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Clinical Trials |
Departments of 1 Medicine and 2 Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Patients with 
4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m2, respectively, x6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2) x18.
Results: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26–63 years), median number of positive nodes was 9 (range, 4–32), and median tumor size was 2.5 cm (range, 0.6–11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study.
Conclusion: FEC x6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The Norton-Simon model predicts that the optimal treatment of a heterogeneous mix of cells (in terms of chemotherapy sensitivity) is to eradicate the numerically dominant, faster-growing cells first, followed by eradication of the more slow-growing, resistant cells (5) . This is termed sequential therapy and is superior to alternating therapy in a randomized clinical trial (6) . Sequential therapy may be more effective because it increases the frequency ("density") of treatments as compared with alternating therapy, thereby minimizing the time during which sensitive cells can regrow before retreatment (4) .
When granulocyte-colony stimulating factor (G-CSF) became available, we performed several pilot studies testing increased dose density at Memorial Sloan-Kettering Cancer (7, 8, 9)
. These led to a randomized trial led by the Cancer and Leukemia Group B (CALGB) for the Intergroup (10)
. This was a two-by-two factorial study for patients with node-positive disease. All of the patients were treated with three drugs, doxorubicin, cyclophosphamide, and paclitaxel, but these were administered either sequentially doxorubicin 
paclitaxel cyclophosphamide or concurrently as doxorubicin/ cyclophosphamide paclitaxel. In addition, all of the patients were randomly assigned to receive their regimen once every 3 weeks or once every 2 weeks (dose-dense). Patients randomized to the dose-dense regimens also received prophylactic G-CSF support, whereas those on the standard (3-week) regimens could receive it as required. In this study doxorubicin paclitaxel cyclophosphamide and doxorubicin and cyclophosphamide paclitaxel were no different, but treatment using 2-week intervals was superior to 3 weekly therapy in both disease-free survival and overall survival.
Many other trials are investigating strategies for improving chemotherapy in general and taxanes specifically. This focus on the taxanes is appropriate given the evidence from trials suggesting that low-dose weekly paclitaxel might be superior to higher doses given less often and that docetaxel might be a more active taxane (11, 12, 13) . To develop a potentially superior adjuvant chemotherapy regimen, we planned this study to test the feasibility and potential efficacy of a dose-dense anthracycline-based regimen followed by prolonged weekly low-dose taxanes. For the anthracycline-based regimen we chose one with known efficacy and >4 cycles because of continued controversy regarding the efficacy of this shorter treatment duration. However, by delivering the 6 cycles using 2-week intervals, we could plan on the same treatment time as is needed for conventional doxorubicin and cyclophosphamide. We specifically chose 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), because we had no evidence that this could be inferior to any other anthracycline-containing regimen and because it constitutes appropriate standard treatment for node-positive breast cancer. We specifically chose FEC 100 in this trial, because the French Adjuvant Study Group 05 showed that FEC 100 is superior to FEC 50 in both relapse-free and overall survival in the adjuvant setting without an unusual risk of secondary leukemia (14) .
To build on the efficacy of the FEC regimen and based on the proven efficacy of taxanes in earlier adjuvant trials, while delivering a potentially superior dose and schedule, we considered single agent paclitaxel or docetaxel for 18 weeks. However, Phase II data in the metastatic setting suggested that these regimens would not be feasible. Hence, we elected to study a novel alternating plan consisting of 9 doses of each taxane so that a total of 18 administrations could be planned. By alternating paclitaxel and docetaxel, we hoped to avoid the significant asthenia with docetaxel and neuropathy with paclitaxel. We chose 18 weekly treatments with taxanes (or 4.5 months), because we wanted to explore a longer taxane regimen than the conventional 3-month duration. The objectives of this trial were to determine the feasibility and safety of this regimen and to evaluate disease-free and overall survival.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1,500/µL and platelet count 100,000/µL; normal total bilirubin; serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase 
2.5 upper limit of normal if alkaline phosphatase upper limit of normal, alkaline phosphatase 4 x upper limit of normal if serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase UNL; normal carcinoembryonic antigen and cancer antigen 15–3; and no evidence of disease on computed tomography of chest, abdomen, and pelvis and bone scan. In addition, normal cardiac function was required as demonstrated by nuclear-gated heart scan or echocardiogram. Patients with known history of unstable angina, myocardial infarction, or congestive heart failure, serious medical illnesses, or inability to give consent were excluded. An informed consent was obtained for each patient. This study was reviewed and approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center.
Treatment Plan
Six cycles of FEC at doses of 500/100/500 mg/m2 x 6 every 2 weeks with G-CSF support at a dose of 5 µg/kg administered subcutaneously on days 3–10, followed by 18 treatments of weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2; 9 treatments per taxane) were planned (Fig. 1)
. Premedications for FEC consisted of a 5-HT3 serotonin receptor antagonist (for example, granisetron 2 mg) orally and dexamethasone 20 mg orally. Premedications for paclitaxel included oral or intravenous dexamethasone (10 mg, or a steroid equivalent), diphenhydramine (50 mg, or another H-1 blocker), and an H-2 blocker 
30 minutes before paclitaxel infusion. If patients did not experience a hypersensitivity reaction after the first 2 doses of paclitaxel, premedications could be altered at the discretion of the physician. Premedications for docetaxel consisted of oral or intravenous dexamethasone (10 mg, or a steroid equivalent) 30 minutes before docetaxel infusion; this could be modified at the discretion of the physician.
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A complete blood count with leukocyte differential was performed before each treatment of chemotherapy. While patients were receiving alternating weekly taxanes, liver function test was performed every 4 weeks. Patients were seen every 2 weeks during treatments for history and physical examination and assessment of performance status and toxicity.
Dose Modifications
5-Fluorouracil, Epirubicin, and Cyclophosphamide.
Patients experiencing neutropenic fever (absolute neutrophil count <1,000/µL and body temperature 38.5°C) and/or grade 3 or 4 nonhematologic toxicity had day-1 doses in subsequent cycles reduced by 25% of the dose administered in the current cycle. A maximum of two dose reductions was allowed. If on the day that chemotherapy in subsequent cycles of treatment was due, platelet counts were <100,000/µL and/or absolute neutrophil count <1,000/µL and/or nonhematologic toxicities (excluding alopecia) had not recovered to grade 1, treatment was delayed by up to a week, and complete blood count and toxicity grading were repeated weekly. If a treatment delay of >3 weeks was required, the patient would be taken off study.
Paclitaxel Alternating with Docetaxel.
Patients experiencing neutropenic fever (absolute neutrophil count <1,000/µL and body temperature 38.5°C) and/or grade 3 or 4 nonhematologic toxicity had the day-1 doses in subsequent treatments reduced by 25% of the dose administered in the current cycle. A maximum of two dose reductions was allowed. If on the day that chemotherapy in subsequent treatments was due, platelet counts were <100,000/µL and/or absolute neutrophil count <1,000/µL and/or nonhematologic toxicities (excluding alopecia) had not recovered to grade 1, treatment was delayed by up to a week, and complete blood count and toxicity grading were repeated weekly. If a treatment delay of >3 weeks was required, the patient would be taken off study.
During taxane treatment, liver function tests were evaluated every 4 weeks. For patients with normal baseline serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase, if bilirubin was upper limit of normal, alkaline phosphatase was 5 x upper limit of normal, and serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase was 1.6–5 x upper limit of normal, taxane was reduced by 25%. If patients had bilirubin of >upper limit of normal or alkaline phosphatase > 5 x upper limit of normal or serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase > 5 x upper limit of normal, treatment was delayed by up to 3 weeks until bilirubin was upper limit of normal or alkaline phosphatase or serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase was 5 x upper limit of normal, and taxane was reduced by 25%. For patients with baseline serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase up to 2.5 x UNL, if bilirubin was upper limit of normal, alkaline phosphatase 5 x upper limit of normal, and serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase 2.6–5 x upper limit of normal, taxane was reduced by 25%.
Radiotherapy
After mastectomy, all of the patients received chest wall radiotherapy, because they all had 4 involved lymph nodes. Patients treated with breast conservation were treated as well using standard institutional dosing guidelines and techniques.
Hormonal Therapy
All of the patients whose tumors were either estrogen or progesterone receptor-positive were offered tamoxifen for 5 years after chemotherapy. If patients were postmenopausal, anastrazole was allowed as an alternative to tamoxifen.
Follow-Up
To obtain an estimate of outcome and to monitor for long-term toxicities, patients were followed closely. Histories and physical examinations were repeated at 4-month intervals for years 1–3, 6-month intervals for years 4–5, and annually after year 5. During these visits, complete blood count, liver function tests, carcinoembryonic antigen, and cancer antigen 15–3 were ordered. Computed tomography scan of chest, abdomen, and pelvis and/or bone scan were considered if clinically indicated by the symptomatology of the patient or by abnormal laboratory values, at the discretion of the physician. Mammography was performed on remaining breast(s) annually.
Biostatistics
This was a pilot study to evaluate the feasibility and toxicity of the adjuvant therapy dose-dense FEC followed by alternating paclitaxel and docetaxel. We planned to accrue 45 patients. Toxicities and adverse events were be tabulated. Any occurrence of significant grade 3/4 treatment-related toxicity would result in reconsideration of the suitability of the regimen. A secondary end point of the trial was efficacy in terms of disease-free and overall survival. Based on historical controls 3-year and 5-year disease-free survival rates for this population were estimated as approximately 13–55% and 10–40%, respectively, and 3-year and 5-year overall survival rates for this population were approximately 40–65% and 25–50%, respectively (3)
. With 45 patients, the confidence interval could be estimated to within approximately ±15%.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The study was closed to accrual before reaching its target because of unacceptable toxicity as described below. The median age was 46 years (range, 26–63 years), the median number of positive nodes was 9 (range, 4–32), and median tumor size was 2.5 cm (range, 0.6–11.0 cm). Three patients withdrew from study after FEC cycle 1 (1 for personal reason and 2 for grade 3 nausea). All of the patients were assessed for toxicities. Only 17 of 44 (39%) completed all of the planned treatment. The most common reason for treatment discontinuation was toxicity attributed to the alternating taxane regimen, as detailed below. The remaining patients completed treatment at the discretion of their treating physician and using one of several modifications in the taxane schedule.
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. During FEC, 2 of 44 (5%) patients developed grade 4 granulocytopenia and were admitted for febrile neutropenia (both after the fifth cycle); 3 of 44 (7%) patients had grade 3 anemia and required transfusion of packed red blood cells; and 2 of 44 (5%) patients had grade 3 thrombocytopenia. During the alternating taxane portion of the treatment, there were no grade 3/4 hematologic toxicities.
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grade 3 anemia in patients receiving alternating taxanes.
Nonhematologic Toxicity
During 5-Fluorouracil, Epirubicin, and Cyclophosphamide.
Grade 2 alopecia was universal. During FEC the following grade 3 toxicities were noted: 4 of 44 (9%) fatigue, 3 of 44 (7%) nausea, 2 of 44 (5%) emesis, 4 of 44 (9%) mucositis, and 1 of 44 (2%) visual change (this patient had transient left visual field deficit and headache, and extensive workup revealed event was due to migraine headache). There were no grade 4 nonhematologic toxicities (Table 3)
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. A clinical diagnosis of pneumonitis was made in 1 patient after FEC cycle 6; in a second patient after FEC cycle 6 and taxane (paclitaxel) cycle 1; in a third patient after FEC, cycle 5; and in the fourth patient after FEC cycle 6 and taxane (paclitaxel) cycle 2 (this patient developed dyspnea after FEC cycle 5 before a clinical diagnosis of pneumonitis was established). All had dyspnea and dry cough and ground-glass appearance of lungs bilaterally on computed tomography scan of chest and were treated with antibiotics empirically for bacterial pneumonia. Three of 4 underwent bronchoscopic examination and had transbronchial biopsies that were negative for malignancy. Bronchial washings were negative for infections (for example, common bacterial organisms, acid-fast bacteria; influenza A and B; parainfluenza 1, 2, and 3; respiratory syncytial virus; and pneumocystis carinii). Three of 4 patients received steroids and all recovered without sequelae. One patient was rechallenged with paclitaxel and did not develop pneumonitis suggesting that this taxane was not responsible for the toxicity. At the discretion of her physician, 1 patient completed treatment using only docetaxel every third week at conventional dose (100 mg/m2) and did not develop recurrent pneumonitis. This patient had initially developed signs of dyspnea and cough after FEC cycle 5, which progressed after FEC cycle 6 and persisted after paclitaxel cycle 2. Based on the timeline of events, it was most likely that her pneumonitis began after FEC cycle 5. After 4 patients had developed this toxicity and no infectious etiologies had been identified in any, we concluded that the most likely diagnosis was a chemical pneumonitis due to FEC administered every other week, and we closed the trial to additional accrual.
During Alternating Taxanes.
Because only 17 patients completed all 18 of the treatments of alternating taxanes as planned, the toxicity reported is limited to only those patients. The following grade 3 toxicities were reported: 1 of 17 (6%), fatigue; 1 of 17 (6%), mucositis; and 1 of 17 (6%), dizziness. There was no grade 3 sensory neuropathy reported during alternating taxane treatment. Grade 1 neuropathy occurred in 11 of 17 (65%) patients, and grade 2 neuropathy occurred in 4 of 17 (24%) patients. Grade 1 or 2 lacrimation was seen in 13 of 17 (76%) patients during alternating taxane therapy (Table 4)
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. One patient was hospitalized 3 weeks after study completion for symptomatic moderate to large pericardial effusion with minimal tamponade as demonstrated by echocardiogram. A computed tomography scan of the chest demonstrated moderate right and small left pleural effusions and moderate pericardial effusion as well. She was hemodynamically stable but required a pericardiocentesis for symptom control, yielding cytology samples that were negative for malignancy. Cultures of pericardial fluid were negative for organisms as well as for acid-fast bacteria, and pericardial tissue biopsy was benign. It may be important that this patient was treated with reduced dosages of dexamethasone premedication. Over the course of 18 weeks (9 treatments with docetaxel) the dexamethasone was tapered from an initial dose of 10 mg intravenously to 4 mg intravenously 30 minutes before docetaxel infusions. In response to our concern that the dexamethasone taper contributed to her effusions, all of the remaining patients were treated with a minimum predocetaxel dexamethasone dose not less than 10 mg intravenously/orally. As an alternative, patients were allowed to receive oral dexamethasone of at least 4 mg orally x3 (the night before, morning of, and evening after each docetaxel treatment), at the discretion of their physician. As an added safety precaution a chest radiograph was required for subsequent patients at weekly taxane treatments no. 12 and 18 (at completion of all therapy). If pleural effusion was seen or pericardial effusion was suspected, then no additional taxane was given, and patients were to be managed appropriately. Despite these treatment and monitoring changes, additional toxicity was seen among patients receiving alternating taxanes. An additional patient had small asymptomatic bilateral pleural effusions, demonstrated on chest radiograph after completing her final week of taxane therapy. She subsequently (2 weeks later) developed dyspnea and had a room air oxygen saturation of 97%. Chest radiograph demonstrated moderate left and small right pleural effusions. Despite supportive care with diuretics, an echocardiogram subsequently revealed a large pericardial effusion with cardiac compression and right atrial collapse. She was treated with pericardiocentesis. Cytology results for the pleural and pericardial fluids as well as pericardial biopsies were all benign. Because this second patient had received docetaxel dexamethasone premedication at a dose of 10 mg intravenously during all of the docetaxel treatments, this toxicity was attributed to the weekly alternating taxane therapy using both docetaxel and paclitaxel. Of note, both of these patients had computed tomography scan of body and bone scan that were unrevealing for distant metastatic disease.
A third patient developed dyspnea several weeks after study completion. Her chest radiograph 1 month after study completion demonstrated bilateral moderate pleural effusions. An echocardiogram revealed large left pleural effusion and an insignificant, small pericardial effusion. She was treated as an outpatient with an oral diuretic and dyspnea resolved. Her docetaxel dexamethasone premedication had been tapered to 6 mg intravenously through her course of taxane treatments.
Based on these events, we determined that the planned treatment regimen was not clinically feasible, and the study was closed. Those patients (n = 18) who were in the midst of the alternating taxane regimen completed therapy with weekly paclitaxel for at least 12 but no more than 18 taxane treatments in total, at the discretion of the physician. Those who had not begun on taxanes received only weekly paclitaxel (n = 6). One patient had received first two doses of weekly paclitaxel but then received four courses of "conventional" docetaxel alone every 3 weeks because of a concern that she might have had paclitaxel-related pneumonitis (later attributed to the 5-FEC). The toxicities of these patients who completed the taxanes at varying schedules are difficult to interpret in a uniform fashion and are not reported.
Hospitalizations
There were 14 hospitalizations in 12 of 44 (27%) patients enrolled: 2 patients had 2 hospitalizations each. Eleven admissions were related to FEC treatments as follows: 4 pneumonitis, 2 febrile neutropenia, 2 cellulitis, 1-phlebitis, 1 grade 3 nausea, and 1 migraine headache with visual field deficit. Two hospitalizations (2 grade 4 pericardial and grade 3 pleural effusions) were due to alternating taxanes. One admission was secondary to drug fever related to prophylactic sulfamethoxazole given to a patient who was on prednisone for treatment of chemical pneumonitis from FEC.
Treatment Delays
During FEC 19 of 44 (43%) patients had treatment delays as defined per protocol as follows: 10 infections (3 cellulitis, 2 upper respiratory infections, 1 otitis, 1 parotiditis, 1 dental abscess, 1 herpes zoster infection of perirectal region, and 1 herpes simplex viral infection of oropharynx), 3 grade 2/3 fatigue, 2 pneumonitis, 1 febrile neutropenia, 1 grade 3 migraine headache with visual field deficit, 1 grade 1 thrombocytopenia, and 1 personal reason).
During alternating taxane therapy 7 of 17 (41%) patients had treatment delays as defined per protocol as follows: 2 grade 2 mucositis, 2 personal reasons, 1 chemotherapy extravasation, and 2 pneumonitis due to FEC. In the latter 2 patients, clinical pneumonitis due to 5-fluorouracil, epirubicin, and cyclophosphamide was diagnosed after both patients already started taxanes (one and two doses, respectively), and rechallenge of taxanes did not result in recurrent pneumonitis.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Another method to increase dose intensity is dose density, which has demonstrated improved outcomes (10) . The present study was designed to extend the benefits of dose density and the benefits of both the anthracycline and taxane components of care. Specifically, the goal was to maintain the benefits of dose-dense scheduling, while extending the treatment duration to address concerns that four courses of an anthracycline as the standard in the doxorubicin and cyclophosphamide regimen was inadequate. By extension, there was concern that four courses of adjuvant taxane (same duration as doxorubicin and cyclophosphamide) might also be inadequate. Neither CALGB 9344 nor the subsequent report of NSAPB B-28 address these possibilities (20 , 21) .
To develop an "ideal" adjuvant chemotherapy regimen, we chose FEC x 6 followed by weekly paclitaxel alternating with docetaxel x18. Thus, this regimen included 6 cycles of an anthracycline-based regimen and 18 weeks of taxane therapy and, if feasible, could not be criticized as compromising (underdelivering) chemotherapy treatment. Unfortunately, as designed this regimen was not feasible. Only 17 of 44 (39%) patients completed the study as planned, and the study was closed early because 2 of 17 (12%) patients experienced grade 4 pericardial and grade 3 pleural effusions, requiring surgical treatment. With extensive evaluation, it was felt that the pericardial/pleural effusions were most likely due to alternating schedule of taxanes.
Docetaxel has been associated with serous effusions, but we had hoped that delivering it only every other week and interdigitated with paclitaxel would mitigate this toxicity allowing a longer overall treatment regimen and resultant increased efficacy (22, 23, 24) . The incidence of fluid retention from weekly docetaxel has been reported to occur at a median cumulative dose of about 480–600 mg/m2 with dexamethasone premedication as 4–8 mg orally x 3 (night before, morning of, and night after each treatment; refs. 22 , 23 ). In prior studies with docetaxel administered on an every-3-week schedule without steroid premedication, fluid retention developed at a median cumulative dose of about 300–400 mg/m2 and at median cumulative dose of about 500–600 mg/m2 when steroid premedications were given at various schedules (25, 26, 27, 28, 29, 30, 31) . Most of these events were grade 1–2. In our study, the cumulative dose of docetaxel was only 315 mg/m2. Paclitaxel has not been associated with serous effusions. It is probable that the grade 4 pericardial effusion/grade 3 pleural effusion in 2 of 17 (12%) patients and grade 2 pleural effusion in 1 of 17 (6%) patients in our study is due to suboptimal steroid premedication for docetaxel and to a possible interaction of the two taxanes when given in a weekly alternating fashion.
During FEC 4 of 44 (9%) patients experienced significant pneumonitis. An infectious source was not identified in any of these patients. Neither the 3-weekly FEC 100 (500/100/500 mg/m2 respectively administered intravenously every 3 weeks x 6 cycles) regimen nor 4-weekly cyclophosphamide, epirubicin, 5-fluorouracil (cyclophosphamide = 75 mg/m2 orally days 1–14, epirubicin = 60 mg/m2 intravenously days 1 and 8, and 5-fluorouracil = 500 mg/m2 intravenously days 1 and 8 every 4 weeks x 6 cycles) schedule are reported to cause pneumonitis (14 , 32) . Furthermore, studies of dose-dense every 2 weekly epirubicin–cyclophosphamide have not reported pneumonitis as a toxicity (33 , 34) . Thus, FEC every 2 weeks x 6 may present a special risk for this toxicity perhaps attributable to an interaction of the 5-fluorouracil, the epirubicin–cyclophosphamide combination, the every other week dosing, and/or the G-CSF. It is reassuring that all of the patients recovered without sequelae, and the hematologic toxicities of FEC were acceptable with only 5% incidence of febrile neutropenia and only 3 of 44 (7%) patients needing packed red blood cell transfusions. Notably, a significant proportion of patients (19 of 44, 43%) received erythropoietin support, during FEC mostly for grade 2 anemia.
All of the patients will be followed long term to assess for any delayed adverse events. Any survival data will be difficult to interpret, because only 17 of 44 (39%) patients completed study as planned, and the remaining patients completed chemotherapy with various schedules of taxanes.
Based on this pilot study every other week administration of FEC x 6 followed by weekly paclitaxel alternating with docetaxel x 18 cannot be recommended for additional study. However, the positive results of CALGB 9741 motivate additional studies of dose-dense regimens (for example, adding biological agents and additionally shortening intertreatment intervals) to further enhance the efficacy of chemotherapy for early stage breast cancer.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Chau T. Dang, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Howard 713, New York, NY 10021. Phone: 212-639-7940; Fax: 212-772-8441; E-mail: dangc{at}mskcc.org
Received 4/ 2/04; accepted 4/22/04.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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