Weekly Paclitaxel Improves Pathologic Complete Remission in Operable Breast Cancer When Compared With Paclitaxel Once Every 3 Weeks
http://www.100md.com
《临床肿瘤学》
The University of Texas M.D. Anderson Cancer Center, Houston, TX
Brown University, Providence, RI
ABSTRACT
PURPOSE: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST).
PATIENTS AND METHODS: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy.
RESULTS: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05).
CONCLUSION: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.
INTRODUCTION
The use of anthracyclines in combination therapy is superior to the use of nonanthracycline-containing regimens. Anthracyclines have become a key component of routine care for patients with breast cancer.1 Paclitaxel induces high response rates when administered once every 3 weeks to treat metastatic breast cancer (23% to 56%) and has a non–cross-resistant mechanism of action when compared with anthracyclines.2-5 Several studies have evaluated the use of paclitaxel in the adjuvant setting.6-9 The addition of paclitaxel to anthracycline-based therapy improves both disease-free survival and overall survival for patients with node-positive early-stage breast cancer. Dose-dense paclitaxel (paclitaxel given on a frequent or weekly schedule) has been shown to be a safe and effective treatment of metastatic breast cancer, inducing tumor responses in more than 50% of patients with metastatic breast cancer.10,11 Recent retrospective data evaluating patients with metastatic breast cancer has demonstrated that weekly administration of paclitaxel is associated with both improved response rate and time to tumor progression when compared with the standard every-3-week paclitaxel.12 A phase II study published in 199713 was among the first to demonstrate that dose intensity as well as dose density of paclitaxel could have an impact on response rate for patients with locally advanced or metastatic breast cancer.
Our current study was designed to determine whether a change in the schedule from administering paclitaxel once every 3 weeks to once every week could impact the disease-free survival rates for patients with early-stage breast cancer. Another important end point was the determination of the pathologic complete response (pCR) rate in the breast and lymph nodes when patients with invasive breast cancer were treated with primary systemic chemotherapy (PST). This article presents the pathologic response data for this randomized phase III trial.
PATIENTS AND METHODS
Patients
All patients with histologically confirmed noninflammatory clinical T1-3, N0-1, and M0 (including T1N0 and T0N1) invasive carcinoma of the breast were eligible for this study. For patients receiving PST, all patients had to have bidimensional measurable locoregional disease and had to have not received local therapy for their cancer. Patients were required to have adequate bone marrow function (peripheral granulocyte count of 1,500/mm3 and platelet count 100,000/mm3). Adequate liver function with a bilirubin within normal laboratory values was required. Serum creatinine was required to be less than 2.5 mg/100 mL. Patients with uncompensated congestive heart failure were excluded. Patients with a concomitant or prior history of other invasive carcinoma, except for localized squamous cell or basal cell carcinoma of the skin or in situ squamous cell carcinoma of the cervix, were excluded. Two institutions participated in this clinical study: The University of Texas M.D. Anderson Cancer Center (Houston, TX) and the Brown University Oncology Group (Providence, RI). The institutional review boards of both institutions approved the study. Patients were instructed regarding the investigational design of this study and were required to sign a written institutional review board–approved informed consent form in compliance with institutional and federal regulations.
Clinical, Radiologic, and Pathologic Evaluation
Before initiation of therapy, all patients underwent an evaluation that included a complete medical history and physical examination, a complete blood count, chemistry profile, chest radiograph, liver ultrasound or computed tomography scan of the liver, and a bone scan. Bone scan and imaging studies of the liver for stage I patients were optional.
Patients were diagnosed with invasive cancer by either core biopsy or incisional biopsy. All tumors were evaluated by immunohistochemistry (IHC) for estrogen (ER) and progesterone (PR) receptors as well as Her-2/neu by IHC and/or fluorescence in situ hybridization (FISH). Patients were determined to have Her-2/neu positive disease if they were either 3+ by IHC or if they were determined to have gene amplification by FISH. Patients who underwent incisional biopsy were required to have residual measurable disease (either in the breast and/or axilla) in order to be included in the trial. All patients had baseline bilateral mammogram and an ultrasound of the affected breast and ipsilateral nodal basin.
Patients with lymph nodes that seemed palpable or abnormal by ultrasound examination underwent fine needle aspiration (FNA) to diagnose metastasis. Therefore, all patients assessed to have node-positive disease had cytologic confirmation of lymph node metastases.
Members of the medical, surgical, and radiation teams evaluated each patient. Tumor measurements were recorded in centimeters. Patients underwent clinical evaluation of the tumor before each cycle of therapy. Patients also underwent mammogram and ultrasound evaluation of the breast and axilla after completion of both paclitaxel and fluorouracil/doxorubicin/cyclophosphamide (FAC). Guided by ultrasound, metallic coils were placed in the tumor bed to indicate the primary tumor site for patients who might have breast-conserving surgery at the completion of the chemotherapy.
Complete clinical response (CR) was defined as the clinical absence of all evidence of active tumor in the breast and lymph nodes. Partial response was defined as a 50% reduction in the product of the perpendicular diameters of the measurable lesion(s) without progression of any lesion or appearance of any new disease. Stable disease was defined as no change, or as a decrease in tumor measurements insufficient to qualify as a partial remission. Progression of disease was defined as a 25% increase in size of (any) tumor and/or the appearance of new lesions. Combined clinical response included mammographic and ultrasound evaluations combined with physical examination.
The breast and all excised axillary lymph nodes were fully evaluated at the time of surgery. Residual gross tumor was measured in three dimensions. Specimens without a residual gross tumor mass were sectioned and radiographed for comparison with mammograms. The entire tumor bed was submitted for histopathologic analysis. Axillary lymph nodes were entirely submitted for histopathologic analysis. Complete pathologic response was defined as no histopathologic evidence of any residual invasive cancer cells in the breast or axillary lymph nodes.
Treatment Plan
The overall treatment schema for patients treated with PST is shown in Figure 1. All patients were prospectively registered for the study in our online institutional research database, regardless of the site of enrollment. Patients were stratified by age (< 50 years or 50 years), tumor size, and by nodal status (N0 or N1).
Chemotherapy
Paclitaxel. The chemotherapy schema for paclitaxel is shown in Figure 2. All chemotherapy was administered in the outpatient setting. Patients assigned to the once-every-3-weeks arm received paclitaxel 225 mg/m2 administered as a continuous intravenous infusion over a period of 24 hours on day 1. Patients received dexamethasone 20 mg, diphenhydramine 50 mg, and cimetidine 300 mg intravenously 30 minutes before chemotherapy. Therapy was given every 21 days for four cycles before receiving FAC.
Patients assigned to doses of weekly paclitaxel received different doses based on their nodal status because of the potential toxicity associated with "high-dose" weekly paclitaxel. Patients that were at a lower perceived risk of recurrence (node-negative) received a more standard dose of weekly paclitaxel. Only patients perceived to be at a higher risk of recurrence (node-positive) received dose-intense weekly paclitaxel therapy. Patients who were randomly assigned to weekly paclitaxel and had a lymph node metastasis diagnosed by FNA initially received paclitaxel 175 mg/m2 given as a 3-hour intravenous infusion every week for 6 weeks followed by a 2-week break. This constituted one cycle of therapy. Patients randomly assigned to this dose/schedule received two cycles of treatment. However, analysis of toxicity after the first cohort of patients (n = 13) revealed unacceptable levels of grade 3 neurotoxicity (76.9%), and the dose of paclitaxel was therefore reduced to 150 mg/m2, maintaining the same schedule.
Evaluation of the second cohort of patients treated with high-dose paclitaxel at 150 mg/m2 (n = 14) showed a reduction in grade 3 neurotoxicity (50%) but that an increasing number of patients had delay in delivery of their dose at week 4 due to neutropenia.14 Therefore, the schedule of paclitaxel was changed for this group. The remainder of the patients treated with high-dose weekly paclitaxel (n = 29) received 150 mg/m2 over a period of 3 hours every week for 3 weeks, followed by a one-week rest. This constituted one cycle of therapy. Four cycles of paclitaxel were administered at this dose and schedule to the remainder of the patients with lymph node involvement who were randomly assigned to receive weekly paclitaxel therapy. Patients receiving high-dose weekly paclitaxel received dexamethasone 20 mg intravenously 30 minutes before chemotherapy. Diphenhydramine 50 mg and cimetidine 300 mg were optional.
The clinically N0 patients randomly assigned to the weekly schedule received paclitaxel 80 mg/m2 administered as an intravenous infusion over a period of 1 hour every week for 12 weeks. Dexamethasone 10 mg was given intravenously 30 minutes before paclitaxel for the first three doses. If the patient had no symptoms or signs of allergic reaction to paclitaxel, then the dose of dexamethasone was decreased to 5 mg intravenously 30 minutes before chemotherapy.
FAC. FAC chemotherapy consisted of fluorouracil 500 mg/m2 administered intravenously on days 1 and 4; cyclophosphamide 500 mg/m2 administered intravenously on day 1; and doxorubicin 50 mg/m2 administered as a 72-hour continuous intravenous infusion through a central catheter. FAC was administered every 21 days for four cycles to all patients after completion of all doses of paclitaxel. All chemotherapy (paclitaxel x 4 and FAC x 4) was given before locoregional therapy.
Dose modification criteria. National Cancer Institute toxicity criteria version 2.0 was used to assess all treatment-related toxicities. Of the patients receiving low-dose weekly paclitaxel (80 mg/m2/wk), the dose of paclitaxel was reduced by 25% for those patients with neurotoxicity of NCI grade 3 or higher. Of the patients receiving high-dose weekly paclitaxel (175 or 150 mg/m2), if they developed grade 3 NCI neurotoxicity, the paclitaxel dose was stopped until the neurotoxicity diminished to grade 2 or lower, and then paclitaxel was resumed at 80 mg/m2 for the remainder of the cycles. If a patient receiving high-dose weekly paclitaxel had NCI grade 2 neurotoxicity on the day therapy was due to be administered, the paclitaxel dose was reduced to 80 mg/m2 for the remaining doses. If the dose of paclitaxel was reduced to 80 mg/m2, the doses were delivered weekly without any breaks. The dose of weekly paclitaxel was reduced by 20% for other nonhematologic NCI grade 3/4 organ toxicities. While receiving FAC, the dose of FAC was reduced by 20% for nonhematologic toxicities that were NCI grade 3 or higher, if not controlled by conservative management. Patients did not receive routine hematopoietic growth factor (granulocyte colony stimulating factor). If a patient experienced neutropenic fever, granulocyte colony stimulating factor was prescribed.
Statistical Considerations
This report focuses on the neoadjuvant arm of a larger trial of 480 patients that will assess the impact of different schedules of paclitaxel, given as either PST or adjuvant therapy, on disease-free survival. The initial trial design anticipated that at least 220 of the 480 patients would present with intact tumors and therefore they would receive PST. This would thereby provide 80% power for a further objective to detect an 18% difference in clinical CR rates between groups treated with weekly or once-every-3-weeks paclitaxel schedules (two-sided type 1 error =.05). Because pCR is now recognized as a more reproducible measure of response and a better predictor of long-term patient outcomes, the analysis of results focuses on pathologic results, although clinical response results are also presented. pCR was defined as the absence of invasive cancer cells in both the breast and the lymph nodes. This definition allowed residual noninvasive breast cancer. The data presented here is defined as per the American Joint Committee on Cancer staging guidelines published in 2002.15
Clinical response was determined by physical examination. Combined clinical response was calculated by combining physical examination with mammogram and ultrasound. For patients randomly assigned to receive PST, but who received therapy in the adjuvant setting or for whom data was not sufficient for analysis of clinical response, clinical response was described as not assessable.
Tabulated response results were compared using the 2 test, or Fisher's exact test in the case of some small subsets. Results were compared separately for patients with N0 disease and those with N1 disease, and then combined using the Mantel-Haenszel method.
Compliance With Treatment
Of the 258 patients, one patient randomly assigned to receive paclitaxel once every 3 weeks and three patients randomly assigned to receive paclitaxel weekly chose to have surgery before receiving PST. In order to include all randomly assigned patients, the response results determined at the time of surgery for these patients were included, even though these patients had not had benefit from chemotherapy at that time. These patients received chemotherapy according to the randomized assignment, after surgery.
For another nine patients, surgical pathology results were not available. For six of these nine patients who were randomly assigned to once-every-3-weeks paclitaxel, reasons for unavailability were the following: treated at outside facility with no pathology report available (three patients), disease progression (two patients), and death secondary to sepsis (one patient). For three of these nine patients who were randomly assigned to weekly paclitaxel, reasons for unavailability were the following: treated at outside facility with no pathology report available (one patient), patient refused surgery (one patient), and disease progression (one patient). All of the nine patients were included in the totals as not achieving pCR in tabulations for the primary analyses, but were omitted from the tabulations regarding size of tumor involvement in breast and nodes if data were not sufficient for analysis.
RESULTS
Between November 1998 and July 2001, of the 480 patients enrolled onto the study, 258 patients with intact breast cancer received PST with either weekly or once-every-three-weeks doses of paclitaxel. The remaining patients enrolled onto the study received therapy in the adjuvant setting. Data regarding these patients will be described in a separate article. One hundred ten patients were documented to have axillary lymph node involvement after FNA of suspected lymph nodes. Of these 110 patients, 54 received paclitaxel once every 3 weeks and 56 patients received paclitaxel on a weekly schedule. One hundred forty-eight patients had normal appearing lymph nodes, based on physical examination and ultrasound. Seventy-three of these 148 patients received paclitaxel once every 3 weeks and 75 patients received paclitaxel on a weekly schedule. Table 1 lists the pretreatment patient and tumor characteristics. Approximately 70% of all patients had T2 tumors. Approximately 40% or more of all patients had cytologically proven lymph node involvement. More than half of all patients enrolled had hormone-receptor–positive tumors (ER and/or PR) and more than 70% of patients were Her-2/neu–negative by either IHC (0+, 1+, or 2+) or FISH.
Table 2 lists clinical response and combined clinical response to PST based on treatment schedule, as well as on the method of local therapy. The combined clinical response includes physical examination as well as mammogram/ultrasonography. Twenty-four percent of patients receiving paclitaxel once every 3 weeks obtained a clinical CR after completion of paclitaxel administration. Four patients receiving once-every-3-weeks paclitaxel had progression of disease on therapy, including one patient who progressed before receiving any therapy. Thirty-four percent of patients receiving weekly paclitaxel obtained a clinical CR after completion of paclitaxel. One patient developed metastatic progression on weekly paclitaxel therapy. There was no statistical difference in clinical response based on treatment schedule (P = .25). Breast-conserving therapy was completed for 48 patients who received paclitaxel once every 3 weeks compared with 61 patients who received paclitaxel on a weekly schedule (P = .05).
Table 3 lists the median cumulative dose of paclitaxel received per treatment arm as well as the relative median dose intensity per treatment arm calculated based on the cumulative dose/duration of therapy (weeks).
The pathologic response to therapy based on examination of the breasts and lymph nodes is listed in Tables 4 and 5. The pCR in the breast alone is listed in Table 6. Six patients who received once-every-3-weeks paclitaxel had measurable disease only in the axilla before chemotherapy (five patients' status after excisional biopsy; one patient T0). Ten patients who received weekly paclitaxel had undergone excisional biopsy and had measurable disease only in the axillae before chemotherapy. All of these patients were included in the intent-to-treat analysis.
After completion of once-every-3-weeks paclitaxel and FAC, 15.7% of patients had no residual disease in the breast and axillae. For those patients who received weekly paclitaxel followed by FAC, 28.2% of patients obtained a pathologic complete response in the breast and axillae (P = .02; Fig 3). The magnitude of response was similar for patients receiving paclitaxel once every 3 weeks, regardless of nodal status. For patients receiving differing doses of weekly paclitaxel, the magnitude of pCR was also similar.
An unplanned analysis of pCR in the breast and lymph nodes based on ER/PR status is listed in Table 7. Patients with ER/PR–negative tumors, as well as those with ER- and/or PR-positive tumors, receiving weekly paclitaxel had increased pCR rates compared with those receiving once-every-3-weeks paclitaxel (P = .007). Patients with ER/PR–negative tumors had a higher pCR rate compared with those patients with ER- and/or PR-positive tumors, regardless of the paclitaxel schedule administered. However, the magnitude of benefit observed with the use of weekly paclitaxel was increased in patients with ER- and/or PR-positive tumors (pCR, 22%) compared with those patients receiving once-every-3-weeks paclitaxel (pCR, 11%).
Toxicities of both treatment schedules are listed in Table 8. Patients initially randomly assigned to receive paclitaxel at a dose of 175 mg/m2 had an unacceptable level of grade 3 neurotoxicity (76.9%). With reduction of the dose of weekly paclitaxel to 150 mg/m2, neurotoxicity was reduced to 45.5%. Of the patients receiving weekly paclitaxel at a dose of 80 mg/m2/wk, 13.5% developed grade 3 neurotoxicity. The rate of infection was low for patients receiving weekly paclitaxel regardless of the dose of paclitaxel used.
DISCUSSION
Paclitaxel, when given on a standard once-every-3-weeks schedule following or preceding an anthracycline-containing regimen, improves disease-free and overall survival in patients with lymph-node–positive breast cancer.7,8,9 The activity of paclitaxel is directly related to the cell cycle. It is hypothesized that administration of paclitaxel on a more frequent or continuous schedule will improve the efficacy of this agent. Paclitaxel given on a frequent basis also potentially exhibits antiangiogenic and pro-apoptotic effects, thereby enhancing the efficacy of this schedule.16-18 For example, Symmans et al19 found that the apoptotic response to paclitaxel was almost complete within 4 days, suggesting that more frequent dosing (such as the weekly dose we tested in our study) of paclitaxel might be beneficial to maintain continued apoptotic response. A preclinical study20 also demonstrated that tumoral apoptotic response after paclitaxel treatment is associated with a significant decrease in interstitial pressure, and with vasodilatation and increased endothelial surface area. This decompression in the tumor continues for several days after the apoptotic response, so in humans, by day 7 there is probably still a period of favorable intratumoral perfusion and drug delivery to the cancer cells. Our prospective clinical trial was planned to evaluate whether the schedule of paclitaxel treatment affects the in vivo response to PST, as defined by the pathologic response in the breast and lymph nodes.
PST has many theoretical benefits. However, the timing of chemotherapy has not demonstrated definitively an impact on overall survival.21,22 The ability of a chemotherapy regimen to eradicate invasive breast cancer in the breast (and lymph nodes) has been retrospectively correlated with long-term survival.21-24 It can be hypothesized that any regimen that improves the pCR rate when compared with a known standard will likely be able to improve overall survival.25 Therefore, pCR may be a biologic surrogate to disease-free survival and overall survival. This feature of neoadjuvant chemotherapy is being studied prospectively in several randomized trials, including National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27.26
Several published studies have evaluated the use of taxanes as a component of PST. The majority of these are phase II studies evaluating anthracycline- and taxane-based therapy in the preoperative setting for locally advanced breast cancer with a wide range of pCR rates (8% to 22%) in a heterogeneous group of patients.27-29 The largest phase III study, NSABP B-27, compared patients receiving docetaxel once every 3 weeks for four cycles after four cycles of doxorubicin and cyclophosphamide (AC) with patients who only received four cycles of AC. Patients receiving AC followed by docetaxel achieved a pCR of 25.6% in the breast alone compared with a pCR of 13.7% for patients receiving only AC.26 In our study, the pCR in the breast alone was 21.2% for patients receiving once-every-3-weeks paclitaxel followed by FAC versus 31% for those patients receiving weekly paclitaxel followed by FAC. As our study was designed to evaluate both the breast and lymph nodes, direct comparisons across studies should be done with caution.
Many studies evaluating PST present the data regarding pCR in reference to the breast alone, as in NSABP B-27; however, residual disease in the axilla can negatively predict survival.24,30 Our study evaluates the pCR in the breast and axillae. When evaluated on an intent-to-treat basis, we have shown that changing the schedule of paclitaxel results in significantly improved ability to eradicate invasive cancer in both the breast and lymph nodes. If patients treated in the adjuvant setting despite being randomly assigned to PST are excluded from analysis, the results reveal that the pCR is still increased for patients receiving weekly paclitaxel (29%) compared with those receiving paclitaxel once every 3 weeks (16%). In addition, the difference in magnitude of pCR is maintained in both hormone-receptor–positive and –negative patients receiving weekly paclitaxel, with 22% of patients with ER- and/or PR-positive patients obtaining a pCR in the breast and lymph nodes compared with 11% for those patients treated with once-every-3-weeks paclitaxel and FAC.
Toxicities were not the same in the treatment groups. Patients randomly assigned to receive high-dose weekly paclitaxel had significant neurotoxicity limiting the usefulness of this dose for routine clinical use. Paclitaxel administered at a lower dose of 80 mg/m2 was very well tolerated, with a reduced risk of neutropenic fever and grade 3 neuropathy, compared with once-every-3-weeks paclitaxel. This is in keeping with the results of a randomized trial comparing weekly paclitaxel at low and high doses in the metastatic setting.31 One patient died of a treatment-related septic episode during the FAC portion of chemotherapy. This patient had been randomly assigned to receive the standard once-every-3-weeks paclitaxel followed by FAC.
Recent data from the Cancer and Leukemia Group B (CALGB) demonstrated that chemotherapy administered on a more "dose-dense" schedule (every 2 weeks) resulted in improved disease-free and overall survival compared with therapy given on a standard once-every-3-weeks schedule.8 It is possible that the main determinant of this difference in survival is the administration of paclitaxel on a more frequent schedule. This advantage is consistent with the results of our current study. We demonstrate a significant therapeutic improvement with weekly paclitaxel. This is possibly because a more frequent schedule is favorably aligned with the timing of pathophysiologic responses to paclitaxel in the tumor. In that circumstance, the advantages obtained from frequent administration of paclitaxel may outweigh the effects of higher dose. Although the ideal dose of weekly paclitaxel is not defined,; doses between 80 and 100 mg/m2 have demonstrated safety in the metastatic setting. Whether increasing, or even decreasing, the dose of paclitaxel will result in a superior outcome is to be determined. However, the high-dose weekly paclitaxel schedule in this study seems to not have had an impact on the magnitude of benefit, but the toxicity of the higher dose limits its utility. Additional follow-up will be needed in order to determine whether the change in schedule of paclitaxel improves survival for patients with operable breast cancer, and if so, whether dose intensity adds any benefit to the schedule change.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported in part by a research grant from Bristol-Meyers Squibb.
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; and in Green MC, Thomas E: Preoperative systemic therapy for operable breast cancer, in Singletary E (ed): Advanced Therapy of Breast Disease. Hamilton, Ontario, Canada, BC Decker, 2004, pp 479-488.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Brown University, Providence, RI
ABSTRACT
PURPOSE: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST).
PATIENTS AND METHODS: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy.
RESULTS: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05).
CONCLUSION: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.
INTRODUCTION
The use of anthracyclines in combination therapy is superior to the use of nonanthracycline-containing regimens. Anthracyclines have become a key component of routine care for patients with breast cancer.1 Paclitaxel induces high response rates when administered once every 3 weeks to treat metastatic breast cancer (23% to 56%) and has a non–cross-resistant mechanism of action when compared with anthracyclines.2-5 Several studies have evaluated the use of paclitaxel in the adjuvant setting.6-9 The addition of paclitaxel to anthracycline-based therapy improves both disease-free survival and overall survival for patients with node-positive early-stage breast cancer. Dose-dense paclitaxel (paclitaxel given on a frequent or weekly schedule) has been shown to be a safe and effective treatment of metastatic breast cancer, inducing tumor responses in more than 50% of patients with metastatic breast cancer.10,11 Recent retrospective data evaluating patients with metastatic breast cancer has demonstrated that weekly administration of paclitaxel is associated with both improved response rate and time to tumor progression when compared with the standard every-3-week paclitaxel.12 A phase II study published in 199713 was among the first to demonstrate that dose intensity as well as dose density of paclitaxel could have an impact on response rate for patients with locally advanced or metastatic breast cancer.
Our current study was designed to determine whether a change in the schedule from administering paclitaxel once every 3 weeks to once every week could impact the disease-free survival rates for patients with early-stage breast cancer. Another important end point was the determination of the pathologic complete response (pCR) rate in the breast and lymph nodes when patients with invasive breast cancer were treated with primary systemic chemotherapy (PST). This article presents the pathologic response data for this randomized phase III trial.
PATIENTS AND METHODS
Patients
All patients with histologically confirmed noninflammatory clinical T1-3, N0-1, and M0 (including T1N0 and T0N1) invasive carcinoma of the breast were eligible for this study. For patients receiving PST, all patients had to have bidimensional measurable locoregional disease and had to have not received local therapy for their cancer. Patients were required to have adequate bone marrow function (peripheral granulocyte count of 1,500/mm3 and platelet count 100,000/mm3). Adequate liver function with a bilirubin within normal laboratory values was required. Serum creatinine was required to be less than 2.5 mg/100 mL. Patients with uncompensated congestive heart failure were excluded. Patients with a concomitant or prior history of other invasive carcinoma, except for localized squamous cell or basal cell carcinoma of the skin or in situ squamous cell carcinoma of the cervix, were excluded. Two institutions participated in this clinical study: The University of Texas M.D. Anderson Cancer Center (Houston, TX) and the Brown University Oncology Group (Providence, RI). The institutional review boards of both institutions approved the study. Patients were instructed regarding the investigational design of this study and were required to sign a written institutional review board–approved informed consent form in compliance with institutional and federal regulations.
Clinical, Radiologic, and Pathologic Evaluation
Before initiation of therapy, all patients underwent an evaluation that included a complete medical history and physical examination, a complete blood count, chemistry profile, chest radiograph, liver ultrasound or computed tomography scan of the liver, and a bone scan. Bone scan and imaging studies of the liver for stage I patients were optional.
Patients were diagnosed with invasive cancer by either core biopsy or incisional biopsy. All tumors were evaluated by immunohistochemistry (IHC) for estrogen (ER) and progesterone (PR) receptors as well as Her-2/neu by IHC and/or fluorescence in situ hybridization (FISH). Patients were determined to have Her-2/neu positive disease if they were either 3+ by IHC or if they were determined to have gene amplification by FISH. Patients who underwent incisional biopsy were required to have residual measurable disease (either in the breast and/or axilla) in order to be included in the trial. All patients had baseline bilateral mammogram and an ultrasound of the affected breast and ipsilateral nodal basin.
Patients with lymph nodes that seemed palpable or abnormal by ultrasound examination underwent fine needle aspiration (FNA) to diagnose metastasis. Therefore, all patients assessed to have node-positive disease had cytologic confirmation of lymph node metastases.
Members of the medical, surgical, and radiation teams evaluated each patient. Tumor measurements were recorded in centimeters. Patients underwent clinical evaluation of the tumor before each cycle of therapy. Patients also underwent mammogram and ultrasound evaluation of the breast and axilla after completion of both paclitaxel and fluorouracil/doxorubicin/cyclophosphamide (FAC). Guided by ultrasound, metallic coils were placed in the tumor bed to indicate the primary tumor site for patients who might have breast-conserving surgery at the completion of the chemotherapy.
Complete clinical response (CR) was defined as the clinical absence of all evidence of active tumor in the breast and lymph nodes. Partial response was defined as a 50% reduction in the product of the perpendicular diameters of the measurable lesion(s) without progression of any lesion or appearance of any new disease. Stable disease was defined as no change, or as a decrease in tumor measurements insufficient to qualify as a partial remission. Progression of disease was defined as a 25% increase in size of (any) tumor and/or the appearance of new lesions. Combined clinical response included mammographic and ultrasound evaluations combined with physical examination.
The breast and all excised axillary lymph nodes were fully evaluated at the time of surgery. Residual gross tumor was measured in three dimensions. Specimens without a residual gross tumor mass were sectioned and radiographed for comparison with mammograms. The entire tumor bed was submitted for histopathologic analysis. Axillary lymph nodes were entirely submitted for histopathologic analysis. Complete pathologic response was defined as no histopathologic evidence of any residual invasive cancer cells in the breast or axillary lymph nodes.
Treatment Plan
The overall treatment schema for patients treated with PST is shown in Figure 1. All patients were prospectively registered for the study in our online institutional research database, regardless of the site of enrollment. Patients were stratified by age (< 50 years or 50 years), tumor size, and by nodal status (N0 or N1).
Chemotherapy
Paclitaxel. The chemotherapy schema for paclitaxel is shown in Figure 2. All chemotherapy was administered in the outpatient setting. Patients assigned to the once-every-3-weeks arm received paclitaxel 225 mg/m2 administered as a continuous intravenous infusion over a period of 24 hours on day 1. Patients received dexamethasone 20 mg, diphenhydramine 50 mg, and cimetidine 300 mg intravenously 30 minutes before chemotherapy. Therapy was given every 21 days for four cycles before receiving FAC.
Patients assigned to doses of weekly paclitaxel received different doses based on their nodal status because of the potential toxicity associated with "high-dose" weekly paclitaxel. Patients that were at a lower perceived risk of recurrence (node-negative) received a more standard dose of weekly paclitaxel. Only patients perceived to be at a higher risk of recurrence (node-positive) received dose-intense weekly paclitaxel therapy. Patients who were randomly assigned to weekly paclitaxel and had a lymph node metastasis diagnosed by FNA initially received paclitaxel 175 mg/m2 given as a 3-hour intravenous infusion every week for 6 weeks followed by a 2-week break. This constituted one cycle of therapy. Patients randomly assigned to this dose/schedule received two cycles of treatment. However, analysis of toxicity after the first cohort of patients (n = 13) revealed unacceptable levels of grade 3 neurotoxicity (76.9%), and the dose of paclitaxel was therefore reduced to 150 mg/m2, maintaining the same schedule.
Evaluation of the second cohort of patients treated with high-dose paclitaxel at 150 mg/m2 (n = 14) showed a reduction in grade 3 neurotoxicity (50%) but that an increasing number of patients had delay in delivery of their dose at week 4 due to neutropenia.14 Therefore, the schedule of paclitaxel was changed for this group. The remainder of the patients treated with high-dose weekly paclitaxel (n = 29) received 150 mg/m2 over a period of 3 hours every week for 3 weeks, followed by a one-week rest. This constituted one cycle of therapy. Four cycles of paclitaxel were administered at this dose and schedule to the remainder of the patients with lymph node involvement who were randomly assigned to receive weekly paclitaxel therapy. Patients receiving high-dose weekly paclitaxel received dexamethasone 20 mg intravenously 30 minutes before chemotherapy. Diphenhydramine 50 mg and cimetidine 300 mg were optional.
The clinically N0 patients randomly assigned to the weekly schedule received paclitaxel 80 mg/m2 administered as an intravenous infusion over a period of 1 hour every week for 12 weeks. Dexamethasone 10 mg was given intravenously 30 minutes before paclitaxel for the first three doses. If the patient had no symptoms or signs of allergic reaction to paclitaxel, then the dose of dexamethasone was decreased to 5 mg intravenously 30 minutes before chemotherapy.
FAC. FAC chemotherapy consisted of fluorouracil 500 mg/m2 administered intravenously on days 1 and 4; cyclophosphamide 500 mg/m2 administered intravenously on day 1; and doxorubicin 50 mg/m2 administered as a 72-hour continuous intravenous infusion through a central catheter. FAC was administered every 21 days for four cycles to all patients after completion of all doses of paclitaxel. All chemotherapy (paclitaxel x 4 and FAC x 4) was given before locoregional therapy.
Dose modification criteria. National Cancer Institute toxicity criteria version 2.0 was used to assess all treatment-related toxicities. Of the patients receiving low-dose weekly paclitaxel (80 mg/m2/wk), the dose of paclitaxel was reduced by 25% for those patients with neurotoxicity of NCI grade 3 or higher. Of the patients receiving high-dose weekly paclitaxel (175 or 150 mg/m2), if they developed grade 3 NCI neurotoxicity, the paclitaxel dose was stopped until the neurotoxicity diminished to grade 2 or lower, and then paclitaxel was resumed at 80 mg/m2 for the remainder of the cycles. If a patient receiving high-dose weekly paclitaxel had NCI grade 2 neurotoxicity on the day therapy was due to be administered, the paclitaxel dose was reduced to 80 mg/m2 for the remaining doses. If the dose of paclitaxel was reduced to 80 mg/m2, the doses were delivered weekly without any breaks. The dose of weekly paclitaxel was reduced by 20% for other nonhematologic NCI grade 3/4 organ toxicities. While receiving FAC, the dose of FAC was reduced by 20% for nonhematologic toxicities that were NCI grade 3 or higher, if not controlled by conservative management. Patients did not receive routine hematopoietic growth factor (granulocyte colony stimulating factor). If a patient experienced neutropenic fever, granulocyte colony stimulating factor was prescribed.
Statistical Considerations
This report focuses on the neoadjuvant arm of a larger trial of 480 patients that will assess the impact of different schedules of paclitaxel, given as either PST or adjuvant therapy, on disease-free survival. The initial trial design anticipated that at least 220 of the 480 patients would present with intact tumors and therefore they would receive PST. This would thereby provide 80% power for a further objective to detect an 18% difference in clinical CR rates between groups treated with weekly or once-every-3-weeks paclitaxel schedules (two-sided type 1 error =.05). Because pCR is now recognized as a more reproducible measure of response and a better predictor of long-term patient outcomes, the analysis of results focuses on pathologic results, although clinical response results are also presented. pCR was defined as the absence of invasive cancer cells in both the breast and the lymph nodes. This definition allowed residual noninvasive breast cancer. The data presented here is defined as per the American Joint Committee on Cancer staging guidelines published in 2002.15
Clinical response was determined by physical examination. Combined clinical response was calculated by combining physical examination with mammogram and ultrasound. For patients randomly assigned to receive PST, but who received therapy in the adjuvant setting or for whom data was not sufficient for analysis of clinical response, clinical response was described as not assessable.
Tabulated response results were compared using the 2 test, or Fisher's exact test in the case of some small subsets. Results were compared separately for patients with N0 disease and those with N1 disease, and then combined using the Mantel-Haenszel method.
Compliance With Treatment
Of the 258 patients, one patient randomly assigned to receive paclitaxel once every 3 weeks and three patients randomly assigned to receive paclitaxel weekly chose to have surgery before receiving PST. In order to include all randomly assigned patients, the response results determined at the time of surgery for these patients were included, even though these patients had not had benefit from chemotherapy at that time. These patients received chemotherapy according to the randomized assignment, after surgery.
For another nine patients, surgical pathology results were not available. For six of these nine patients who were randomly assigned to once-every-3-weeks paclitaxel, reasons for unavailability were the following: treated at outside facility with no pathology report available (three patients), disease progression (two patients), and death secondary to sepsis (one patient). For three of these nine patients who were randomly assigned to weekly paclitaxel, reasons for unavailability were the following: treated at outside facility with no pathology report available (one patient), patient refused surgery (one patient), and disease progression (one patient). All of the nine patients were included in the totals as not achieving pCR in tabulations for the primary analyses, but were omitted from the tabulations regarding size of tumor involvement in breast and nodes if data were not sufficient for analysis.
RESULTS
Between November 1998 and July 2001, of the 480 patients enrolled onto the study, 258 patients with intact breast cancer received PST with either weekly or once-every-three-weeks doses of paclitaxel. The remaining patients enrolled onto the study received therapy in the adjuvant setting. Data regarding these patients will be described in a separate article. One hundred ten patients were documented to have axillary lymph node involvement after FNA of suspected lymph nodes. Of these 110 patients, 54 received paclitaxel once every 3 weeks and 56 patients received paclitaxel on a weekly schedule. One hundred forty-eight patients had normal appearing lymph nodes, based on physical examination and ultrasound. Seventy-three of these 148 patients received paclitaxel once every 3 weeks and 75 patients received paclitaxel on a weekly schedule. Table 1 lists the pretreatment patient and tumor characteristics. Approximately 70% of all patients had T2 tumors. Approximately 40% or more of all patients had cytologically proven lymph node involvement. More than half of all patients enrolled had hormone-receptor–positive tumors (ER and/or PR) and more than 70% of patients were Her-2/neu–negative by either IHC (0+, 1+, or 2+) or FISH.
Table 2 lists clinical response and combined clinical response to PST based on treatment schedule, as well as on the method of local therapy. The combined clinical response includes physical examination as well as mammogram/ultrasonography. Twenty-four percent of patients receiving paclitaxel once every 3 weeks obtained a clinical CR after completion of paclitaxel administration. Four patients receiving once-every-3-weeks paclitaxel had progression of disease on therapy, including one patient who progressed before receiving any therapy. Thirty-four percent of patients receiving weekly paclitaxel obtained a clinical CR after completion of paclitaxel. One patient developed metastatic progression on weekly paclitaxel therapy. There was no statistical difference in clinical response based on treatment schedule (P = .25). Breast-conserving therapy was completed for 48 patients who received paclitaxel once every 3 weeks compared with 61 patients who received paclitaxel on a weekly schedule (P = .05).
Table 3 lists the median cumulative dose of paclitaxel received per treatment arm as well as the relative median dose intensity per treatment arm calculated based on the cumulative dose/duration of therapy (weeks).
The pathologic response to therapy based on examination of the breasts and lymph nodes is listed in Tables 4 and 5. The pCR in the breast alone is listed in Table 6. Six patients who received once-every-3-weeks paclitaxel had measurable disease only in the axilla before chemotherapy (five patients' status after excisional biopsy; one patient T0). Ten patients who received weekly paclitaxel had undergone excisional biopsy and had measurable disease only in the axillae before chemotherapy. All of these patients were included in the intent-to-treat analysis.
After completion of once-every-3-weeks paclitaxel and FAC, 15.7% of patients had no residual disease in the breast and axillae. For those patients who received weekly paclitaxel followed by FAC, 28.2% of patients obtained a pathologic complete response in the breast and axillae (P = .02; Fig 3). The magnitude of response was similar for patients receiving paclitaxel once every 3 weeks, regardless of nodal status. For patients receiving differing doses of weekly paclitaxel, the magnitude of pCR was also similar.
An unplanned analysis of pCR in the breast and lymph nodes based on ER/PR status is listed in Table 7. Patients with ER/PR–negative tumors, as well as those with ER- and/or PR-positive tumors, receiving weekly paclitaxel had increased pCR rates compared with those receiving once-every-3-weeks paclitaxel (P = .007). Patients with ER/PR–negative tumors had a higher pCR rate compared with those patients with ER- and/or PR-positive tumors, regardless of the paclitaxel schedule administered. However, the magnitude of benefit observed with the use of weekly paclitaxel was increased in patients with ER- and/or PR-positive tumors (pCR, 22%) compared with those patients receiving once-every-3-weeks paclitaxel (pCR, 11%).
Toxicities of both treatment schedules are listed in Table 8. Patients initially randomly assigned to receive paclitaxel at a dose of 175 mg/m2 had an unacceptable level of grade 3 neurotoxicity (76.9%). With reduction of the dose of weekly paclitaxel to 150 mg/m2, neurotoxicity was reduced to 45.5%. Of the patients receiving weekly paclitaxel at a dose of 80 mg/m2/wk, 13.5% developed grade 3 neurotoxicity. The rate of infection was low for patients receiving weekly paclitaxel regardless of the dose of paclitaxel used.
DISCUSSION
Paclitaxel, when given on a standard once-every-3-weeks schedule following or preceding an anthracycline-containing regimen, improves disease-free and overall survival in patients with lymph-node–positive breast cancer.7,8,9 The activity of paclitaxel is directly related to the cell cycle. It is hypothesized that administration of paclitaxel on a more frequent or continuous schedule will improve the efficacy of this agent. Paclitaxel given on a frequent basis also potentially exhibits antiangiogenic and pro-apoptotic effects, thereby enhancing the efficacy of this schedule.16-18 For example, Symmans et al19 found that the apoptotic response to paclitaxel was almost complete within 4 days, suggesting that more frequent dosing (such as the weekly dose we tested in our study) of paclitaxel might be beneficial to maintain continued apoptotic response. A preclinical study20 also demonstrated that tumoral apoptotic response after paclitaxel treatment is associated with a significant decrease in interstitial pressure, and with vasodilatation and increased endothelial surface area. This decompression in the tumor continues for several days after the apoptotic response, so in humans, by day 7 there is probably still a period of favorable intratumoral perfusion and drug delivery to the cancer cells. Our prospective clinical trial was planned to evaluate whether the schedule of paclitaxel treatment affects the in vivo response to PST, as defined by the pathologic response in the breast and lymph nodes.
PST has many theoretical benefits. However, the timing of chemotherapy has not demonstrated definitively an impact on overall survival.21,22 The ability of a chemotherapy regimen to eradicate invasive breast cancer in the breast (and lymph nodes) has been retrospectively correlated with long-term survival.21-24 It can be hypothesized that any regimen that improves the pCR rate when compared with a known standard will likely be able to improve overall survival.25 Therefore, pCR may be a biologic surrogate to disease-free survival and overall survival. This feature of neoadjuvant chemotherapy is being studied prospectively in several randomized trials, including National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27.26
Several published studies have evaluated the use of taxanes as a component of PST. The majority of these are phase II studies evaluating anthracycline- and taxane-based therapy in the preoperative setting for locally advanced breast cancer with a wide range of pCR rates (8% to 22%) in a heterogeneous group of patients.27-29 The largest phase III study, NSABP B-27, compared patients receiving docetaxel once every 3 weeks for four cycles after four cycles of doxorubicin and cyclophosphamide (AC) with patients who only received four cycles of AC. Patients receiving AC followed by docetaxel achieved a pCR of 25.6% in the breast alone compared with a pCR of 13.7% for patients receiving only AC.26 In our study, the pCR in the breast alone was 21.2% for patients receiving once-every-3-weeks paclitaxel followed by FAC versus 31% for those patients receiving weekly paclitaxel followed by FAC. As our study was designed to evaluate both the breast and lymph nodes, direct comparisons across studies should be done with caution.
Many studies evaluating PST present the data regarding pCR in reference to the breast alone, as in NSABP B-27; however, residual disease in the axilla can negatively predict survival.24,30 Our study evaluates the pCR in the breast and axillae. When evaluated on an intent-to-treat basis, we have shown that changing the schedule of paclitaxel results in significantly improved ability to eradicate invasive cancer in both the breast and lymph nodes. If patients treated in the adjuvant setting despite being randomly assigned to PST are excluded from analysis, the results reveal that the pCR is still increased for patients receiving weekly paclitaxel (29%) compared with those receiving paclitaxel once every 3 weeks (16%). In addition, the difference in magnitude of pCR is maintained in both hormone-receptor–positive and –negative patients receiving weekly paclitaxel, with 22% of patients with ER- and/or PR-positive patients obtaining a pCR in the breast and lymph nodes compared with 11% for those patients treated with once-every-3-weeks paclitaxel and FAC.
Toxicities were not the same in the treatment groups. Patients randomly assigned to receive high-dose weekly paclitaxel had significant neurotoxicity limiting the usefulness of this dose for routine clinical use. Paclitaxel administered at a lower dose of 80 mg/m2 was very well tolerated, with a reduced risk of neutropenic fever and grade 3 neuropathy, compared with once-every-3-weeks paclitaxel. This is in keeping with the results of a randomized trial comparing weekly paclitaxel at low and high doses in the metastatic setting.31 One patient died of a treatment-related septic episode during the FAC portion of chemotherapy. This patient had been randomly assigned to receive the standard once-every-3-weeks paclitaxel followed by FAC.
Recent data from the Cancer and Leukemia Group B (CALGB) demonstrated that chemotherapy administered on a more "dose-dense" schedule (every 2 weeks) resulted in improved disease-free and overall survival compared with therapy given on a standard once-every-3-weeks schedule.8 It is possible that the main determinant of this difference in survival is the administration of paclitaxel on a more frequent schedule. This advantage is consistent with the results of our current study. We demonstrate a significant therapeutic improvement with weekly paclitaxel. This is possibly because a more frequent schedule is favorably aligned with the timing of pathophysiologic responses to paclitaxel in the tumor. In that circumstance, the advantages obtained from frequent administration of paclitaxel may outweigh the effects of higher dose. Although the ideal dose of weekly paclitaxel is not defined,; doses between 80 and 100 mg/m2 have demonstrated safety in the metastatic setting. Whether increasing, or even decreasing, the dose of paclitaxel will result in a superior outcome is to be determined. However, the high-dose weekly paclitaxel schedule in this study seems to not have had an impact on the magnitude of benefit, but the toxicity of the higher dose limits its utility. Additional follow-up will be needed in order to determine whether the change in schedule of paclitaxel improves survival for patients with operable breast cancer, and if so, whether dose intensity adds any benefit to the schedule change.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported in part by a research grant from Bristol-Meyers Squibb.
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; and in Green MC, Thomas E: Preoperative systemic therapy for operable breast cancer, in Singletary E (ed): Advanced Therapy of Breast Disease. Hamilton, Ontario, Canada, BC Decker, 2004, pp 479-488.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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