|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Paclitaxel Versus Doxorubicin as First-Line Single-Agent Chemotherapy for Metastatic Breast Cancer: A European Organization for Research and Treatment of Cancer Randomized Study With Cross-OverFrom the University Hospital Gasthuisberg, Leuven; and Investigational Drug Branch for Breast Cancer; and European Organization for Research and Treatment of Cancer Data Center; and Institut Jules Bordet, Brussels, Belgium; and Netherlands Cancer Institute, Amsterdam; and Daniel den Hoed Klinik and Academic Hospital, Rotterdam, The Netherlands; and Istituto Regina Helena, Rome, Italy; and Guy’s Hospital, London; and Weston Park Hospital, Sheffield, United Kingdom; and Rabin Medical Centre, Tel Aviv, Israel. Address reprint requests to Robert Paridaens, MD, Department of Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; email Robert.Paridaens{at}uz.kuleuven.oc.be
PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival [PFS]) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m2, 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m2, intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P = .003) for doxorubicin (response rate [RR], 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P < .001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P = .38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.
ALTHOUGH ADVANCED breast cancer may be considered incurable, efficient palliation can be achieved with the optimal use of therapeutic resources, ie, radiotherapy, hormonotherapy, biphosphonates, and chemotherapy. In this setting, chemotherapy is generally prescribed after failure of endocrine therapy. However, it is prescribed as first-line treatment for patients with receptor-negative tumors or with life-threatening visceral metastases. Among the presently available cytotoxic drugs, doxorubicin is generally considered as the most active agent in advanced breast cancer.1 Although the best chemotherapy regimen remains a matter of debate, the results of several studies indicate that there is a dose-response relationship for this agent and that, at the maximum-tolerated dose of 75 mg/m2, the results obtained with monotherapy are comparable with those achieved with a standard combination such as cyclophosphamide, methotrexate, and fluorouracil.2-5 When progression occurs after first-line chemotherapy, the response to salvage treatment is generally disappointing, indicating that similar mechanisms of resistance affect most conventional regimens. In this regard, paclitaxel represents a major advance. This cytotoxic compound, originally extracted from the bark of the Pacific yew (Taxus brevifolia), stabilizes polymerized microtubules, thereby disrupting mitosis.6,7 It was selected in 1977 by the National Cancer Institute (NCI) for further development as an antitumor drug and proved, subsequently, to be active in a broad panel of tumors, including ovarian and breast cancer.8 In breast cancer, paclitaxel seemed particularly promising because it elicited impressive response rates in phase II studies as second- or third-line therapy in patients with demonstrated resistance to anthracyclines.9-20 The purpose of the present phase III trial was to compare the efficacy of paclitaxel and doxorubicin given as single agents in first-line therapy of advanced breast cancer. A cross-over applied systematically on demonstrated progression during first-line treatment, unless contraindicated or refused by the patient, intended to explore further the degree of cross-resistance between the two agents.
Eligibility Criteria To be eligible, patients were required to have histologically or cytologically proven adenocarcinoma of the breast and metastatic disease in overt progression with uni- or bidimensionally measurable lesions. Prior hormonotherapy, radiotherapy, or immunotherapy for adjuvant or neoadjuvant purposes or for advanced disease was allowed but had to be stopped at study entry. No prior chemotherapy for advanced disease was permitted. Prior adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil or comparable regimens was authorized on the provision that patients had never been exposed to anthracyclines or to taxanes and that all cytotoxic drugs were stopped at least 3 months before study entry. Other requirements for eligibility were an age greater than 18 years, a World Health Organization performance status of 0 to 2, a life expectancy of at least 3 months, adequate hematologic parameters (absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L), adequate renal and hepatic functions (total bilirubin and creatinine < 1.25 x upper normal limit), a normal cardiac function, and absence of cardiac disease or significant arythmia as demonstrated by ECG and left ventricular ejection fraction (LVEF) measurement (echocardiography or multiple gated aquisition scan). Men and pregnant or lactating women were excluded. The protocol was approved by the European Organization for Research and Treatment of Cancer (EORTC) Protocol Review Committee and by the ethics committee of each participating center; all patients gave their written informed consent to participate in the trial.
Treatment Allocation and Administration
Cycles were repeated every 3 weeks, with weekly monitoring of hematology. For patients who did not achieve hematologic recovery (ANC In first-line treatment, a maximum of seven cycles of doxorubicin were planned (cumulative dose 525 mg/m2), whereas paclitaxel therapy could be either stopped after seven cycles or pursued in responding patients at the discretion of the treating physician. Patients progressing during their seven courses were to undergo early cross-over to the alternative drug, whereas a delayed cross-over was optional for the remainder at the time of disease progression.
Pretreatment and Follow-Up Studies
Criteria of Evaluation All case report forms were regularly reviewed and source verified. A large proportion of the objective remissions (CR or PR) (85% and 90% for first- and second-line treatment, respectively) and a sample of disease stabilizations (22% of first-line stable disease) were reviewed. The cases were presented by the local investigators to two independent radiologists who were blinded to treatment arm.
Study End Points and Statistical Methods
Results were analyzed according to the intent-to-treat principle. The
Treatment Delivery Between August 1993 and May 1996, 331 patients from 14 institutions were randomized to receive either paclitaxel (166 patients) or doxorubicin (165 patients) as first-line chemotherapy. Sixteen patients were considered not eligible because of the absence of measurable lesions (n = 9), inadequate organ function (n = 4), the presence of brain metastases (n = 2), or prior chemotherapy for metastatic disease (n = 1). Patient characteristics were similar in the two groups, and, as listed in Table 1, there was no significant imbalance in classical prognostic factors. The details of treatment delivery in both first- and second-line treatments are given in Table 2. Two patients in each group never started first-line treatment, leaving 164 and 163 patients who received at least one course of paclitaxel and doxorubicin, respectively.
First-line treatment. A median of seven cycles was administered per patient in both the paclitaxel arm (range, one to 22 cycles) and the doxorubicin arm (range, one to nine cycles). Twenty-one patients versus one patient received more than seven cycles of therapy in the paclitaxel and doxorubicin arms, respectively. However, because dose reductions and treatment delays were more frequent in the doxorubicin arm, the average dose-intensity achieved with doxorubicin (93% of planned dose-intensity; range, 53% to 103%) was lower than with paclitaxel (99% of planned dose-intensity; range, 72% to 107%). In patients receiving paclitaxel, the most frequent reasons for delaying treatment were neutropenia, neutropenic fever, and neurotoxicity, and infection was the most frequent reason for dose reduction. In the doxorubicin arm, neutropenia and stomatitis were the principal causes of treatment delay, and neutropenia, stomatitis, and neutropenic fever were the principal causes of dose reduction. The most frequent toxicities leading to treatment interruption were gastrointestinal (four patients), hematologic (three patients), infection (two patients), and cardiac function (17 patients) with doxorubicin, and neurotoxicity (four patients) with paclitaxel. The most frequent reasons for stopping first-line paclitaxel were disease progression, including death caused by malignancy (90 patients; 55%), treatment completion (57 patients; 35%), and excessive toxicity and/or patient refusal (12 patients; 7%). Eighty-one doxorubicin patients (50%) ended first-line therapy because of treatment completion, 37 (23%) because of excessive toxicity and/or patient refusal, and 36 (22%) because of PD. Second-line treatment. Among those patients eligible for early cross-over, 65 (76%) out of 86 paclitaxel-resistant patients received doxorubicin, whereas 24 (75%) out of 32 doxorubicin-resistant patients received paclitaxel. Overall, 168 patients have been crossed to the alternate drug, for a total of 77 patients receiving paclitaxel and 91 patients receiving doxorubicin. Late cross-over was performed in 26 (46%) out of 57 patients previously exposed to paclitaxel and in 53 (65%) out of 81 patients first treated with doxorubicin. Overall, a median of five cycles (range, one to 15 cycles) were administered per patient in the paclitaxel arm, and a median of six cycles (range, one to eight cycles) were administered in the doxorubicin arm. Five percent of the cycles of paclitaxel and 18% of doxorubicin cycles were delayed, mainly for neutropenia and neutropenic fever. Approximately 10% of the cycles were dose-reduced in the two treatment arms. The most frequent reasons for stopping second-line therapy were disease progression (61% of patients) under paclitaxel and treatment completion (47% of patients) under doxorubicin. Data on second-line therapy are available for 95% and 91% of the first-line paclitaxel and first-line doxorubicin patients, respectively, who did not cross over. Fifty-five percent of paclitaxel first-line patients received a further systemic treatment (hormonotherapy 20% and chemotherapy 80%); 60% of the second-line regimens were anthracycline-based. A second-line chemotherapy was received by 62% of the patients previously treated with doxorubicin. A taxane-based regimen was received by 21% of these patients.
Response and Efficacy Data The patterns of response achieved under paclitaxel or doxorubicin in first- and in second-line treatment are depicted in Table 3. The objective remission rate (CR + PR) was significantly better for doxorubicin than for paclitaxel in first-line treatment (41%; 95% confidence interval, 33.1% to 48.1% v 25%; 95% confidence interval, 18.7 to 31.9%, respectively; P = .003). In second line treatment, the response rates were 30% for doxorubicin and 16% for paclitaxel. Response by disease site (number of responses/number of sites) for first-line doxorubicin and paclitaxel, respectively, was as follows: soft tissue, 67% (76 of 114) versus 38% (36 of 95); liver, 42% (32 of 77) versus 19% (14 of 72); lung, 34% (12 of 35) versus 43% (20 of 46); and bone, 0% (zero of 14) versus 14% (two of 14). Response by disease site for second-line doxorubicin and paclitaxel, respectively, was as follows: soft tissue, 33% (15 of 45) versus 40% (14 of 35); liver, 38% (17 of 45) versus 18% (seven of 39); lung, 26% (six of 23) versus 25% (three of 12); and bone, 43% (three of seven) versus 0% (zero of eight).
The median duration of objective response in first-line treatment was 9.7 months (range, 3.4 to 45.8+ months) for doxorubicin and 7.7 months (range, 3.8 to 55.5+ months) for paclitaxel. In second-line treatment, median duration of response was 8.3 months (range, 3.0 to 25.3 months) for doxorubicin, and 5.6 months (range, 4.4 to 11.5 months) for paclitaxel. PFS curves for first-line therapy are presented in Fig 1. PFS in first-line therapy was significantly longer for doxorubicin than for paclitaxel (median, 7.5 months v 3.9 months, respectively; P = .0001). We did not compare the time to disease progression in patients who stopped after seven cycles with those who continued beyond seven cycles because this is a subgroup analysis of two groups of patients that were not determined by randomization and, therefore, are almost certainly not comparable. There was no significant difference in OS between the two study arms (P = .38), with a median survival of 18.3 months in the doxorubicin arm and 15.6 months in the paclitaxel arm (Fig 2).
The relationship between treatment and prognostic factors on response, PFS, and OS has been examined. The prognostic factors selected by univariate analyses were age, performance status, dominant site, number of sites, prior adjuvant chemotherapy, and disease-free interval. After adjusting for these factors, doxorubicin remained more active than paclitaxel in terms of RR and PFS; again, no difference in OS was demonstrated (Table 4).
Toxicity Toxicities and clinically relevant adverse events encountered during treatment in first- and second-line therapy are presented in Tables 5 and 6, respectively. As expected, the toxicity profiles of the two drugs were different. Doxorubicin was more toxic than paclitaxel in terms of hematologic, gastrointestinal, and cardiac side effects. In contrast, paclitaxel elicited more neurotoxicity (mainly sensory) and arthralgia/myalgia. Neutropenia, febrile neutropenia (fever  38.5°C, associated with an ANC of < 0.5 x 109/L, and requiring hospitalization and intravenous antibiotic treatment), documented infections, and hospital admission for serious adverse events were more frequently observed in the doxorubicin arm. No severe hypersensitivity reaction necessitating prolongation of the 3-hour paclitaxel infusion was reported.
Six toxic deaths were encountered: three after doxorubicin in first-line therapy (two patients died as a result of a neutropenic sepsis and one patient suffered an episode of acute dyspnea and died at home 2 weeks after the first cycle of chemotherapy); two in second-line therapy (two myocardiopathies after a cumulative dose of 525 mg/m2 of doxorubicin); and one after paclitaxel was encountered in second-line treatment (neutropenic sepsis).
Regarding cardiotoxicity, a total of 12 patients developed congestive heart failure, six patients (4%) on first-line doxorubicin, two on second-line paclitaxel, and four on second-line doxorubicin. Of all these patients, the median age was 60 years (range, 42 to 69 years), and the median cumulative dose of doxorubicin was 480 mg/m2 (range, 300 to 675 mg/m2). Twenty-nine patients (17 on first-line doxorubicin and 12 on second-line doxorubicin) ceased therapy because of a drop in LVEF of
QOL
This study demonstrates that, in advanced breast cancer, monotherapy with doxorubicin given at the dose of 75 mg/m2 every 3 weeks achieves better disease control than paclitaxel 200 mg/m2 given as a 3-hour infusion every 3 weeks. In first-line treatment, therapy with doxorubicin results in a higher objective RR and almost twice the median PFS achieved after therapy with paclitaxel (7.5 months with doxorubicin v 3.9 months with paclitaxel). No significant survival difference was observed between the two treatment groups; however, the cross-over design of the study may reduce the likelihood of observing such a difference. The greater efficacy of doxorubicin is associated with better pain control but is counterbalanced by higher hematologic, gastrointestinal, and cardiac toxicity. Doxorubicin should, therefore, be proposed as first-line therapy to patients who are symptomatic or affected by life-threatening disease. In asymptomatic patients, however, paclitaxel remains a reasonable first-line option because of its favorable toxicity profile and the observation that the efficacy of doxorubicin is sufficiently maintained in second-line therapy and that the paclitaxel followed by doxorubicin sequence does not adversely affect survival. Another randomized trial conducted by the American Intergroup has compared paclitaxel with doxorubicin in first-line treatment for metastatic disease. In that three-arm study, reported by Sledge et al.27 at the American Society of Clinical Oncology meeting in 1997, 739 patients were randomized to receive either doxorubicin (60 mg/m2) or paclitaxel (175 mg/m2) continuous infusion over 24 hours or the combination of doxorubicin (50 mg/m2) and paclitaxel (150 mg/m2) over 24 hours plus granulocyte colony-stimulating factor support. Patients receiving single-agent chemotherapy were crossed to the alternate drug at the time of progression. RRs and median durations of PFS in first-line therapy were almost identical for paclitaxel (33% RR; 5.9 months) and doxorubicin (34% RR; 6.2 months) but were significantly better for the combination of doxorubicin and paclitaxel (46% RR; 8 months). There was no significant difference in OS between the three arms of the study. Cross-over from doxorubicin to paclitaxel yielded a 20% RR, whereas the alternate sequence resulted in a 16% RR (P = .06). The results of the monotherapy arms of the American trial are difficult to compare with those of the present study because the Intergroup used a lower dose of doxorubicin (60 instead of 75 mg/m2) and a different dose and schedule of administration of paclitaxel (175 mg/m2 over 24 hours instead of 200 mg/m2 over 3 hours). The ideal dose and schedule of paclitaxel are yet to be defined. Using the 3-hour infusion, increasing the dose of paclitaxel from 175 up to 250 mg/m2 does not significantly improve efficacy but does increase toxicity.28 Prolonging the duration of infusion of paclitaxel, at a fixed dose of 250 mg/m2, from 3 to 24 hours results in higher RRs but does not improve PFS or OS.29 A randomized trial comparing paclitaxel 250 mg/m2 as a 3-hour infusion with paclitaxel 140 mg/m2 as a 96-hour infusion did not demonstrate any difference between the schedules in terms of RR, median duration of response, and OS.30 However, prolonged infusion of 120 to 140 mg/m2 over 96 hours may still elicit responses in patients who have become refractory to higher doses given over 3 hours.31 Finally, new strategies, such as the weekly administration of lower doses of paclitaxel, are under investigation.32 However, the above-mentioned data would suggest that the 3-hour infusion and the dose of 175 mg/m2 are an adequate way of administering paclitaxel in advanced breast cancer patients. Should we assume that the superiority of doxorubicin over paclitaxel in our study is because of the use of a higher dose of doxorubicin? The role of dose-intensity in anthracycline-based therapy is still an open question. Several studies have shown that an increased dose of anthracycline per course correlates with a higher RR; however, only a few of the studies were randomized, and they did not demonstrate an impact of higher doses on time to progression.5,33-39 Doxorubicin 75 mg/m2 has been used as the control arm of a phase III study in which metastatic breast cancer patients, who failed an alkylating-containing regimen, were randomized to receive either the doxorubicin treatment or docetaxel at the dose of 100 mg/m2 as a 1-hour infusion every 3 weeks.40 Among 196 assessable patients, docetaxel showed a higher response rate than the anthracycline. The results of that trial affect neither the interpretation of our study (because we are dealing with two different compounds and a different patient population) nor our conclusions. In fact, we do not believe that the main issue in the future will be which drug, either the anthracycline or the taxane, should be used as first-line treatment but what will be the best way of administering the two drugs together. The essential question to be addressed, therefore, is whether it would be preferable to combine reduced doses of paclitaxel and doxorubicin within a combination regimen or to give each drug at full dose in a sequential schedule. The American Intergroup Trial has shown that the combination of doxorubicin and paclitaxel 24-hour infusion is superior to both single agents in terms of RR and median time to treatment failure.27 Although very high remission rates were observed in pilot studies of paclitaxel given as a 3-hour infusion plus doxorubicin, a surprisingly high incidence of congestive heart failure was also reported.41,42 This was unexpected in view of the lack of cardiotoxicity reported in early studies with paclitaxel, in which only anecdotal asymptomatic cardiac rhythm disturbances were reported.43 Subsequent pharmacokinetic studies provided a plausible explanation for this phenomenon, suggesting a 30% increase in doxorubicin exposure when given before paclitaxel.44,45 Recent data suggest that the combination is safe provided that a total dose of 360 mg/m2 of doxorubicin is not exceeded.46 A recently completed IDBBC-ECSG randomized study has compared the safety and efficacy of six courses of doxorubicin 60 mg/m2 plus paclitaxel 175 mg/m2 (3-hour infusion) with a standard doxorubicin/cyclophosphamide combination. If the doxorubicin/paclitaxel combination proves superior to the control arm, single-agent paclitaxel could be offered as consolidation therapy to responding patients.47 Gianni et al47 have evaluated the cumulative response in 47 patients treated with doxorubicin plus paclitaxel in a 3-hour infusion for six or eight cycles followed by single-agent paclitaxel. Six treatment cycles were sufficient to achieve at least a partial response in all the responding patients, but continuing treatment with the taxane after the combination increased the patients’ chances of complete response. The sequential administration of doxorubicin and paclitaxel is very attractive as a strategy for overcoming the pharmacokinetic interaction between these two agents. Moreover, the data presented by Henderson et al48 at the American Society of Clinical Oncology in 1998 strongly suggest the benefit of using paclitaxel in sequence with a standard anthracycline-containing regimen in the adjuvant setting.48 At present, we can assert that single-agent doxorubicin, given at the dose of 75 mg/m2 every 3 weeks, is more active in terms of RR and PFS than paclitaxel 200 mg/m2 given as a 3-hour infusion every 3 weeks, as first-line treatment of metastatic breast cancer. No matter what sequence doxorubicin and paclitaxel are administered in, no total cross-resistance has been observed.
1. Fisher B, Osborne CK, Margolese RG, et al: Neoplasms of the breast, in Holland JF, Bast RC Jr, Morton DL, et al (eds): Cancer Medicine. Williams and Wilkins, Baltimore, MD; 1977, pp 2349-2429 2. De Lena M, Brambilla C, Morabito A, et al: Adriamycin plus vincristine compared to and combined with cyclophosphamide, methotrexate and fluorouracil for advanced breast cancer. Cancer 35:1108-1115, 1975[Medline] 3. Steiner R, Stewart JF, Cantwell BMJ, et al: Adriamycin alone or combined with vincristine in the treatment of advanced breast cancer. Eur J Cancer Clin Oncol 19:1553-1557, 1983[Medline] 4. Rubens RD, Begent RHJ, Knight RK, et al: Combined cytotoxic and progestogen therapy for advanced breast cancer. Cancer 42:1680-1686, 1978[Medline] 5. Richards MA, Hopwood P, Ramirez AJ, et al: doxorubicin in advanced breast cancer: Influence of the schedule on response, survival and quality of life. Eur J Cancer 28A:1023-1028, 1992 6. Wani MC, Taylor HL, Wall ME, et al: Plant antitumor agents: VI. The isolation and structure of Taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93:2325-2327, 1971[Medline] 7. Schiff PB, Fant J, Horwitz SB: Promotion of microtubule assembly in vitro by Taxol. Nature 77:665-667, 1979 8. Wall ME, Wani MC: Antineoplastic agents from plants. Ann Rev Pharmacol Toxicol 17:117-132, 1977[Medline]
9.
Holmes FA, Walters RS, Theriault RL: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797-1805, 1991 10. Hainsworth JD, Greco FA: Paclitaxel administered by 1-hour infusion. Cancer 74:1377-1382, 1994[Medline] 11. Seidman AD, Hudis CA, Norton L: Memorial Sloan-Kettering Cancer experience with paclitaxel in the treatment of breast cancer: From advanced disease to adjuvant therapy. Semin Oncol 22:3-8, 1995 (suppl 8)[Medline] 12. Seidman AD, Tiersten A, Hudis C, et al: Phase II trial of paclitaxel by 3-hour infusion as initial salvage chemotherapy for metastatic breast cancer. J Clin Oncol 13:2575-2581, 1995[Abstract]
13.
Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858-1867, 1996
14.
Gianni L, Munzone E, Capri G, et al: Paclitaxel in metastatic breast cancer: A trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines. J Natl Cancer Inst 87:1169-1175, 1995 15. Vermorken JB, ten Bokkel Huinink WW, Mandjes IAM, et al: High dose paclitaxel with granulocyte colony-stimulating factor in patients with advanced breast cancer refractory to anthracycline therapy: A European Cancer Center trial. Semin Oncol 22:16-22, 1995 (suppl 8)[Medline] 16. Holmes FA: Update: The M.D. Anderson Cancer Center experience with paclitaxel in the management of breast carcinoma. Semin Oncol 22:9-15, 1995 (suppl 8) 17. Seidman AD, Reichman BS, Crown JPA, et al: Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol 13:1152-1159, 1995[Abstract] 18. Abrams JS, Vena DA, Baltz J, et al: Paclitaxel activity in heavily pretreated breast cancer: A National Cancer Institute treatment referral center trial. Oncol 13:2056-2065, 1995
19.
Wilson WH, Berg SL, Bryant G, et al: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour infusion. J Clin Oncol 12:1621-1629, 1994 20. Seidman AD, Hochhauser D, Yao TJ, et al: 96-hour paclitaxel after prior short taxane infusion: Phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. Proc Am Soc Clin Oncol 14:113, 1995 (abstr 151) 21. MacDonald J, Haller D, Mayer R: Grading of toxicity, in MacDonald J, Haller D, Mayer R (eds): Manual of Oncologic Therapeutics. Philadelphia, PA,Lippincott, 1995, pp 519-523 22. De Haes JCJM, van Knippenberg FCE, Neijt JP: Measuring physiological and physical distress in cancer patients: Structure and application of the Rotterdam Symptom Checklist. Br J Cancer 62:1034-1038, 1990[Medline] 23. Hayward JL, Carbone PP, Heuson JC: Assessment of response to therapy in advanced breast cancer. Eur J Cancer 13:89-94, 1977 24. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. Assoc 53:457-481, 1958 25. Parmar MKB, Machin D: Survival analysis: A practical approach. Chichester, England,John Wiley and Sons, 1995 26. Cox DR: Regression models and life-tables. JR Stat Soc 34:187-202, 1972 27. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs paclitaxel vs doxorubicin plus paclitaxel as first line therapy for metastatic breast cancer: An Intergroup trial. Proc Am Soc Clin Oncol 16:1a, 1997 (abstr 2) 28. Winer E, Berry D, Duggan D, et al: Failure of higher dose paclitaxel to improve outcome in patients with metastatic breast cancer: Results from CALGB 9342. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 388) 29. Mamounas E, Brown A, Smith R, et al: Effect of Taxol duration of infusion in advanced breast cancer (ABC): Results from NSABP B-26 trial comparing 3- to 24-hour infusion of high-dose Taxol. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 389) 30. Holmes FA, Valero V, Buzdsar AU, et al: Final results: Randomized phase III trial of paclitaxel by 3-hour versus 96-hour infusion in patients (pt) with metastatic breast cancer (MBC)—The long & short of it. Proc Am Soc Clin Oncol 17:110a, 1998 (abstr 426) 31. Seidman AD, Hochhauser D, Gollub M: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. Oncol 14:1877-1882, 1996 32. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353-3361, 1998[Abstract] 33. Hoogstraten B, George SL, Samal B, et al: Combination chemotherapy and Adriamycin in patients with advanced breast cancer. Cancer 38:13-20, 1976[Medline] 34. Brambilla C, Rossi A, Bofante V, et al: Phase II study of doxorubicin versus epirubicin an advanced breast cancer. Treat Rep 70:261-266, 1986 35. Carmo-Pereira J, Costa FQ, Heriques E, et al: A comparison of two doses of Adriamycin in the primary chemotherapy of disseminated breast carcinoma. Br J Cancer 56:471-473, 1987[Medline] 36. Ingle JN, Mailliard JA, Schaid DJ, et al: Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer. Am J Clin Oncol 12:474-480, 1989[Medline]
37.
Jain KK, Casper ES, Geller NL, et al: A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 3:818-826, 1985 38. Gottlieb JA, Rivkin SE, Spigel SC, et al: Superiority of Adriamycin over oral nitrosoureas in patients with advanced breast carcinoma: A Southwestern Cancer Chemotherapy Group Study. Cancer 33:519-526, 1974[Medline] 39. Fredriksen PL, Joergensen ST, Roesdahl K, et al: Activity of Adriamycin in metastatic breast cancer resistant to combination regimen with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone. Cancer Treat Rep 62:449-450, 1978[Medline] 40. Chan S, Friedrichs K, Noël D, et al: A randomized phase III study of Taxotere (T) versus doxorubicin (D) in patients (pts) with metastatic breast cancer (MBC) who have failed an alkylating containing regimen: Preliminary results. Proc Am Soc Clin Oncol 16:154a, 1997 (abstr 540) 41. 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 study. Clin Oncol 13:2688-2699, 1995
42.
Gehl K, Boesgaard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7:687-693, 1996 43. Rowinski EK, Mc Guire WP, Guarnieri T, et al: Cardiac disturbances during the administration of Taxol. J Clin Oncol 9:1704-1712, 1991[Abstract]
44.
Holmes FA, Madden T, Newman R, 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
45.
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 46. Gianni L, Dombernowsky P, Sledge G, et al: Cardiac function following combination therapy with Taxol® (T) and doxorubicin (A) for advanced breast cancer (ABC). Proc Am Soc Clin Oncol 17:115a, 1998 (abstr 444) 47. Gianni L, Capri G: Experience at the Istituto Nazionale Turmori with paclitaxel in combination with doxorubicin in women with untreated breast cancer. Semin Oncol 24:S3-1-S3-3, 1997 (suppl 3) 48. 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 April 12, 1999; accepted October 29, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test and Fisher’s exact test were used to compare response rate and toxicity. The duration of response was computed from the date of randomization until documentation of PD. OS and PFS were estimated using the Kaplan-Meier method
