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© 2001 American Society for Clinical Oncology Phase II Study of Docetaxel, Doxorubicin, and Cyclophosphamide as First-Line Chemotherapy for Metastatic Breast CancerFrom the Cross Cancer Institute, Edmonton; Tom Baker Cancer Centre, Calgary, Alberta; Hôpital Sacré-Coeur de Montréal, Montréal, Québec; Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada; and Aventis Pharma, Inc, Antony, France. Address reprint requests to Jean-Marc Nabholtz, MD, Director, Cancer Therapy Development Program, University of California at Los Angeles, PUVB #3360B, 10945 Le Conte Ave, Los Angeles, CA 90095; email jean-marc.nabholtz{at}bcirg.com
PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.
THE BREAST IS ONE of the leading cancer sites in women, and in the United States, there are around 175,000 new cases per year (29% of all cancer sites) and 43,300 deaths (16% of all cancer deaths).1 Women with metastatic breast cancer are essentially incurable with standard therapy and have a median survival of approximately 2 years after documentation of metastasis.2 Many cytotoxic agents have demonstrated activity in advanced breast cancer, the most active and commonly used agents being cyclophosphamide, fluorouracil, doxorubicin, methotrexate, and mitomycin, either as single agents or in combination regimens.3 Objective response rates for single-agent activity vary between 20% and 50%, with doxorubicin having been the most active single agent with 40% to 50% response rates as first-line therapy. The use of combination chemotherapy has been associated with increased response rates compared with single agents.3 The most commonly used nonanthracycline-containing regimens yield response rates in the range of 50% to 60% with median duration of response around 10 to 12 months. Anthracycline-containing regimens such as fluorouracil, doxorubicin, and cyclophosphamide (FAC), doxorubicin and cyclophosphamide (AC), and fluorouracil, epidoxorubicin, and cyclophosphamide induce objective response rates in the range of 50% to 80% with fewer than 10% complete responses. Median duration of response is usually between 10 and 18 months with median survival times between 18 and 26 months.2 The anthracycline-based polychemotherapy results have shown only modest superiority when compared in a randomized fashion with the nonanthracycline-containing polychemotherapy regimens.3 Although substantial palliation is achieved in responding patients, remissions are usually short-lasting. There is, therefore, still no standardized pattern for the use of chemotherapy in metastatic breast cancer, highlighting the need for new strategies as well as new agents, among which the taxanes (paclitaxel and docetaxel) seem to be the most promising. Paclitaxel was the first taxane to show activity in breast cancer.4,5 Docetaxel was subsequently developed, and several phase II trials reported a high activity in first- and second-line therapy of metastatic breast cancer as well as in patients previously exposed or resistant to anthracyclines.6,7 These data were recently confirmed by phase III trials establishing docetaxel as a powerful chemotherapeutic agent in breast cancer.8,9 The high objective response rates achievable with both docetaxel and doxorubicin as single agents in the clinical setting, combined with the lack of complete clinical cross-resistance, provide the rationale for combination chemotherapy regimens based on these two drugs. A phase I dose-finding study, performed by Misset et al,10 established the recommended doses of the combination doxorubicin-docetaxel (AT protocol) as being respectively either 50 mg/m2 and 75 mg/m2 or 60 mg/m2 and 60 mg/m2. At the highest dose levels, grade 4 neutropenia and febrile neutropenia were the main toxicity. However, the infection rate was low, no septic death was reported, and the extrahematologic toxicity profile was favorable, particularly the lack of cardiac toxicity. Additionally, some promising activity was observed, justifying further development. Considering these results, it was decided to proceed with a pilot program in patients with untreated metastatic breast cancer aimed at defining a AT-based multidrug regimen that could later be randomly compared, in first-line metastatic and adjuvant settings, with a standard doxorubicin-containing regimen with an equal dose of doxorubicin in both arms (50 mg/m2). The FAC protocol (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) was identified as an acceptable potential control arm, and thus required development of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) as the experimental arm for potential phase III trials comparing TAC with FAC. This represented the rationale for this pilot phase II study of TAC, in which the main end points were both efficacy and the safety profile.
Study Design and Patients This was a phase II, open-label, nonrandomized study conducted at four centers in Canada (Edmonton, Saskatoon, Montreal, and Calgary) between May 1996 and January 1998. The study was conducted in accordance with the Declaration of Helsinki, in compliance with local regulations, and with the approval of an independent ethics committee. Informed consent (written or witnessed oral) was obtained from all participants.
The study population consisted of women aged 18 to 70 years with histopathologically proven breast cancer, requiring first-line chemotherapy for metastatic disease. Histologic or cytologic proof of metastasis was needed for those with a single metastatic lesion. Further inclusion criteria were as follows: measurable disease; a World Health Organisation (WHO) performance status
Patients were excluded from the study if they had received prior chemotherapy for metastatic disease. Prior adjuvant or neoadjuvant chemotherapy was allowed with non–anthracycline-containing regimens if more than 1 year before study. Previous treatment with taxoids was not permitted. Hormonal therapy could have been given as adjuvant treatment or for metastatic disease, provided the patient had progressive disease at study entry. Prior radiation therapy was permitted at sites other than those used to assess response in this study; if
Further exclusion criteria included a history of malignancy other than breast cancer; however, patients with therapeutically cured skin cancer (except melanoma), excised in situ cervical carcinoma, and other therapeutically cured cancer with no evidence of disease for
Treatment Plan All patients were given prophylactic corticosteroid premedication: oral dexamethasone (8 mg) given at 12-, 3-, and 1-hour intervals before docetaxel infusion and at 12, 24, and 36 hours after docetaxel infusion. Patients also received prophylactic antibiotic therapy (oral ciprofloxacin 500 mg twice daily unless contraindicated) on days 5 to 15 after each cycle of TAC chemotherapy. Prophylactic recombinant granulocyte colony-stimulating factor (G-CSF) was not given. Standard antiemetic and antidiarrhea therapies were administered as needed, on a prophylactic or treatment basis. Treatment was planned for eight cycles unless there was evidence of disease progression or unacceptable toxicity. Dose modifications were planned for severe toxicity. Patients who experienced febrile neutropenia or a documented infection were to be given prophylactic G-CSF in subsequent cycles; if a second episode of febrile neutropenia or a documented infection occurred, docetaxel was to be reduced to 60 mg/m2. If grade 3/4 nausea, vomiting, or diarrhea were experienced despite prophylactic therapy, doxorubicin was to be reduced to 40 mg/m2. For grade 3/4 stomatitis, docetaxel was to be reduced to 60 mg/m2; if stomatitis still occurred, doxorubicin was to be reduced to 40 mg/m2. Grade 3/4 neuropathy was planned to lead to patient withdrawal. For other toxicities, treatment was generally to be discontinued until recovery to grade 1 and restarted for the subsequent cycle at a dose modified as appropriate to the toxicity. Doses reduced for toxicity could not be re-escalated.
Patient and Treatment Evaluation
Tumor measurements were repeated every three cycles. Response was classified according to WHO criteria.11 Complete response (no detectable tumor, including bone) and partial response ( Toxicity was graded according to National Cancer Institute Common Toxicity Criteria. Patients were monitored regularly for clinical and laboratory toxicity and were asked to report the occurrence of adverse experiences to the investigator. Hematologic assessments were made weekly or, in cases of febrile neutropenia, every day until recovery. LVEF was measured every three cycles during the treatment period and every 3 months thereafter in cases of an abnormal result. Irrespective of the reason for study discontinuation, patients were monitored for any late adverse events during at least the first month after the last study treatment. Patients were then followed up every 3 months until death to monitor progression and survival.
Data Analysis For tumor response evaluation, patients must have received at least two cycles of study treatment and had at least one follow-up tumor assessment. The duration of response for responding patients (partial or complete response) dated from the start of treatment until the first documentation of progressive disease. The time to first response and time to progression were defined from the start of treatment to the first occurrence of response and first progression, respectively. Survival was calculated from the date of first administration of TAC to death by any cause. Toxicity and tolerability analyses were performed on the intent-to-treat population, ie, on patients who received at least one dose of study treatment.
Patient Characteristics Fifty-four patients requiring first-line chemotherapy for metastatic breast cancer received the study treatment. The characteristics of the patients are outlined in Table 1. The median age was 53 years (range, 33 to 70 years) and the median WHO performance status was grade 1. Approximately one half of patients (54%) had three or more involved organs, whereas 69% had visceral involvement. The most frequent disease sites were bone and lymph nodes (both 59%). Around one third of patients (31%) had received previous adjuvant and/or neoadjuvant chemotherapy. As per inclusion criteria, no patient had been previously exposed to anthracyclines. The median time from last chemotherapy to first infusion on study was 34.4 months (range, 12.5 to 91.1 months).
Forty-seven patients were assessable for tumor response. Reasons for nonassessability included absence of measurable disease (n = 4), presence of a brain metastasis at baseline (n = 1), and administration of only one cycle with no tumor assessment made after chemotherapy (n = 2).
Chemotherapy Administration
Most treatment cycles (308 of 359; 86%) were administered, as planned, every 3 weeks. Of the 51 delays, 34 (67%) were for no longer than 1 week. Twenty-two delays (43%) were a result of toxicity (16 hematologic, four nonhematologic, two both). Dose reduction was required for 10 cycles; most decreases were a result of toxicity (five hematologic, three nonhematologic, one both). Prophylactic G-CSF was given in 27 cycles (8%).
Efficacy
The median duration of response was 59 weeks (range, 11 to 112 weeks), and the median time to progression was 42 weeks (range, 6 to 112 weeks) (Table 4). No death occurred during the study. At a median follow-up time of 32 months, the median survival time had not been reached; the 2-year survival rate was 57%.
Tolerability and Toxicity
As expected with these three hematotoxic drugs, neutropenia and its complications were the most frequent adverse events (Table 5). Grade 4 neutropenia occurred in all evaluated patients; the median nadir was 0.1 x 1,000/mm3, and the median duration of grade 4 neutropenia was 7 days. Around one third of patients (34%) experienced febrile neutropenia, defined as grade 4 neutropenia with grade
Acute nonhematologic toxicities were usually mild (Table 6) with infrequent grade 3 nausea (9%), stomatitis (6%) and diarrhea (4%). No grade 4 episodes of acute nonhematologic toxicity were reported. The most common treatment-related chronic nonhematologic toxicity was alopecia (87%), with long-lasting (longer than 2 years) partial alopecia in four patients. Severe asthenia was observed in 13% of patients. Allergy (6%), neurosensory (56%), and cutaneous (35%) side effects were mild. Docetaxel-specific toxicities such as fluid retention and nail changes were not frequent (33% and 20%, respectively) and infrequently severe (2% and 0%, respectively). Only one patient discontinued treatment because of fluid retention. No cases of hyperglycemia were observed among the four diabetic patients entered onto the study. Hyperglycemia, which could potentially be worsened by the 3-day corticosteroid premedication, was present at baseline in one nondiabetic patient and continued throughout eight cycles without worsening.
In terms of cardiac toxicity, two patients presented with evidence of congestive heart failure (CHF) (4%): one after nine courses of therapy (cumulative dose of doxorubicin: 464 mg/m2) and the second one 2 months after completion of eight cycles of TAC (cumulative dose of doxorubicin: 404 mg/m2). For the first patient, the CHF was fatal, whereas the second case was reversible with medical therapies. Additionally, 14 patients (26%) presented with asymptomatic decrease of LVEF on radionuclide heart scan (MUGA) 10 of whom were detected among the 31 patients evaluated during the follow-up period. LVEF decrease was defined as a 10% absolute decrease associated with a decline to a LVEF level below 50%,12 and occurred in six patients at cumulative doses of doxorubicin less than 360 mg/m2 and the others at cumulative doses greater than 360 mg/m2. LVEF decrease was reversible during the follow-up in eight patients, whereas LVEF values remained between 45% and 50% in four other patients. Two patients withdrew from therapy because of LVEF decrease (at cycle seven, cumulative doses of doxorubicin: 339 and 349 mg/m2): one patient recovered a normal LVEF during follow-up, and the other one maintained LVEF values at 48%.
In an attempt to modify the natural history of breast cancer, a strong emphasis has been placed on the development of programs integrating anthracyclines and taxanes into the various strategies aiming at first-line therapy and, most importantly, adjuvant therapy for metastatic disease. Anthracycline-taxane–containing regimens have been developed for both paclitaxel and docetaxel to test the potential for integration of taxanes in anthracycline-taxane–containing polychemotherapy.10,13-21 In this context, we proceeded with this pilot phase II study of the triple combination TAC, with the intention to prepare for a phase III trial program comparing TAC with a widely used anthracycline-containing combination such as FAC. This comparison has the advantage of equal doses of doxorubicin and cyclophosphamide in both arms (randomized program TAC v FAC in first-line metastatic and adjuvant treatment of breast cancer). The first goal of this study was to assess the efficacy of TAC in terms of response rates, as well as time to progression and overall survival. After a review by an independent panel, TAC results in a high overall objective response rate of 77%. These results are in keeping with response rates reported in a phase II trial with the doublet AT (74%) using docetaxel and doxorubicin at the same doses (75 mg/m2 and 50 mg/m2, respectively).14 However, in a phase II series with AT using doses of 60 mg/m2 for both agents, the response rate was reported as 57%.13 Although these different results could suggest that maintaining the dose of docetaxel may be an important factor for efficacy, caution should be exerted when interpreting these phase II results using multiple drug regimens. The complete response rate with TAC seems low (6%) but should be put into perspective with the high incidence of bone metastases (59% of our patient population), for which no complete response was recorded. Responses were observed in all sites, but a particular mention should be made for visceral disease, including liver metastases and bone metastases, for which reported response rates were equal to or higher than 80%. Visceral involvement, and particularly liver metastases, are known for their poor prognosis, with response rates rarely rising above 30% to 50% when using anthracyclines either as single agents or in combination.2 Duration of response, time to progression, and survival seem acceptable for this type of patient population with metastatic breast cancer, but the very nature of this series (phase II) necessitates exercising caution in the interpretation of these results. However, the 57% survival rate at 2 years seems noteworthy for a metastatic population with an incidence of visceral metastases close to 60%. Again, these results are consistent with the 2-year survival seen in the phase II trial of AT (66%).14 Considering the safety profile previously reported with the combination docetaxel-doxorubicin10,13 (high incidence of febrile neutropenia but favorable extrahematologic toxicity and cardiac side effects being no higher than expected with any anthracycline-containing regimen), the second goal of this pilot study was to assess the toxicity profile of the TAC combination, after addition of cyclophosphamide to the doublet AT. As expected from the data on AT, hematologic toxicity with neutropenia and febrile neutropenia is the main toxicity. One must be cautious in comparing phase II studies, but the incidence of febrile neutropenia with TAC in our study does seem slightly lower than in the series with AT (34% of patients v 42%, respectively). This may raise the question of the potential use of oral antibiotic prophylaxis in the context of docetaxel-anthracycline–based polychemotherapy regimens. In contrast with the AT series,10,14 prophylactic ciprofloxacin was systematically given in our study, but cytokines were only introduced for cycles subsequent to a first episode of febrile neutropenia or infection. After these protocol guidelines, documented infections were infrequently diagnosed and no septic death occurred on TAC. Additionally, we observed that the great majority of episodes of febrile neutropenia were reported after the first three courses of TAC chemotherapy. Patients whose first three cycles were uneventful (> two thirds of the patient population) had a low probability of presenting subsequently with a febrile neutropenic episode. Considering these observations, the prophylactic strategy followed in our study seems reasonable and we do not believe that there is sufficient argument to support the upfront use of cytokines for all patients treated with TAC chemotherapy. As no significant toxicity seemed to be related to the corticosteroid premedication, we would recommend the use of the same 3-day premedication for TAC as for single-agent docetaxel. The other important finding with regard to safety is the favorable nonhematologic toxicity profile noted in this study. There were no grade 4 and infrequent grade 3 side effects, mostly gastrointestinal and related to fatigue. Toxicity associated with taxanes, such as allergic reactions and neurologic side effects, were also infrequent and mild. Docetaxel-specific toxicities (fluid retention, nail changes, skin toxicity) were rarely severe and not considered a significant clinical problem: only one patient experienced severe fluid retention leading to treatment discontinuation. Overall, the extrahematologic toxicity profile of TAC seems to be more favorable than that reported with docetaxel monochemotherapy given at a dose of 100 mg/m2. One of the reasons could be the partially nonoverlapping toxicities of the three drugs, but these results also suggest that a threshold of extrahematologic toxicity may exist for docetaxel between 75 and 100 mg/m2. The third important toxicity finding is the lack of added cardiac toxicity for TAC as compared with anthracycline-containing regimens, which confirms previous observations.3 With an incidence of CHF less than 4%, our results are in keeping with the incidence of CHF reported in the literature with doxorubicin alone or with combinations such as AC or FAC.3,8,22,23 Moreover, our clinical observations with TAC are confirmed by recent pharmacokinetic data showing that docetaxel has no effect on doxorubicin pharmacokinetics regardless of the interval between the infusions of both drugs (1 hour or less).24,25 These results contrast with the data available with short infusions of paclitaxel (3 hours) and doxorubicin, for which the incidence of CHF at the time of therapy can be as high as 21% to 23%.15,16 The high efficacy seen in these initial series for metastatic breast cancer patients with short infusions of paclitaxel (3 hours) combined with doxorubicin (response rates up to 94%) has been counterbalanced by the significant cardiac toxicity. The reason for these observations seems to be related to the existence of a pharmacokinetic interaction between paclitaxel and doxorubicin accounting for an increase in area under the curve of doxorubicin.26 As a consequence of this increased cardiac toxicity and the fact that the majority of cardiac events are seen beyond a cumulative dose of doxorubicin of 360 mg/m2, some authors have introduced the concept of decreasing the usable cumulative dose of doxorubicin to 360 mg/m2 when using the combination of a paclitaxel 3-hour infusion plus doxorubicin. Other strategies trying to limit these side effects use either combinations of paclitaxel, given over 24-hour infusion, and doxorubicin, a time interval of 16 hours between paclitaxel and doxorubicin, or sequential administration regimes, such as four cycles of AC followed by four cycles of paclitaxel.19,27,28 Following the results of this phase II study of TAC, two large international phase III trials comparing TAC to FAC have been performed in first-line metastatic and adjuvant therapy of breast cancer. Additionally, TAC is now being compared with various other chemotherapy strategies in four other large international phase III trials involving breast cancer patients in the adjuvant setting. In conclusion, the docetaxel-doxorubicin–based TAC combination seems to be active in first-line treatment of patients with breast cancer. Although neutropenia is frequent, its consequences are manageable. The rest of the toxicity profile seems acceptable, with no significant extrahematologic toxicities, including docetaxel-specific toxicities. Moreover, we have found no evidence of added cardiac toxicity for TAC compared with classical anthracycline-containing combinations. These data have led to multiple phase III studies in both first-line metastatic and adjuvant treatment of patients with breast cancer. Results of such controlled trials will help define whether taxanes, in this case docetaxel, will further impact on the treatment strategies and the natural history of breast cancer.
Supported by Aventis Pharma Research and Development, Antony, France. We thank F. Delorme (Aventis, Montréal, Quebéc, Canada) for his input into this study.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999 2. Henderson IC: Chemotherapy for metastatic disease, in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases, ed 2. Philadelphia, PA, Lippincott, 1991, pp 604-665 3. Fossati R, Confalonieri C, Torri V, et al: Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16: 3439-3460, 1998[Abstract]
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Chevallier B, Fumoleau P, Kerbrat P, et al: Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: A phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 13: 314-322, 1995 7. Van Oosterom AT, Schrijvers D: Docetaxel (Taxotere): A review of preclinical and clinical experience. Part II: Clinical experience. Anticancer Drugs 6: 356-368, 1995[Medline]
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Misset JL, Dieras V, Gruia G, et al: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10: 553-560, 1999 11. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 1218-1225, 1981 12. Alexander J, Dainiak N, Berger HJ, et al: Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 300: 278-283, 1979[Abstract] 13. Sparano J-A, Hu P, Schaefer PL, et al: Phase II trial of doxorubicin and docetaxel (Taxotere) plus granulocyte colony-stimulating factor (G-CSF) in metastatic breast cancer: An Eastern Cooperative Oncology Group Study (E1196). Breast Cancer Res Treat 50: 233, 1998 (abstr 27) 14. Dieras V, Barthier S, Beuzeboc P, et al: Phase II study of [TM]Taxotere[/TM] (T) in combination with doxorubicin (A) as first line chemotherapy of metastatic breast cancer. Breast Cancer Res Treat 50: 262, 1998 (abstr 226)
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Gehl J, Boesgaard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7: 687-693, 1996 16. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13: 2688-2699, 1995[Abstract]
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Berg SL, Cowan KH, Balis FM, et al: Pharmacokinetics of taxol and doxorubicin administered alone and in combination by continuous 72-hour infusion. J Natl Cancer Inst 86: 143-145, 1994
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Holmes FA, Madden T, Newman RA, et al: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 14: 2713-2721, 1996 19. Sledge GW Jr, Robert N, Sparano JA, et al: Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: The Eastern Cooperative Oncology Group experience. Semin Oncol 21: 15-18, 1994 (suppl 8)
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Fisherman JS, Cowan KH, Noone M, et al: Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer. J Clin Oncol 14: 774-782, 1996 21. Sledge GW Jr, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs paclitaxel vs doxorubicin + paclitaxel as first-line therapy for metastatic breast cancer: An intergroup trial. Proc Am Soc Clin Oncol 16: 1a, 1997 (abstr 2)
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Gianni L, Vigano L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15: 1906-1915, 1997 27. Amadori D, Frassineti GL, Zoli W, et al: Doxorubicin and paclitaxel (sequential combination) in the treatment of advanced breast cancer. Oncology (Huntingt) 11: 30-33, 1997 (suppl 3) 28. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (pts) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17: 101a, 1998 (abstr 390A) Submitted February 8, 2000; accepted September 5, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2; normal hematology values (WBCs 
4 x 109/L, absolute neutrophil count 
