of adjuvant systemictherapy. Adjuvant chemotherapy and hormonal therapy reduced the risk ofrecurrence and the death rate in both premenopausal and postmenopausal patientswith breast cancer.
Adjuvant therapy provided the same proportional degree of benefit to bothnode-positive and node-negative patients; however, the benefit of chemotherapyis more evident in several subsets, such as younger patients andestrogen-receptor (ER)-negative patients. Furthermore, it has been shown thatanthracycline-containing adjuvant regimens are superior to regimens that do notinclude an anthracycline. Adjuvant anthracycline therapy additionally reducedthe risk of recurrence by 12% and the risk of death by 11%. In summary,adjuvant therapy has changed the natural history of early breast cancer.
Primary chemotherapy, also known as neoadjuvant, induction, or preoperativechemotherapy, was initially introduced as the primary treatment of patients withoperable and inoperable locally advanced breast cancer. It became an integralcomponent of the multidisciplinary approach to the treatment of locally advancedbreast cancer. This strategy includes primary chemotherapy; often followed byregional therapy in the form of surgery, radiation therapy, or both; followed,in turn, by additional postoperative chemotherapy, radiation therapy (if notpreviously administered), and hormonal therapy (ER-positive).
Primary chemotherapy has dramatically transformed the natural history oflocally advanced breast cancer over the last 2 decades.[4-11] It is now a widelyaccepted treatment strategy for these patients. More than 70% of patientsachieve a clinical objective response (including pathologic complete remissionsin 10%-15%) after primary chemotherapy, and most patients experiencedownstaging of the primary tumor and regional lymph node metastases. As aresult, breast conservation surgery has now been established as a potentialalternative to modified radical mastectomy in 10% to 30% of patients withlocally advanced breast cancer.[7-8,10]
After multidisciplinary therapy, almost all patients are initially rendereddisease free, and more than 70% achieve long-term local control. In TheUniversity of Texas M. D.Anderson Cancer Center experience, the 5-year disease-free survival rates forpatients with stage IIB/IIIA and stage IIIB disease were 71% and 33%,respectively. The 5-year overall survival rates for stage IIB/IIIA and stageIIIB disease were 84% and 44%, respectively; the 10-year overall survival rateswere 56% and 26%, respectively.[7-8] Patients without microscopic residualdisease had better disease-free and overall survival patterns. Among patientswhose mastectomy axillary nodes specimen did not contain residual disease,pathologic complete remission, more than 75% achieved a 5-year survival.
Primary Chemotherapy in Operable Breast Cancer
With the goal of enhancing the breast conservation rate and disease-free andoverall survival, primary chemotherapy was later introduced as induction therapyin patients with large, operable stage II and stage IIIA breast cancer.[12-21]Several biological and clinical advantages initially provided the rationale forthis approach rather than adjuvant chemotherapy. They included: (1) the in vivotumor response assessment; (2) no postsurgical growth spurt; (3) intact tumorvasculature; (4) early initiation of systemic treatment; (5) down staging ofprimary tumor and lymph node metastasis to increase the possibility ofoperability (locally advanced breast cancer) and breast conservation surgery(locally advanced breast cancer and large operable breast cancer); (6) earlybiological surrogate markers to assess the efficacy of therapy; and (7) adecrease in drug resistance by early exposure to systemic therapy.
A number of promising phase II trials were reported in patients with largeoperable breast cancer.[12-13] Significant antitumor efficacy and a higher rateof breast conservation surgery were achieved. The Milan group presented thelargest experience. Their results included data from 536 patients who hadbeen enrolled in several nonrandomized clinical trials. The initial seriesincluded patients who were considered to be candidates for mastectomy becausetheir tumors were clinically > 3.0 cm (later trials included patients withtumors measuring 2.5 cm or more). They received either three or four cycles of primarychemotherapy (CMF [cyclophosphamide (Cytoxan, Neosar), methotrexate,fluorouracil (5-FU)] or FAC/FEC [5-FU, doxorubicin (Adriamycin),cyclophosphamide/5-FU, epirubicin (Ellence), cyclophosphamide]). The clinicaloverall response rate was 76%, with a clinical complete remission seen in 16%;however, only 3% achieved a pathologic complete response. The incidence ofbreast conservation surgery was greater than 85%.
Phase III Trials of Primary Therapy
Several large randomized phase III trials of primary therapy for operablebreast cancer have been reported.[14-21] A summary of these trials is presentedin Table 1.[14-21] The largest trial was conducted by the National SurgicalAdjuvant Breast and Bowel Project (NSABP) B-18.[14,15] Approximately 1,523 womenwith stage II and III breast cancer (T1-3, N0, M0) were randomized to receivefour cycles of doxorubicin, 60 mg/m², and cyclophosphamide, 600 mg/m² (AC),either before (primary chemotherapy) or after surgery (adjuvant chemotherapy).The administration of primary chemotherapy resulted in a clinical completeresponse in 36% and a clinical partial response in 44%, for an overall clinicalresponse rate of 80%. Patients randomized to receive primary chemotherapydemonstrated a pathologic complete response rate of 13%.
There was a significant improvement in the rate of breast conservationsurgery (ie, lumpectomy) in patients in the primary chemotherapy arm vs theadjuvant therapy arm (68% vs 60%; P = .002). The 5-year disease-free survival(67%) and overall survival (80%) in the primary chemotherapy arm and theadjuvant therapy arm were identical. In addition, there was no difference in therate of ipsilateral locoregional recurrence.
Of interest, however, was the demonstration of a significant correlationbetween pathologic complete response (breast only) to preoperative chemotherapyin terms of survival outcome. Those who also achieved a pathologic completeresponse had a significantly improved disease-free and overall survival (84% and87%, respectively) compared with those who were found to have residual invasivecarcinoma at the time of surgery (72% and 78%, respectively). The results ofthis correlation have persisted through 8 years of follow-up.
In summary, previously conducted phase III randomized trials failed todemonstrate an improvement in the disease-free and overall survival rates withprimary vs adjuvant chemotherapy. However, the trials confirmed the clinicaladvantage of an increase in the breast conservation surgery rate and downstagingof both clinical and pathologic involvement of axillary nodes. Importantly, thedemonstration of a correlation between tumor response (ie, pathologic completeresponse) and patient survival (disease-free and overall) provides a usefulearly surrogate marker of favorable outcome. Dividing patients into groupsaccording to tumor response after primary chemotherapy might provide an avenuefor improved clinical management. With the development of new, highly activechemotherapy agents over the last 10 years, it is possible to use newstrategies to improve the outcome of patients with breast cancer.
Phase II/III Single-Agent Trials
The results of two phase II and two phase III trials of single-agentdocetaxel for primary chemotherapy are now available. The first phase II studywas conducted at the Northwestern University Cancer Center. The trialincluded 33 patients with stage III breast cancer, 36% of whom had stage IIIBdisease. Patients were treated with docetaxel, 100 mg/m² every 3 weeks × 4,followed by surgery and adjuvant AC × 4, radiation therapy if indicated, andtamoxifen if ER-positive or over age 50 years. The median age of patients was 50years. The major side effects were hematologic, with neutropenic fever occurringin 7% of patients. The clinical overall response rate was 85% (18% completeresponse, 67% partial response); only one patient achieved a pathologic completeresponse.
A second phase II study using preoperative docetaxel at 100 mg/m² every 3weeks for six cycles was reported by Amat et al. Among enrolled patients, 20had stage IIA disease, 21 had stage IIB, 14 had stage IIIA, and 6 had stage IIIBdisease. The median tumor size was 5 cm. Neutropenic fever was the most seriousadverse event. Clinical examination, ultrasound, mammogram, or magneticresonance imaging (MRI) determined the objective responses. The clinicalobjective response rate for the 54 evaluable patients was 72%, with a pathologiccomplete response rate of 33%. Breast conservation surgery was performed in 74%of patients.
The Aberdeen University Trial
A randomized phase III trial of docetaxelas primary chemotherapy was conducted at Aberdeen University in the UnitedKingdom.[25,26] The study was designed to determine the efficacy of sequentialdocetaxel following treatment with the doxorubicin-containing primarychemotherapy regimen CVAP (cyclophosphamide, doxorubicin, vincristine,prednisolone). After four cycles of CVAP, patients who demonstrated a clinicalresponse (clinical complete or clinical partial response) were randomized toreceive CVAP for four additional cycles or docetaxel, 100 mg/m² for four cycles.Patients who did not demonstrate a response to CVAP were also treated with fourcycles of docetaxel. A total of 162 patients were entered into the trial.Patient tumor characteristics included 39% with T2 of 3 cm or more, 42% with T3, 19%with T4, and 10% with any T, N2.
Results showed that hematologic toxicities, including leukopenic (P = .03)and granulocytopenic (P = .006) events, were significantly higher in patientswho received CVAP compared with those who received docetaxel. Among the 104patients who responded to the four initial cycles of CVAP (overall response rate67%) and were subsequently randomized and evaluable were 50 patients whoreceived additional CVAP and 47 patients who received docetaxel. Patientsrandomized to docetaxel after an initial response to CVAP demonstrated aclinical response rate of 94% vs 66% for patients randomized to additional CVAP,a difference that was statistically significant (P = .001). The pathologiccomplete response rate was also significantly improved for patients treated withdocetaxel vs CVAP, at 34% vs 18%. The percentage of patients able to undergobreast conservation surgery rate was also significantly higher among thoserandomized to docetaxel vs CVAP, with 67% vs 48% (P = .01) undergoinglumpectomy. Importantly, the 3-year overall survival and 3-year disease-freesurvival rates were significantly improved in the docetaxel arm vs the CVAP arm,97% vs 84% and 90% vs 77% (P = .03), respectively.
In summary, four cycles of docetaxel sequential to CVAP produced a higheroverall clinical response rate and pathologic complete response rate compared tofour additional cycles of CVAP as preoperative chemotherapy. These resultstranslated into a survival advantage for docetaxel-treated patients, whose3-year disease-free and overall survivals were significantly improved. Thesefindings are of particular interest because they compare an equivalent number ofcycles (ie, 8) in each treatment arm. Therefore, the improved outcome cannot beattributed to cumulative duration of therapy, but rather to the chemotherapyadministeredsingle-agent docetaxel.
The NSABP B-27 Trial
The preliminary results of the largest randomizedtrial of primary chemotherapy with single-agent docetaxel, NSABP B-27, were alsoreported at the 2001 San Antonio Breast Cancer Symposium. The trial comparedprimary chemotherapy with AC vs primary chemotherapy with AC followed bydocetaxel, administered as primary or adjuvant chemotherapy. The trial wasclosed to accrual in December, 2000 with 2,411 patients enrolled. The three armswere (1) primary AC (60 mg/m²/600 mg/m² IV) × 4; (2) primary AC × 4 followedby docetaxel, 100 mg/m² × 4; and (3) primary AC × 4 and adjuvant docetaxel(100 mg/m² IV) × 4. The treatment arms were well matched by patientdemographics including age, clinical tumor size, nodal status, and proposedsurgery (ie, mastectomy or lumpectomy) at baseline.
Results demonstrated that the addition of primary docetaxel to AC resulted ina significant increase in the rate of clinical complete responses, at 65% vs 40%for preoperative AC alone. In addition, the pathologic complete response ratewas superior at 25.6% for AC/docetaxel vs 13.7% for AC alone (P < .001).Treatment in the AC/docetaxel arm resulted in a decrease in the rate ofhistologically positive axillary nodes, with 40.5% for AC/docetaxel vs 48.5% forAC alone (P = .01).
The rate of lumpectomies (breast conservation surgery) performed was notsignificantly different between the groups at 63% for AC/docetaxel and 61% forAC (P = .70). There was an increase in the incidence of grade 3/4 toxicities inthe AC/docetaxel (40%) arm vs AC alone (23%). The most common grade 3/4toxicities in patients receiving docetaxel included febrile neutropenia (22%),infection (7%), and arthralgia/myalgia (4%). Of six deaths in the AC/docetaxelarm, three were related to sepsis, and one each was due to liver failure/diseaserecurrence, sudden death, and bowel perforation. Two deaths were reported in theAC-alone group, resulting from liver failure/disease recurrence and suicide.
The preliminary results of the NSABP-27 trial confirm the resultsdemonstrated in NSABP-18, with a nearly identical preoperative pathologiccomplete response rate of 13.7% for AC. Preoperative AC followed by docetaxelimproved these findings with a pathologic complete response rate of 25.6%. Theoverall and disease-free survival rates are not yet available, but based on thecorrelation between improved survival in patients achieving clinical andpathologic complete responses, the results may indeed show an improvement inoverall and disease-free survival as a result of the addition of preoperativedocetaxel to preoperative AC.
The preliminary results of the first phase III randomized trial of primarychemotherapy with the docetaxel/doxorubicin combination have been reported.Patients with inoperable, locally advanced breast cancer were randomized topreoperative treatment with AT (doxorubicin at 50 mg/m² and docetaxel at 75 mg/m²) vs FAC (5-FU at 500mg/m², doxorubicin at 50 mg/m², and cyclophosphamideat 500 mg/m²). Of 407 patients enrolled, 390 patients were evaluable for the17-month interim analysis. The side effect profiles for the two arms weresimilar. Although a higher rate of neutropenia was seen in the AT arm, it wasmanageable and uncomplicated. A significantly improved overall clinicalobjective response rate was demonstrated for AT (72%) compared to FAC (63%) (P =.056). A trend toward an improved pathologic complete response rate was noted,with 16% for AT compared to 11% for FAC. The long-term effect of these findingson overall survival will be assessed.
The German Adjuvant Breast Cancer Study Group
The German Adjuvant BreastCancer Study Group evaluated the combination of doxorubicin at 50 mg/m² anddocetaxel at 75 mg/m², with prophylactic granulocyte colony-stimulating factor(G-CSF [Neupogen]) as primary therapy, for a total of four cycles. In thisphase II study in 42 enrolled patients, 24 received therapy every 2 weeks, while18 were treated every 3 weeks. The median age of patients was 50 years, and50% had stage II, 25%, stage IIIA, and 17%, stage IIIB disease. No unexpectedtoxicities were seen. Grade 3 toxicities included stomatitis (7%), infection(5%), and neuropathy (2%). The overall clinical response rate was 93% asdetermined by physical examination and 67% as determined by breast ultrasound.The clinical complete response rate did not significantly differ between the 2-and 3-week administration cycles. Two patients (5%) achieved a pathologiccomplete response. Following primary chemotherapy, the breast conservationsurgery rate increased to 59%, with only 36% of the patients consideredpotential candidates at baseline.
The second trial, conducted by the same investigators, included 250 patientswith T > 3 cm, N0-2, M0 disease who were treated with AT (doxorubicin, 50 mg/m², and docetaxel, 75mg/m²) every 2 weeks × 4, plus or minus 30-mgtamoxifen (T) daily and G-CSF on days 5 to 10. Following surgery, patientsreceived radiation therapy if indicated, and tamoxifen for 5 years. The AT+T armincluded 122 patients, and the AT-alone arm, 128. The median age of patients was48 years (range: 27-67 years) with a median tumor size of 4 cm (range: 3-10cm). Approximately 51% were node-negative and 59% were ER-positive. Nounexpected toxicities were seen; however, the rate of toxicities was higher inthe tamoxifen-containing arm. Less than 5% experienced peripheral neuropathy,diarrhea, infections, and mucositis.
The overall clinical objective response rate was 53% by physical palpation,with a clinical complete response rate of 10% by ultrasound or mammography. Thepathologic complete response rate was similar in the two arms (9% for AT+T and10% for AT alone), and the rate of breast conservation surgery was also similarin both arms (69%).
An M. D. Anderson Cancer Center Trial
At M. D. Anderson Cancer Center,we evaluated a regimen of doxorubicin at 60 mg/m² and docetaxel at 60 mg/m²,administered every 3 weeks for four to six cycles in 88 patients with locallyadvanced breast cancer, with 79 patients evaluable for response.Prophylactic granulocyte macrophage colony-stimulating factor (GM-CSF [Leukine])was administered after a high incidence of neutropenia was reported in the first11 patients. The median age of patients was 50 years (range: 27-67 years),with 22% staged as IIIA, 46%, IIIB, and 32%, (regional) IV. The ER status ofpatients included 34% positive, 64% negative, and 2% unknown. Toxicitiesincluded neutropenia, mucositis, and colitis. The overall response rate was 90%,and the pathologic complete response rate was 12%. Approximately 65% of tumorswere downstaged, and eight patients underwent breast conservation surgery.
The Hoosier Oncology Group and Walter-Cancer Institute Trial
The HoosierOncology Group and Walter-Cancer Institute compared sequential vs combinedadministration of doxorubicin and docetaxel in a pilot study. The sequentialdose-dense regimen was doxorubicin, 75 mg/m² every 2 weeks for three cycles,followed by docetaxel, 100 mg/m² administered in the same time sequence. Thesecond arm received the combination of doxorubicin, 56 mg/m², plus docetaxel, 75mg/m², every 3 weeks for four cycles. G-CSF was administered in both arms ondays 2 to 11. The median age of the 40 randomized patients was 46.5 years, andmedian tumor size was 5.75 cm. Of patients in the sequential therapy arm, 47%had palpable axillary nodes as did 66% in the combination arm.
Grade 4 neutropenia was more common in the combination arm (76% vs 37%).Grade 3/4 hand-foot syndrome was seen in 42% of patients in the sequential armcompared with mild hand-foot syndrome in one patient only in the combinationtherapy arm. Grade 4 diarrhea occurred more commonly in the combination arm (14%vs 5%). Efficacy was similar in the two arms, with an overall clinical responserate in 87% and complete responses in 20%. More patients who received sequentialtherapy achieved a complete response (n = 6 sequential; n = 2 combo); however, this trend did not reach statisticalsignificance. A pathologic complete response was seen in 12.8% of patients.Those receiving sequential therapy had fewer positive lymph nodes at surgery (2vs 5, P = .037), and were more likely to undergo breast conservation surgery(37%) compared to those treated with combination therapy (19%).
The H. Lee Moffitt Cancer Center Trial
Investigators at H. Lee Moffitt CancerCenter are conducting a phase II trial of primary treatment with sequentiallyadministered doxorubicin and docetaxel. Patients with stage III breastcancer receive three cycles of doxorubicin, 80 mg/m² every 2 weeks, followed bythree cycles of docetaxel, 100 mg/m² every 2 weeks. To maintain dose intensity,all patients receive G-CSF 5 µg/kg on days 3 to 10. Of the 42 patients enrolled,39 completed primary chemotherapy. Among patients who have completedchemotherapy, grade 3 toxicities attributed to doxorubicin included mucositis(8%), and neutropenic fever (2.5%). Grade 3 toxicities attributed to docetaxelincluded hand-foot syndrome (26%), bone pain/myalgia (13%), nausea/vomiting(10%), fatigue (8%), and neuropathy (8%). The four patients who were unable tocomplete all six cycles of chemotherapy developed toxicities that includedhand-foot syndrome (n = 2), neuropathy (n = 1), and anorexia (n = 1).Preliminary results demonstrate an overall clinical response rate of 89% wasdemonstrated, with a clinical complete response rate of 23%. A pathologiccomplete response was demonstrated in 24%, and breast conservation surgery wasperformed in 24%.
The GOTI Trial
The Spanish group, GOTI, presented the preliminaryresults of a phase II trial of weekly docetaxel in combination withdoxorubicin. Patients received doxorubicin, 50 mg/m² on day 1, anddocetaxel, 36 mg/m² on days 1, 8, and 15, every 28 days. All 45 patientsenrolled were evaluable for toxicity, which included grade 3/4 neutropenia (7%),nausea (4%), asthenia (3%), and vomiting (3%). Among the 42 patients who wereevaluable for response, the overall clinical response rate was 90% and thepathologic complete response rate, 32%.
Docetaxel and Epirubicin
The University of Vienna group evaluated the combination of docetaxel at 75 mg/m²and epirubicin at 75 mg/m², administered every 21 days with G-CSF forthree to eight cycles to best clinical response. If fewer than six cycleswere administered preoperatively, the remainder, to a total of six cycles, weregiven postoperatively. Patients achieving a pathologic complete response at thetime of surgery underwent adjuvant chemotherapy with CMF for four cycles, whilepatients not obtaining a pathologic complete response received CMF for sixcycles. Of the 60 enrolled patients, 54 had tumors > 2 cm. No unexpectedtoxicities were reported. The objective clinical response rate was 86%, withpathologic complete responses documented in 16%; 58% of patients were able toundergo breast conservation surgery, whereas none were supposed candidates atbaseline.
The French group, Groupe Interregional de Recherche en Cancérologie (GIREC),conducted a phase II multicenter trial in 112 patients with operable T2-4tumors. Patients received 5-FU at 500 mg/m², epirubicin at 100 mg/m², andcyclophosphamide at 500 mg/m² (FEC-100) for six cycles, or epirubicin at 100 mg/m²and docetaxel at 75 mg/m² (ED) for six cycles. A total of 96 patients wereassessable for safety and 76 for efficacy. The incidence of grade 3/4nonhematologic toxicities were equivalent in each arm at 10%. Febrileneutropenia was more common in the ED arm vs the FEC arm at 10% vs 1%,respectively. Prophylactic G-CSF was administered more frequently in the ED armvs FEC arm (30% vs 4%), and more hospitalizations were required (10 vs 1). Theoverall clinical response rate was 55% in the FEC arm and 81% in the ED arm. Thepathologic complete response rate was 23% for FEC and 18% for ED, which was notsignificantly different. Finally, breast conservation surgery was performed at ahigher rate in those who received ED than in those who received FEC, 80% vs 75%,respectively.
In a phase II study from the University of Miami, Hurley et al explored thecombination of docetaxel at 70 mg/m² and cisplatin at 70 mg/m², every 3 weeksfor four cycles with G-CSF, followed by surgery and adjuvant chemotherapy in 25patients with locally advanced breast cancer. The median age of patients was49 years and the median largest tumor diameter was 9 cm. In the total patientpopulation, 56% had T3 tumors, 28% inoperable T4 tumors, and 16% hadinflammatory disease; 72% were ER-positive and 28% ER-negative. Approximately 25patients received four cycles of chemotherapy. The most common toxicity wasgrade 1/2 anemia. The clinical objective response rate was 96%, with a clinicalcomplete response rate of 52% and a pathologic complete response rate of 20%.
Docetaxel, Cisplatin, and Trastuzumab
As a result of their previously promising findings, Hurley and colleaguesconducted a follow-up study of trastuzumab (Herceptin) added to the primarychemotherapy combination of docetaxel/cisplatin (TCisH) in 33 breast cancerpatients with HER2/neu overexpressing tumors (2+ or 3+ by immunohistochemistry [IHC]).Eligible patients were required to have an Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1, and normal hematologic, renal, and cardiacfunction. Patients with metastatic disease (with the exception of ipsilateralsupraclavicular node) were not eligible for enrollment.
The preoperative treatment regimen included docetaxel at 70 mg/m² andcisplatin at 70 mg/m², administered every 3 weeks for a total of four cycles.Trastuzumab at 4 mg/kg was administered on day 1 and weekly thereafter at 2mg/kg for 12 weeks of total therapy. Prophylactic hematopoietic growth factors,G-CSF and erythropoietin, were administered during the neoadjuvant chemotherapyphase. Following surgery, all patients received the AC regimen adjuvantly forfour cycles plus radiation therapy, and patients with estrogen- and/orprogesterone-positive disease also received tamoxifen.
The median patient age was 52 years (range: 22-66 years), and median tumorsize was 8 cm (range: 4-37 cm). Clinical stage IIIA disease was present in 17patients, stage IIIB in 7 patients, and stage IV in 1 patient, based on aninvolved supraclavicular node. Regarding HER2/neu status, 10 patients were 2+and 23 patients were 3+ overexpressors by immunohistochemistry. Pathologicresponse data was available for 27 patients who had undergone surgery at thetime of this report.
The pathologic complete response rate was 22% (6/27). At the time of surgery,node-negative disease was confirmed in 56% of patients (15/27), an increase of26% compared to baseline. Primary therapy was well tolerated, with no patientdemonstrating grade 4 toxicities. The most common grade 3 toxicities includedhyperglycemia (33%), nausea/vomiting (6%), catheter infection (6%), and a 6%decline in the left ventricular ejection fraction (LVEF). The study demonstratedthat the TCisH combination administered for four cycles was active in locallyadvanced breast cancer. The unusually high rate of axillary node clearance waspromising, since negative nodal status is a predictor of overall survival. Thefinal outcome of this trial is awaited.
To date, data from previously conducted phase III randomized trialsdemonstrated that primary chemotherapy provides disease-free and overallsurvival rates similar to those attained with adjuvant chemotherapy in stage IIand III breast cancer. However, primary chemotherapy has resulted in severalclinical advantages. It significantly increased the rate of breast conservationsurgery, and provided early surrogate markers of efficacy. In addition, primarychemotherapy serves as an in vivo model of tumor biology and treatment effect,and may allow additional understanding of tumor molecular biology in the future.The experience gained from several trials (the NSABP B-11, B-14 studies) found acorrelation between the rate of pathologic complete responses and improveddisease-free and overall survival. It is likely (although not yet proven), thatnew regimens that give increased rates of pathologic complete responses willgive improved long-term disease-free and overall survival. Thus new regimenswith higher rates of pathologic complete response appear particularly promising.
Several large randomized clinical trials are exploring the efficacy ofdocetaxel as a component of primary chemotherapy. Docetaxel has been evaluatedsequentially as a single agent and in combination with anthracyclines,cisplatin, and trastuzumab in patients with high-risk early breast cancer (Table 2 andTable 3).[23-28, 30-38] Preliminary results from two large, phase IIIrandomized trials have demonstrated that incorporation of single-agentsequential docetaxel to an anthracycline-containing preoperative regimenimproves the rate of breast conservation surgery and results in improved overallclinical and pathologic complete response rates. In one study, these resultstranslated into an improved 3-year disease-free and overall survival.
The long-term analysis of NSABP B-27 could potentially demonstrate improveddisease-free and overall survivals for the docetaxel-containing neoadjuvant armdue to the improved clinical and pathologic complete response rates observed.The final analysis of the results of this trial, including survival from thedocetaxel-adjuvant arm, are awaited.
Additional randomized studies have evaluated docetaxel in combination withthe anthracylines doxorubicin and epirubicin. Compared to anthracycline-basedregimens, the preliminary results are promising. Docetaxel has also beensuccessfully combined with cisplatin, with high clinical and pathologic responserates, and a tolerable side-effect profile. In patients with HER2/neu-positivetumors, the triple-drug combination of docetaxel, cisplatin, and trastuzumab hasproduced a high rate of axillary node clearance at the time of surgery.
Clearly, there is a lot of interest in using docetaxel as a component ofprimary chemotherapy regimens in the treatment of patients with breast cancer.Continued research efforts will explore ways to further improve on the promisingresults demonstrated to date.
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