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© 2001 American Society for Clinical Oncology Phase II Study of Sequential Administration of Docetaxel Followed by Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast CancerByFrom the Hôpital de la Pitié Salpétrière, Paris; Centre Jean Perrin, Clermont-Ferrand; Aventis Pharma, Inc, Antony, France; Centro di Riferimento Oncologico, Aviano; and Ospedale S Chiara, Trento, Italy. Address reprint requests to D. Khayat, MD, PhD, Service d’Oncologie Médicale, Hôpital de la Pitié Salpétrière, 47, Blvd de l’Hôpital, 75013 Paris, France; email: david.khayat{at}psl .ap-hop-paris.fr.
PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m2 every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m2 every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m2 (range, 150 to 543 mg/m2), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.
DOCETAXEL (TAXOTERE; Aventis Pharma, Antony, France), has shown good efficacy in treatment of metastatic breast cancer. In the first-line setting, single-agent docetaxel has achieved overall response rates of 54% to 68%, which compare favorably to response rates reported with the most active agents and are at least equivalent to those achieved with standard polychemotherapy.1-3 Docetaxel is also effective in patients with anthracycline-resistant disease, producing objective responses of 53% to 58%.4-6 Furthermore, in one prospective randomized trial comparing docetaxel to mitomycin plus vinblastine in metastatic patients progressing despite previous treatment with anthracyclines, docetaxel-treated patients had significantly longer survival.7 In addition, anthracycline-based regimens have been shown to be active as second-line therapy in patients previously treated with docetaxel, with a response rate of 30%.8 These clinical data indicate that docetaxel and doxorubicin may only exhibit partial cross-resistance and that their sequential or concomitant administration could enhance efficacy.9 This has stimulated interest in the development of different regimens based on docetaxel and anthracyclines.10-13 A phase I dose-finding study has shown doxorubicin in combination with docetaxel (AT regimen) to be an effective and safe first-line chemotherapy for metastatic breast cancer.11 The effectiveness of AT was confirmed by the results of a phase III trial comparing AT to doxorubicin and cyclophosphamide (AC) in the same patient population. In this study, AT was significantly superior to AC in terms of response rates, time to progression, and time to treatment failure. This superiority was obtained despite a lower dose of doxorubicin in the AT regimen.14 As expected with these two hematotoxic drugs, grade 4 neutropenia and febrile neutropenia were the main toxicities of the combination, although the rate of infections was rather low and no septic deaths were reported among AT patients. One other approach to maintain the efficacy of docetaxel and doxorubicin while minimizing the incidence and severity of toxicity is sequential administration of the two agents. The rationale of such an approach comes from the Gompertzian kinetic model proposed by Norton and Simon.15,16 This model argued that the rate of tumor regression is directly related to the tumor growth rate, and in a heterogeneous tumor, faster-dividing cells will regress more quickly in response to chemotherapy than those with a slower rate of cell division. The authors hypothesized that the best management strategy would be to treat the faster-dividing cell first, then the slower-dividing cell populations. This would be accomplished most efficiently by sequential chemotherapy with multiple cycles of a first active agent given at the highest feasible dose, followed by multiple cycles of a second active agent or regimen, also used at the highest feasible dose. In the context of an extensive phase II program evaluating different sequential and alternating regimens of docetaxel and doxorubicin (Gianni, personal communication),17 this phase II pilot study was conducted to investigate the feasibility and activity of sequential administration of docetaxel followed by AC with consolidation treatment with docetaxel or AC. Other sequential schedules, including the reverse sequence, are being explored by other investigators (L. Gianni, personal communication, February, 2000). An alternating schedule of doxorubicin and docetaxel given on a cycle-by-cycle basis has also been investigated.17 Earlier studies showed that single-agent docetaxel 100 mg/m2 without routine premedication induced fluid retention, which was a frequent reason for treatment discontinuation.18 Sequential scheduling may allow recovery from this toxicity, permitting optimal single-agent dose administration with optimal duration of therapy.
The study population consisted of women aged 18 to 75 years with cytologically or histologically proven metastatic breast cancer and no previous chemotherapy for metastatic disease. Further inclusion criteria included measurable disease, Karnofsky performance status of 60% or higher, adequate hematologic, renal and hepatic functions (total bilirubin < one times the upper normal limit [UNL], ALT and AST  2.5 times the UNL, and alkaline phosphatase five times the UNL, 1.5 N), and normal baseline cardiac function as confirmed by left ventricular ejection fraction (LVEF). The protocol was approved by an independent ethics committee, and all patients gave written informed consent. Patients were excluded from the study if they had received prior chemotherapy for metastatic disease. However, prior neoadjuvant and/or adjuvant chemotherapy was allowed provided at least 12 months had elapsed before study entry and the cumulative doses of prior doxorubicin or epirubicin were less than or equal to 300 mg/m2 and less than or equal to 500 mg/m2, respectively. Prior treatment with taxanes was not permitted. Previous hormonal therapy as adjuvant treatment or for metastatic disease was permitted, provided the patient had progressive disease at study entry. Prior radiation therapy was permitted at sites other than those used to assess response; if 20% or more of bone marrow was included, a 4-week interval must have elapsed since the last fraction. 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, or other therapeutically cured cancer with no evidence of disease for 5 years or more were eligible. Patients were also excluded if they had known clinical brain or leptomeningeal involvement, pre-existing motor or sensory neurotoxicity, or a history of other serious illness.
Treatment Plan
During treatment with docetaxel, patients were given prophylactic premedication with dexamethasone, to avoid hypersensitivity reactions and to prevent the occurrence of fluid retention. Dexamethasone (8 mg orally) was administered 24 hours, 16 hours, 8 hours, and 1 hour before docetaxel infusion and continued twice daily for 3 days, starting 7 hours from the end of the docetaxel infusion.
Dose modifications were planned for severe toxicity. Patients who experienced febrile neutropenia, documented infection, or grade 4 neutropenia lasting more than 7 days were treated at subsequent cycles with a reduced doses (docetaxel 75 mg/m2 or doxorubicin 50 mg/m2/cyclophosphamide 500 mg/m2). If grade 3 or 4 nausea, vomiting, or diarrhea was experienced despite prophylactic measures, docetaxel or doxorubicin doses were reduced as above. Grade 3 or 4 neuropathy was considered a reason to discontinue docetaxel. Patients were withdrawn from the study if congestive heart failure (CHF) and/or functional criteria for cardiotoxicity developed (ie, absolute decrease in LVEF
Patient and Treatment Evaluation Tumor assessments were repeated every 6 weeks and at the end of the study. Response was classified according to World Health Organization criteria.19,20 CR required the disappearance of all known disease as determined by two observations not less than 4 weeks apart. PR required a 50% or greater decrease in the sum of the products of the diameters of all measurable lesions, with no simultaneous increase in any lesion or the appearance of an unequivocal new lesion. Progressive disease required a more than 25% increase in the size of any measurable lesion or the appearance of an unequivocal new lesion. Patients were considered to have stable disease if they had no progressive disease at least 6 weeks after the start of the treatment and if an objective response (PR or CR) was not confirmed by a second tumor evaluation more than 4 weeks later. All patient responses were reviewed by an independent radiologist. All adverse events were documented and either graded according to National Cancer Institute common toxicity criteria or recorded as mild, moderate, or severe. All patients were evaluated during each cycle of treatment and upon completion of the treatment schedule. Physical examinations, assessments of performance status, and biochemistry analyses were repeated every cycle, and hematology parameters were analyzed weekly or every 2 days in case of febrile neutropenia or grade 4 neutropenia. Cardiac function was assessed during treatment with AC. Repeat LVEF measurements were taken once the cumulative dose of doxorubicin was greater than or equal to 300 mg/m2 and then at every cycle once the cumulative dose of doxorubicin was greater than or equal to 450 mg/m2. After study completion, all patients were monitored for any late adverse event for at least the first month after the last cycle and every 3 months thereafter or until death.
Data Analysis Efficacy analysis was performed on both intent-to-treat and on eligible and assessable patient populations. Efficacy end points were response rates (CR, PR, and overall response rate [CR + PR]), duration of response, time to progression, and survival. In case of further antitumor treatment before disease progression, time to progression was censored at the date of the last tumor assessment. Log-rank tests and Kaplan-Meier estimations were performed for duration of response, time to progression, and survival. Objective response rates were calculated with 95% confidence intervals. Toxicity analyses were performed on the intent-to-treat population, ie, on patients who received at least one dose of study treatment.
Patient Characteristics From October 1994 to October 1996, 48 patients with first-line metastatic breast cancer were entered onto the trial. The characteristics of these patients are listed in Table 1. The median age was 51 years (range, 28 to 72 years), and the median World Health Organization performance status was 0 (range, 0 to 2). Thirty patients (62.5%) had visceral disease, and 16 (33.3%) had at least three organs involved. Twenty-two patients (45.8%) had received prior adjuvant anthracycline treatment, at a median cumulative dose of 200 mg/m2 (range, 44 to 320 mg/m2). The median time between the last cycle of prior anthracycline therapy and study entry was 38.4 months (range, 17.1 to 147.6 months).
Of the 48 registered and treated patients, 42 patients (87.5%) were assessable for tumor response. Reasons for nonassessability included absence of measurable disease (three patients), absence of any tumor lesion (one patient), and incomplete tumor assessment during the study (two patients).
Chemotherapy
Of these 48 patients, 42 entered the second phase of treatment and six patients were taken off study because of disease progression (four patients) or patient refusal (two patients). These 42 patients received 162 cycles of AC, including 128 cycles (79%) given at the initially planned doses (60/600 mg/m2) with a high median relative dose-intensity for both doxorubicin (0.89) and cyclophosphamide (0.89) (Table 2). At the end of the two planned sequences (Table 2), nine patients discontinued the study and 33 received consolidation treatment with docetaxel (29 patients) or AC (four patients). The median number of cycles of docetaxel was three (range, two to five cycles), and 68 (76.4%) of the 89 cycles were given at 100 mg/m2, with a median relative dose-intensity of 0.95. Overall, the median cumulative doses of docetaxel and doxorubicin were 581 mg/m2 (range, 99 to 935 mg/m2) and 233 mg/m2 (range, 122 to 443 mg/m2), respectively, resulting in a high median relative dose-intensity for both docetaxel (0.97) and for doxorubicin (0.89). Almost all cycles (85%) were given every 3 weeks, as per protocol. Of 65 cycles (15%) that were delayed (only 4.1% by > 7 days), 26 (40.0%) were delayed for nonmedical reasons, and 36 (55.4%) and three (4.6%) were delayed for hematologic and nonhematologic toxicities, respectively.
Toxicity
As expected with these hematotoxic drugs, neutropenia was the most frequent adverse event, occurring in 93.8% of patients (Table 4). The incidence of grade 4 neutropenia was similar for docetaxel and AC treatment and for consolidation treatment with docetaxel (Table 4). The duration of grade 4 neutropenia was also similar between the two sequences, and recovery was rapid since the median number of neutrophils on day 22 ± 3 at each treatment phase was always more than 2 x 103/L.
Febrile neutropenia (grade 4 neutropenia concomitant with grade  2 fever) developed in 12 patients (25.5%). Of these, only three patients (6.4%) required intravenous antibiotics and/or hospitalization, and the majority received oral antibiotics on an outpatient basis. Overall, 17 episodes (4.4%) of febrile neutropenia occurred in 385 assessable cycles, and almost all of them were observed during the docetaxel treatment. Despite the high incidence of grade 4 neutropenia, infection was rare. Infection was observed in seven patients (14.6%) receiving the first sequence with docetaxel and in four patients (9.5%) during treatment with AC. Infection was always grade 1 or 2, except in one patient who developed a grade 3 infection. Gastrointestinal adverse events were generally mild, with few patients experiencing grade 3 or 4 diarrhea, nausea, vomiting, or stomatitis (Table 5). Hypersensitivity reactions occurred in nine patients (19%) during docetaxel treatment, but none was severe. Alopecia was almost universal (Table 5). Asthenia and nail disorders were common but generally mild or moderate. Skin disorders were infrequent and never severe. Neurotoxicity was mainly grade 1 or 2. With a median cumulative dose of docetaxel of 581 mg/m2 (range, 99 to 935 mg/m2), fluid retention was observed in 11 patients (23%), but it was never severe or a reason for treatment discontinuation (Table 5).
The incidence and severity of cardiotoxicity by cumulative dose of doxorubicin is summarized in Table 6. At a median cumulative dose of doxorubicin of 397 mg/m2 (range, 150 to 543 mg/m2), including prior anthracycline and with a median follow-up of 13.7 months (range, 1.5 to 24.9 months), two patients (4.5%) developed unrelated CHF. Out of 44 patients assessable for LVEF decrease, two patients (6.9%) had a LVEF decrease according to Schwartz and Alexander’s criteria22 (absolute decrease in LVEF 10% [EF units] associated with a decline to a level < 50% [EF units]). Importantly, the two episodes of CHF reported during the study were observed only after additional treatment with anthracycline received during follow-up. One of these cases resolved fully during follow-up.
Efficacy The response rates for the 42 patients eligible and assessable for response are reported in Table 7. Five patients (11.9%) had a CR and 25 (59.5%) had a PR, for an overall response rate of 71.4% (95 confidence interval, 55.4% to 84.3%).
When response of the sequential schedule was evaluated by treatment phase, CR rates increased from 0% after docetaxel to 5% after AC and to 12% after consolidation treatment with docetaxel (29 patients) or AC (four patients). Objective response rates increased from 61.9% after initial treatment with docetaxel to 69.0% after AC and to 71.4% after consolidation treatment. It should be noted, however, that among the 21 patients who were assessed as having a stable disease after the first four cycles with docetaxel, 13 patients had a PR or CR that was first noted during docetaxel therapy but was not confirmed before the patient moved on to AC. The median time to first response for eligible and assessable patients was 11.7 weeks (range, 2.7 to 34.6+ weeks) Activity was not affected by prior adjuvant chemotherapy with or without anthracycline and was seen at all disease sites (Table 7). The treatment schedule was highly effective in liver and visceral disease, with an overall response rate of 75% and 66.7%, respectively. Objective responses were achieved in 11 (84.6%) of 13 patients with one organ involved, in 11(73.3%) of 15 patients with two organs involved, and eight (57.1%) of 14 with three or more organs involved. The median duration of response was 52.9 weeks (range, 12+ to 71.6 weeks), and the median time to progression was 45.9 weeks (range, 2.7 to 71.6 weeks) (Fig 2). As of September 30, 1999, and with a median follow-up time of 40.4 months, 27 patients (56%) had died and 21 (44%) were still alive. The median survival time was 32 months (range, 1.5 to 54.9+ months) (Fig 3).
Among the new drugs introduced in the 1990s for the treatment of breast cancer, the taxanes have emerged as the most active agents and have been the subject of an extensive program investigating the benefits of combination with anthracyclines in various strategies. Although, in metastatic disease, the combination of doxorubicin with docetaxel11,13,14,23 seemed to be more practicable than doxorubicin with paclitaxel,24-26 the question of the best strategy for combining taxanes and anthracyclines (eg, concomitant or sequential administrations) is still unresolved and remains an area of active investigation. As of today, no single completed phase III trial addressing this issue and comparing the sequential versus the concomitant administration of the taxanes and doxorubicin has been reported. The sequential administration of docetaxel followed by AC, as it was explored in this pilot phase II study, seems to be a feasible, safe, and active regimen as first-line chemotherapy for metastatic breast cancer. Antitumor activity was very promising, with an overall response rate of 71.4% (95% confidence interval, 55.4% to 84.3%). This high level of activity was observed at all disease sites and was even maintained in patients previously exposed to adjuvant chemotherapy with or without anthracyclines. In addition, the efficacy in patients with liver and visceral disease was impressive, with response rates of 75% and 67%, respectively. The median duration of response was 53 weeks (range, 12+ to 71.6 weeks), and the median time to progression was 46 weeks (range, 2.7 to 71.6 weeks). With a median follow-up time exceeding 3 years, the median survival of 32 months is promising and compares favorably with that observed with the most common anthracycline-containing regimens for first-line metastatic breast cancer.4,27-29 This historical comparison must be viewed cautiously, however, because this sequential study is a phase II nonrandomized trial and is probably the first reported study that aimed to test directly Norton and Simon’s hypothesis with docetaxel followed by anthracycline in metastatic breast cancer. The same approach, with paclitaxel, doxorubicin, and cyclophosphamide in operable breast cancer patients with positive axillary lymph nodes30 and in the metastatic setting with doxorubicin followed by docetaxel,31 has recently been taken. The aim of these two studies was not only to test the feasibility of sequential chemotherapy but also to evaluate the dose-density concept through dose-dense schedules (maximum-tolerated dose of each agent administered every 2 weeks). Therefore, any direct comparison of these two trials with the current study would not be appropriate. These interesting results raised the question of whether the sequential administration of docetaxel and doxorubicin may have a better risk-benefit ratio than the concomitant administration of these two drugs. Although no formal conclusion can be drawn without a well-designed phase III trial, this sequential schedule seems to have activity comparable to that reported for concomitant docetaxel and doxorubicin as reported in phase II studies.11,13,23 The sequential regimen seems less myelotoxic than concomitant administration, although, as in the current study, the rate of severe infection was low and no septic death was reported with docetaxel in combination with doxorubicin.11,13,14 Despite the absence of any prophylactic measure from cycle 1, the rate of neutropenic complications (febrile neutropenia and severe infection) in this sequential regimen was low compared with that observed with the combination. In addition, and considering the high median number of cycles administered during the study (n = 11) and the high relative dose-intensity reached for each drug, there was no evidence of cumulative hematotoxicity. Thus the sequential administration seems to allow a prolonged duration of therapy without any cumulative dose-limiting toxicity. Another important safety consideration is the favorable nonhematologic toxicity profile noted in this study. There were no grade 4 and infrequent grade 3 side effects, which were mostly gastrointestinal and related to fatigue. Taxane-related adverse events, such as allergic reactions and neurologic side effects, were also infrequent and mild. Docetaxel-specific toxicities (fluid retention, nail changes, and skin toxicity) were rarely severe and considered not to be a significant clinical problem (this was also reported for docetaxel in combination with doxorubicin).14 Fluid retention occurred in 11 patients (22.9%) but was never severe or a reason for treatment withdrawal, despite a high median cumulative dose of docetaxel of 581 mg/m2 (range, 99 to 935 mg/m2). Cardiotoxicity was rare despite, a high median cumulative dose of doxorubicin of 397 mg/m2 (range, 150 to 543 mg/m2). No drug-related CHF was observed, although two patients developed unrelated CHF after receiving further anthracyclines or mediastinal irradiation therapy during follow-up. The role of sequential compared with concomitant administration of docetaxel and doxorubicin has not yet been investigated prospectively in the metastatic setting. Nevertheless, the role of sequential administration has already been studied in the adjuvant setting by the Milan trial32 and more recently by an intergroup adjuvant trial.33 Three ongoing or planned phase III trials are now addressing this issue with docetaxel in early breast cancer patients. In the first trial, coordinated by the National Surgical Adjuvant Breast and Bowel Project (NSABP B30; N. Wolmark, personal communication, February 2000), patients with node-positive primary breast cancer are randomized to receive either sequential AC and docetaxel, the combination of docetaxel and doxorubicin (AT regimen), or the combination of docetaxel, doxorubicin, and cyclophosphamide (Table 8). The second trial comes from the Breast Cancer International Research Group (BCIRG 005; J.M. Nabholtz, personal communication, February 2000) and is comparing sequential administration of AC and docetaxel to the original docetaxel/doxorubicin/cyclophosphamide regimen (Table 8). A pilot trial evaluating docetaxel-based sequential and combination regimens in node-positive breast cancer was recently reported and confirmed the feasibility of both regimens.34 This has formed the basis of a large phase III trial conducted under the Breast International Group’s umbrella. This trial (the BIG 2.98 trial; M. Piccart, personal communication, February 2000) is comparing disease-free survival among operable breast cancer patients with positive axillary nodes given different adjuvant chemotherapy regimens. The comparisons are as follows: doxorubicin followed by docetaxel followed by cyclophosphamide, methotrexate, and fluorouracil (CMF) (arm B) versus doxorubicin followed by CMF (arm A1); docetaxel in combination with doxorubicin followed by CMF (arm C) versus doxorubicin in combination with cyclophosphamide followed by CMF (arm A2). This large trial also asks the question whether the sequential administration of doxorubicin followed by docetaxel followed by CMF (arm B) conveys therapeutic benefit in terms of disease-free survival over the combination of docetaxel and doxorubicin followed by CMF (arm C) (Table 8). The results from these phase III studies will be available in the near future and will help to define the ultimate role of combination versus sequential administration of docetaxel and doxorubicin in the treatment of early breast cancer patients.
In conclusion, sequential administration of docetaxel and AC is a feasible treatment that demonstrates high efficacy and a manageable safety profile. It should be considered as a valuable chemotherapeutic option for first-line therapy of metastatic breast cancer patients as well as in the adjuvant setting. Further investigations in the metastatic setting are still warranted. The evaluation of sequential administration of docetaxel and AC as first-line chemotherapy versus docetaxel in combination with doxorubicin with or without cyclophosphamide will help to better establish the role of this innovative schedule in the treatment of metastatic breast cancer patients. Other studies comparing two different sequential schedules (docetaxel followed by anthracyclines v anthracyclines followed by docetaxel) are also awaited.
Sponsored by Aventis Pharma Research and Development, Antony, France.
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Nabholtz JM, Senn HJ, Bezwoda D, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 17: 1413-1424, 1999 8. Delecroix V, Fumoleau P, Perrocheau G, et al: Anthracycline as second-line chemotherapy (CT) for metastatic breast cancer patients previously treated with Taxotere (TXT). Proc Am Soc Clin Oncol 16: 166a, 1997 (abstr 578) 9. Antoine EC, Coeffic D, Gozy M, et al: A phase II study of docetaxel (T) and cisplatin (P) in anthracycline (A)-pretreated metastatic breast cancer (PBMC): Preliminary results. Proc Am Soc Clin Oncol 16: 158a, 1997 (abstr 551)
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Kouroussis C, Xydakis , Potamianou A, et al: Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: A multicenter dose-escalation study—The Greek Breast Cancer Cooperative Group (GBCCG). Ann Oncol 10: 547-552, 1999
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Pagani O, Sessa C, Martinelli G, et al: Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer. Ann Oncol 10: 539-545, 1999 13. Dieras V, Barthier S, Beuzeboc P, et al: Phase II study of Taxotere (T) in combination with doxorubicin (A) as 1st line chemotherapy (CT) of metastatic breast cancer (MBC). Breast Cancer Res Treat: 50: 262, 1998 (abstr 226) 14. Nabholtz JM, Falkson G, Campos D, et al: A phase III trial comparing doxorubicin (D) and docetaxel (T) (AT) to doxorubicin and cyclophosphamide (AC) as first line chemotherapy for MBC. Proc Am Soc Clin Oncol 19: 127a, 1999 (abstr 485) 15. Norton L: A Gompertzian model of human breast cancer growth. Cancer Res 48: 7067-7071, 1988[Medline] 16. Norton L, Simon R: Tumor size, sensitivity to tumor therapy, and design of treatment schedules. Cancer Treat Rep 61: 1307-1317, 1977[Medline] 17. Paridaens R, Van Aelst F, Georgoulias G, et al: A phase II randomized study of doxorubicin (A) alternated to docetaxel (T) (Alt) vs sequential administration of 4 cycles of docetaxel (T) followed by 4 cycles of doxorubicin (A) (seq) as 1st line chemotherapy in metastatic breast cancer patients. Eur J Cancer 35: S314, 1999 (suppl, abstr 1259) 18. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13: 2643-2655, 1995[Abstract] 19. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979 20. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 1218-1225, 1981 21. Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38: 143-151, 1982[Medline] 22. Schwartz RG, McKenzie WB, Alexander J, et al: Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: Seven year experience using serial radionuclide angiocardiography. Am J Med 82: 1109-1118, 1987[Medline] 23. Nabholtz JM, Mackay JR, Smylie M, et al: Final results of a phase II study of Taxotere, doxorubicin and cyclophosphamide (TAC) as 1st line chemotherapy in metastatic breast cancer patients. Breast Cancer Res Treat 50: 262, 1998 (abstr 227) 24. 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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Hudis C, Seidman A, Baselga J, et al: Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: Feasibility and efficacy. J Clin Oncol 17: 93-100, 1999 31. Schwartzberg L, Birch R, Weaver C, et al: Randomized trial of simultaneous (SIM) vs. sequential (SEQ) doxorubicin (A) and docetaxel (T) in patients (Pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 19: 72a, 2000 (abstr 278) 32. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: Ten-year results. JAMA 273: 542-547, 1995[Abstract] 33. Henderson IC, Berry D, Demetri G, et al: Improved disease-free survival (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)
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Di Leo A, Crown J, Nogaret JM, et al: A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node positive breast cancer. Ann Oncol 11: 169-175, 2000 Submitted July 5, 2000; accepted April 9, 2001. This article has been cited by other articles:
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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
