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© 2001 American Society for Clinical Oncology Multicenter Phase II Trial of Weekly Paclitaxel in Women With Metastatic Breast CancerByFrom the Mayo Clinic, Jacksonville; Columbia Cancer Research Network, Aventura, FL; Alta Bates Comprehensive Cancer Center, Berkeley; Comprehensive Blood and Cancer Center, Bakersfield, CA; and Hematology/Oncology Associates of Central New York, Syracuse, NY. Address reprint requests to Edith A. Perez, MD, Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; email: perez.edith{at}mayo.edu
PURPOSE: We evaluated the safety and efficacy of weekly paclitaxel therapy in women with metastatic breast cancer in a phase II multicenter trial. Entry criteria were relatively liberal to reflect the heterogeneity of metastatic breast cancer in clinical practice. PATIENTS AND METHODS: Patients had histologically confirmed and measurable metastatic breast cancer. Up to two prior chemotherapy regimens for metastatic disease, including prior therapy with anthracyclines and taxanes and prior high-dose therapy, were allowed. Paclitaxel 80 mg/m2 was administered weekly for 4 weeks per 4-week cycle.
RESULTS: We enrolled 212 patients; 211 were assessable for toxicity and 177 were assessable for response. Ninety percent of patients had received prior chemotherapy (adjuvant, metastatic, or both), 46% of patients had three or more involved metastatic sites, and 60% of patients had visceral-dominant disease. Responses were documented on two occasions and were independently reviewed. The overall response rate (complete plus partial response) was 21.5% (95% confidence interval, 15.4% to 27.5%), with 41.8% of patients having disease stabilization. Median time to progression was 4.7 months, and overall survival in all 212 patients enrolled was 12.8 months. Therapy was well tolerated, with a 15% incidence of grade 3/4 hematologic toxicity and a 9% incidence of grade 3 neurotoxicity; other serious toxicities were rare. The response rate and toxicity profile in the 34% of patients CONCLUSION: Weekly paclitaxel therapy was well tolerated and demonstrated reasonable activity in this relatively heavily pretreated population with advanced disease. Further study of weekly paclitaxel in combination therapy is warranted.
IN THE YEAR 2001, it is estimated that 192,200 women in the United States will be newly diagnosed with breast cancer and 40,200 women will die of their disease.1 Although advances in breast cancer detection and treatment have improved the odds of long-term survival, breast cancer remains the second most common cause of cancer-related death in women, surpassed only by lung cancer.1 With current treatment modalities, the long-term prognosis for women with early-stage disease is generally very good. However, few patients with metastatic disease will be long-term disease-free survivors.2 In the United States, metastatic disease as an initial diagnosis accounts for approximately 1% to 5% of new breast cancer cases. However, it is estimated that 20% to 30% of patients initially diagnosed with early-stage disease will eventually develop metastatic breast cancer.2 New treatment options for women with metastatic breast cancer are needed. Because many of these patients will have previously received chemotherapy, either as adjuvant therapy or for advanced disease, tolerability of treatment for metastatic disease is an important consideration. Paclitaxel is an effective agent in the treatment of metastatic breast cancer. Overall response rates of 21% to 62% have been reported in phase II and phase III trials evaluating paclitaxel at doses of 135 to 250 mg/m2 administered by either 3- or 24-hour infusion as initial or subsequent therapy to women with metastatic breast cancer.3-13 Neutropenia is generally the most common toxicity reported among these studies, although neuropathy can be dose-limiting, particularly with short infusions of paclitaxel. Recent reports of the activity and tolerability of weekly dosing of paclitaxel have generated much clinical interest. In women with metastatic breast cancer, studies administering paclitaxel weekly by 1-hour infusion at doses ranging from 80 to 100 mg/m2 have reported overall response rates of 50% to 68%.14-20 In general, weekly paclitaxel therapy has been quite well tolerated, causing minimal myelosuppression and no apparent cumulative myelosuppression. Neuropathy, when present, is usually of mild or moderate severity and generally reversible. Although the results of these trials of weekly paclitaxel in metastatic breast cancer have been encouraging, the individual trials reported to date have been relatively small, enrolling 30 or fewer patients. We conducted this large multicenter phase II trial of weekly paclitaxel to more fully characterize the activity and safety of this therapy in women with metastatic breast cancer. Given that several large clinical trials in breast cancer are currently investigating weekly paclitaxel-based regimens, the efficacy and toxicity information of weekly single-agent paclitaxel provided by this study may provide an important perspective for the interpretation of these clinical trials.
Eligibility Criteria Women with histologically or cytologically confirmed metastatic breast cancer with bidimensionally measurable or otherwise assessable and documentable disease, such as mediastinal or pleural-based masses or lytic bone metastases, were eligible for enrollment. Patients were required to be  18 years of age; have an Eastern Cooperative Oncology Group performance status of 0 to 2; have adequate bone marrow, renal, and liver function (absolute granulocyte count 1,500 µL, platelets 100,000 µL, serum creatinine and total bilirubin  two times the upper normal limit, and AST or ALT 2.5 times the upper normal limit); and provide informed consent per institution review board guidelines. Women of childbearing potential must have had a negative prestudy pregnancy test and practice appropriate contraception while on study.
Patients may have received up to two prior chemotherapy regimens for metastatic disease, and in addition may have received prior adjuvant chemotherapy, hormonal therapy, radiation therapy, and immunotherapy. Patients who had been treated with high-dose chemotherapy with stem-cell support were also eligible. Previous treatment with a taxane was allowed provided administration was on a Patients with asymptomatic brain metastases were eligible provided they had completed cranial irradiation more than 4 weeks before study entry therapy and had other assessable sites of disease. Prestudy evaluation included a complete history and physical examination, complete blood cell count with differential, platelet count, serum chemistries, ECG, and tumor measurement and appropriate radiographic or CT imaging for disease assessment.
Exclusion criteria included major surgery, radiation, chemotherapy, or immunotherapy within 3 weeks of study entry (5 weeks for prior nitrosourea, melphalan, or mitomycin therapy), or prior radiation to more than 30% of bone marrow. Patients with bone metastases as their only site of assessable disease were not eligible if bisphosphonate therapy had been initiated less than 2 months before enrollment. Patients with New York Heart Association class 3 or 4 heart disease were excluded, as were patients with preexisting peripheral neuropathy more than grade 1 and those with a corrected serum calcium level of
Study Design
Response and Toxicity Assessment
Tumor measurements for response assessment were obtained every three cycles (12 weeks), and all responses had to be confirmed by a second measurement after an additional 4 weeks. All response claims were independently reviewed. Patients must have completed at least one required on-study evaluation of their disease to be considered assessable for response. However, patients removed from study for disease progression before their first response assessment at 12 weeks were included as assessable provided they had received at least three weekly paclitaxel doses. Response criteria were as follows: complete response was defined as the disappearance of all clinical and radiographic evidence of disease determined on two observations at least 4 weeks apart, partial response was defined as a
Statistical Methods Duration of response was calculated from the day the response was first recorded until day of disease progression. Time to progression and overall survival were calculated from the day of study entry until the day of documented disease progression or death, respectively. Overall survival was calculated from the date of study enrollment until death. Patients who died without documented disease progression were censored on the day of death or last follow-up. Patients who did not expire were censored at the time they were last known to be alive. Time to progression and overall survival distributions were estimated using the Kaplan-Meier method.21
Quality-of-Life Analysis
The study enrolled 212 patients at 27 participating institutions. Patient characteristics are listed in Table 1. The majority of patients (88%) had an Eastern Cooperative Oncology Group performance status of 0 or 1, with comparable percentages for patients younger and older than 65 years. Nearly half of the patients had three or more sites of metastatic disease. Hepatic and/or visceral metastases were present in 72% of patients and were the dominant site of disease in 60% of patients. The time from diagnosis of breast cancer to study entry was more than 12 months in 183 patients (86%), 6 to 12 months in 11 patients (5%), and less than 6 months in 18 patients (9%).
The majority (90%) of patients had received prior chemotherapy, either as adjuvant treatment, therapy for metastatic disease, or both (Table 1). Prior treatment with anthracyclines was reported for 152 patients (72%). Anthracyclines were administered in the adjuvant or neoadjuvant setting in 67 of these patients, as therapy for metastatic disease in 76 patients, and as both adjuvant and metastatic therapy in nine patients. Time from prior anthracycline therapy was less than 3 months for 39 patients, 3 to 6 months for 14 patients, 6 to 12 months for 16 patients, and more than 12 months for 83 patients. The median number of days from prior anthracycline therapy was 462 (range, 21 to 3,185 days). A total of 54 patients (25%) had received prior taxane therapy; 38 patients had received paclitaxel, 15 patients had received docetaxel, and one patient had received both. The taxanes were administered primarily for treatment of metastatic disease, although five patients received paclitaxel as adjuvant therapy. Prior taxane therapy was administered on an every-3-to-4-weeks schedule except in two patients who received only one dose. Time from prior taxane therapy was less than 3 months for 28 patients, 3 to 6 months for 6 patients, 6 to 12 months for 9 patients, and more than 12 months for 11 patients. The median number of days from prior taxane therapy was 83 (range, 21 to 1,047 days). In addition, 20 patients (9%) had undergone prior high-dose therapy with stem-cell support. A total of 1,068 cycles of therapy were administered to 211 patients (one patient refused treatment). The median number of cycles delivered was four (range, 1 to 29)(Fig 1), with a mean weekly delivered dose of 77 mg/m2. Only 14% of doses were delayed or reduced, with 7% being delayed or reduced because of toxicity and 7% because of social or other reasons.
Toxicities Toxicity data were available for 211 patients who had received at least one dose of paclitaxel. Overall, therapy was generally well tolerated and manageable on an outpatient basis (Table 2). Grade 3 or 4 neutropenia occurred in 31 patients (15%). All but two patients who developed grade 3 or 4 neutropenia had received prior chemotherapy, and five of these patients had received prior high-dose chemotherapy. Grade 3 anemia was encountered in 18 patients (9%), and one patient each experienced grades 3 and 4 thrombocytopenia.
There were 30 patients (14%) enrolled with preexisting grade 1 neuropathy. Two of these patients eventually developed grade 3 neuropathy after five and 11 courses of therapy. Overall, the incidence of any grade of neuropathy was 69%; however, grade 3 neuropathy was encountered in only 20 patients (9%), and no patient experienced grade 4 neuropathy. The median number of courses of therapy until development of grade 2 or 3 neuropathy, including patients with preexisting grade 1 toxicity, was five courses (20 weeks) for either, and ranged from one to 13 courses. Grade 3 asthenia and arthralgia/myalgia occurred in 4% and 2% of patients, respectively. Other grade 3 nonhematologic toxicities were quite uncommon, occurring in no more than 1% of patients. Grade 4 nonhematologic toxicity was limited to one patient who experienced a severe anaphylactic reaction.
Given that 34% of patients enrolled were
Response All responses had to be documented on two occasions at least 4 weeks apart, and all reported responses were independently reviewed. In the 177 assessable patients, there were four complete responses (2.3%) and 34 partial responses (19.2%), for an overall response rate of 21.5% (95% confidence interval, 15.4% to 27.5%)(Table 3). The median duration of response was 251 days. Stable disease was achieved in 74 patients (41.8%).
In 19 patients, initial response observations were not documented on a second occasion as required. For 10 of these patients, it was because follow-up evaluations were not performed 4 weeks later, and these patients were classified as having stable disease. However, if responses documented on one occasion were to be considered, the potential response rate in the 177 assessable patients would be 32.2% (95% confidence interval, 25.3% to 39.1%), with six complete responses (3.4%) and 51 partial responses (28.8%). The overall response rates did not differ among patients with zero, one, or two prior chemotherapy regimens for metastatic disease (Table 3). Responses occurred in 23 (17.6%) of the 131 assessable patients who had received prior anthracycline therapy and in seven (15.6%) of the 45 assessable patients who had received prior taxane therapy. These overall response rates were not different between patients who had received prior therapy with either an anthracycline or a taxane and those who did not. Response rates were not different among patients who had received prior adjuvant therapy, those who had received prior high-dose therapy, those with visceral dominant disease, or those with three or more sites of metastatic disease compared with those who did not. Because of sample-size considerations, the power to detect significant differences in theses subset analyses was limited. This limited power and the fact that baseline characteristics among the subsets were not necessarily balanced precluded more in-depth analyses.
In the cohort of 56 assessable patients age
Median follow-up time was 336 days (11 months) and ranged from 8 to 997 days. The median time to progression for assessable patients was 142 days (4.7 months)(Fig 2). Median times to progression for patients who had received no prior chemotherapy for metastatic disease, one prior regimen, and two prior regimens were 174 days (5.7 months), 140 days (4.6 months), and 85 days (2.7 months), respectively. The median time to progression for patients age
The median overall survival for all 212 patients was 387 days (12.8 months)(Fig 3). Median overall survival times were 562 days (18.6 months) for patients who had received no prior chemotherapy for metastatic disease, 378 days (12.5 months) for patients with one prior regimen, and 296 days (9.7 months) for patients with two prior regimens. The median overall survival time for patients 65 years of age was 384 days (12.7 months).
Quality of Life Compliance in completing the quality-of-life questionnaires was good. Baseline and subsequent data were available for 145 (78%) of 187 patients at cycle 2, 120 (75%) of 160 patients at cycle 3, 95 (77%) of 124 patients at cycle 4, 68 (71%) of 96 patients at cycle 5, 55 (75%) of 73 patients at cycle 6, and 16 (32%) of 50 patients at cycle 7. There were no differences in FACT-B total scores between baseline and any subsequent cycle. For the FACT-Taxane analysis, significant differences were noted between baseline and course 4 (P = .045) and baseline and course 5 (P = .015). In both cases, the mean total score was higher at baseline, indicating a higher quality of life. For subscale analyses, significant differences were noted between baseline and all subsequent cycles for emotional well-being, with P values ranging from less than .001 to .021. Significant differences from baseline scores in the social/family well-being subscale were seen at cycles 3, 4, and 5 (P = .006, .026, and .010, respectively). For functional well-being, a significant difference was noted only between baseline and cycle 5 (P = .029). In all cases, mean scores were higher at baseline. There were no differences between baseline and subsequent cycles for the additional concerns–breast subscale. However, the additional concerns–taxane subscale did show significant differences between baseline and cycles 3 through 7, with P values ranging from less than .001 to .044. Analyses were also performed to determine potential differences in scores among patients achieving complete or partial remission, stable disease, and those with disease progression. For patients achieving a complete or partial response compared with patients with stable disease or those with disease progression, the total mean FACT-B scores were significantly higher at cycles 3 and 5 (P = .026 and .013, respectively). In the FACT-Taxane analysis, scores for patients achieving a complete or partial response were significantly higher at cycles 2, 3, and 5 compared with patients with either stable disease or disease progression (P = .018, .013, and .021, respectively).
In this phase multicenter II study, we endeavored to enroll a population of patients reflective of that seen in general clinical practice. Entry criteria allowed patients to have received up to two prior chemotherapy regimens for metastatic disease in addition to adjuvant chemotherapy. Nearly 70% of patients enrolled had received at least one prior chemotherapy regimen for metastatic disease. Also, 9% of patients had undergone prior high-dose therapy with stem-cell support. The disease burden of the patient population was substantial, as approximately half of the patients enrolled had three or more involved metastatic sites, 60% of patients had visceral-dominant disease, and 11% of patients had brain metastases. With weekly paclitaxel therapy, we observed an overall response rate of 21.5% in women with metastatic breast cancer, with all responses documented on two occasions and independently reviewed. Disease stabilization occurred in 41.8% of patients; thus it may be considered that 63.3% of the patients who received weekly paclitaxel had some benefit from therapy. Responses were observed with equal frequency in all subgroups assessed, including patients who had received prior anthracycline or taxane therapy, those with visceral dominant disease, and those with three or more involved metastatic sites. Direct comparison of response rates from one trial to another is inherently difficult, given that studies often differ with respect to entry criteria and population characteristics. Nevertheless, overall response rates of 21% to 49% have been reported from other multicenter trials of single-agent paclitaxel administered at doses of 135 to 250 mg/m2 by 3- or 24-hour infusion every 3 weeks in women with metastatic breast cancer.3-8 In all but one of these studies, patients were limited to one prior chemotherapy regimen for metastatic disease. Thus our response results are within the range observed in other trials of paclitaxel, particularly if prior treatment characteristics and extent of disease are considered. We found weekly paclitaxel therapy to be well tolerated by the majority of patients, supported by the facts that the median duration of therapy was 16 weeks and few patients required dose delays or adjustments. In agreement with other studies of weekly paclitaxel, few patients (15%) encountered serious hematologic toxicity. Grade 3 neuropathy, occurring in 9% of patients, developed after a median of 20 weeks of therapy. Other serious toxicities were uncommon.
An important finding is that patients Quality of life was maintained relatively well in patients treated with weekly paclitaxel, reflected by the fact that there were no significant differences between total scores at baseline and any subsequent cycle for the FACT-B instrument. Differences from baseline quality of life assessed by the FACT-Taxane instrument appeared only in cycles 4 and 5, or after 16 weeks of therapy. There were significant differences from baseline in several subscales, including social well-being and function well-being; however, overall quality of life was reasonably well maintained throughout the course of therapy. Quality-of-life scores improved with therapy for patients achieving complete or partial responses, a finding that has been observed in other breast cancer studies.24,25 Therapy with weekly paclitaxel was well tolerated and demonstrated activity in metastatic breast cancer patients. Although the response rate we observed is lower than that of previously reported single-institution trials of weekly paclitaxel therapy, it is similar to that observed in several multicenter trials of every-3-weeks paclitaxel regimens. Also, the relatively liberal entry criteria allowed, the strict response requirements, and the advanced stage of disease of many of the patients on this trial should be taken into consideration with respect to the response rate observed. Also, because disease stabilization can be a meaningful outcome of therapy for patients with metastatic breast cancer, one interpretation of these data is that 63% of patients had some benefit from therapy. This trial confirms the tolerability of weekly paclitaxel therapy in women with advanced breast cancer noted in several other trials.14-20 The mild toxicity profile also makes weekly paclitaxel a viable candidate for combination with other agents. Studies evaluating weekly paclitaxel in combination with agents such as trastuzumab and carboplatin are currently underway. Ongoing studies comparing the efficacy and tolerability of weekly paclitaxel versus every-3-to-4-weeks administration schedules will help further define the role of this taxane in breast cancer therapy.
Supported by grants from Bristol-Myers Squibb Oncology, Princeton, NJ, and the Breast Cancer Research Foundation, New York, NY.
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Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83: 1797-1805, 1991 14. 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] 15. Waintraub SE, Cantwell S, DeVries J, et al: Phase II study to evaluate the efficacy of weekly paclitaxel (WP) in patients with metastatic breast cancer (MBC) who have failed prior anthracycline (A) +/- taxane (T) therapy. Proc Am Soc Clin Oncol 19: 121a, 2000 (abstr 470) 16. Sola C, Lluch A, Garcia-Conde J, et al: Phase II study of weekly paclitaxel (P) treatment in recurrent breast cancer after high-dose chemotherapy (HDC). Proc Am Soc Clin Oncol 18: 65a, 1999 (abstr 245) 17. Mickiewicz E, Alvarez AM, Brosio C, et al: A promising second line treatment with weekly Taxol (T) in anthracycline recurrent, advanced breast cancer (ABC) patients (PTS). Proc Am Soc Clin Oncol 18: 135a, 1999 (abstr 515) 18. Alvarez AM, Mickiewicz E, Brosio C, et al: Reinduction of response with weekly Taxol (T) in advanced breast cancer (ABC). Proc Am Soc Clin Oncol 18: 165a, 1999 (abstr 636) 19. Breier S, Lebedinsky C, Ayuvuru A, et al: Long-term weekly paclitaxel (P) in metastatic breast cancer (MBC): A phase II trial in pretreated patients (pts). Proc Am Soc Clin Oncol 17: 192a, 1998 (abstr 740) 20. Chang AY, Boros L, Asbury R, et al: Dose-escalation study of weekly 1-hour paclitaxel administration in patients with refractory cancer. Semin Oncol 24: S17-69–S17-71, 1997 (suppl 17) 21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
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Geels P, Eisenhauer E, Bezjak A, et al: Palliative effect of chemotherapy: Objective tumor response is associated with symptom improvement in patients with metastatic breast cancer. J Clin Oncol 18: 2395-2405, 2000 Submitted September 26, 2000; accepted June 26, 2001.
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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 test. 
