- Email: [email protected]
U.S. Experience in Neoadjuvant Therapy of Operable Breast Cancer
U.S. Experience in Neoadjuvant Therapy of Operable Breast Cancer Aman U. Buzdar and Gabriel N. Hortobagyi Primary systemic chemotherapy has become an integral part of treatment for patients with locally advanced or borderline inoperable patients. The objective of this manuscript was to review the US experience with preoperative chemotherapy in patients with operable breast cancer. National Surgical Adjuvant Breast and Bowel Project B-18 protocol was designed to determine whether preoperative doxorubicin cyclophosphamide would permit more lumpectomies to be performed and decrease the incidence of positive lymph nodes in women with primary breast cancer. This study established that preoperative chemotherapy reduced the size of most breast tumors and increased the lumpectomy rate after preoperative chemotherapy. The National Surgical Adjuvant Breast and Bowel Project B-27 protocol was designed to determine the effect of adding docetaxel after four cycles of doxorubicin cyclophosphamide on clinical and pathological response and on disease-free and overall survival. The addition significantly increased the clinical and pathological response rates, but the initial data showed no significant impact on event-free or survival rates, although it significantly reduced recurrence rates. M.D. Anderson Cancer Center (MDACC) ID94-002 study was designed to compare the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin (adriamycin), and cyclophosphamide; the data showed that single-agent paclitaxel as a neoadjuvant therapy had significant antitumor activity and its clinical efficacy was comparable to fluorouracil, doxorubicin (adriamycin), and cyclophosphamide. MDACC ID98-240 study was designed to determine if a change in the schedule of paclitaxel from once every 3 weeks to weekly administration would impact on the pathological complete response rates; the data demonstrated that the therapeutic index of paclitaxel was significantly enhanced when the drug was given on a weekly schedule. The MDACC ID99-146 trial’s primary objective was to compare the pathological complete response rates following chemotherapy alone to the same chemotherapy with trastuzumab in the neoadjuvant setting; data from this study illustrated that the addition of trastuzumab to chemotherapy significantly increased pathological complete response. Semin Breast Dis 7:108 –112 © 2004 Elsevier Inc. All rights reserved.
P
rimary systemic chemotherapy has become an integral part of the treatment of patients with locally advanced or borderline inoperable cancer.1,2 One of the most significant advantages of neoadjuvant chemotherapy is that it allows monitoring the response of the primary tumor to treatment. This is important because long-term outcome significantly correlates with clinical and, more importantly, pathological tumor response. Preoperative chemotherapy also has resulted in an increased rate of breast-conservation therapy in
Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Aman U. Buzdar, MD, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 424, Houston, TX 77030. E-mail: [email protected]
108
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.009
patients with larger tumors who would otherwise require mastectomy.3 Over the past 2 decades, multiple pilot or single-arm clinical trials have documented the clinical and pathological effects of neoadjuvant chemotherapy in locally advanced and large operable breast cancer. Such trials showed that chemotherapy was effective in the great majority of primary breast cancers, resulting in major regressions of primary tumors and regional lymph node deposits. Various combinations including anthracyclines, alkylating agents, vinca alkaloids, taxanes, platinum salts, and fluoropirymidines have been used, with most showing substantial efficacy. However, uncontrolled studies do not provide reliable information about the relative efficacy of a treatment regimen or informative data about time to progression or survival. Therefore, we focused this review on the few reported ran-
Neoadjuvant therapy of operable breast cancer domized trials on the subject of neoadjuvant chemotherapy conducted in the United States (Table 1). A companion paper reviews the European experience in this issue. Randomized trials provided evidence that systemic neoadjuvant therapy did not improve survival compared with the same chemotherapy regimen given as adjuvant treatment. The results of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 illustrated that preoperative chemotherapy was similar in efficacy to postoperative chemotherapy. The disease-free and overall survival rates of the two treatment arms were identical. With the established safety of preoperative chemotherapy, its use has been extended to patients with operable breast cancer. The objective of this manuscript was to review the US experience of preoperative chemotherapy in patients with operable breast cancer. The focus of this paper will be to include data from only randomized trials; the objective of this review is to determine what has been clearly established from these data and what areas of uncertainties remain.
Review of Data NSABP Studies NSABP B-18 Protocol This prospective study was designed to determine whether preoperative doxorubicin cyclophosphamide (AC) would permit more lumpectomies to be performed and decrease the incidence of positive lymph nodes in women with primary breast cancer.3 The study included 1523 patients; of these, 759 eligible women received postoperative AC, whereas 747 had preoperative AC. Tumor response to preoperative therapy was clinically evaluated as clinical complete response (cCR), partial response (cPR), stable disease (cSD), or progressive disease (cPD). The entire surgical specimen from patients with cCR was evaluated for pathological complete response (pCR), defined as no residual invasive breast cancer within the involved breast. In this study, breast tumor size was reduced by more than 50% in 80% of the patients after preoperative chemotherapy, and 36% achieved clinical complete response; tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with cCR had pCR. Clinical nodal response occurred in 89% of node-positive patients; 73% of these had a cCR, and 44% of those achieved a pCR. There was a 37% increase in the incidence of pathologically negative nodes in the patients treated with preoperative chemotherapy. Overall, 12% more lumpectomies were performed in the preoperative group of women with tumors ⱖ5.1 cm than in the group treated with surgery first. The data from this landmark study established that preoperative chemotherapy reduces the size of most operable breast tumors and decreases the incidence of positive nodes. Furthermore, there was an increase in lumpectomy rates after preoperative chemotherapy in patients with tumors ⬎5 cm. Approximately 13% of primary breast carcinoma cases exhibited both a cCR and a pCR to preoperative AC. An additional 7% of patients exhibited a pCR in the absence of cCR.
109 A pCR occurred in 38% of those determined to have achieved cCR. Poor nuclear grade of tumor cells determined in the pre-entry fine-needle aspiration (FNA) or true-cut specimens significantly predicted pCR. In this study, detailed evaluation of the lymph nodes was also correlated with outcome. Patients with micrometastases (⬍2 mm) or mini-micrometastases (⬍1 mm) detected by immunohistochemistry and true negative lymph node status (not converted to positive nodes by immunohistochemical studies) had different prognoses.4 Those with mini-micrometastases had significantly worse overall survival compared with those with true negative lymph node status (P ⫽ 0.0007). Disease-free survival was worse for the patients with micrometastases and mini-micrometastases compared with those with negative nodes, although it was better than that for patients with macrometastases (P ⫽ 0.02). The follow-up of this study illustrated that there were no significant differences in disease-free survival, distant disease-free survival, or overall survival among patients treated with preoperative chemotherapy and those who received the same therapy in the adjuvant setting. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy. Rates of ipsilateral breast tumor recurrences after lumpectomy were similar between the two groups (7.9% and 5.8%, respectively; P ⫽ 0.23). The outcome was better for women who had a pCR than for those with cPR or cNR. The authors of this study concluded that preoperative chemotherapy was an effective approach and as effective as postoperative chemotherapy; however, preoperative chemotherapy resulted in more lumpectomies for patients with stage I and stage II disease. It was further noted that combined modality therapy that includes preoperative chemotherapy was a good model for studying breast cancer biology. NSABP B-27 NSABP B-27 protocol was designed to determine the effects of adding docetaxel after four cycles of preoperative AC on cCR, pCR, and disease-free and overall survival of women with operable breast cancer.4 This study included 2411 women with operable breast cancer. Patients were randomly assigned to either 4 cycles of preoperative AC followed by surgery (n ⫽ 804) or 4 cycles of AC followed by 4 cycles of docetaxel followed by surgery (n ⫽ 805) or 4 cycles of AC followed by surgery and then 4 cycles of docetaxel (n ⫽ 802). cCRs and pCRs to preoperative chemotherapy were assessed. The addition of docetaxel increased the cCR rate from 40.2% to 63.6% (P ⫽ 0.001). Overall cCRs were 85.7% versus 90.7% for preoperative AC and preoperative AC and docetaxel, respectively (P ⫽ 0.001). pCR rates for the same two groups were 13.7% versus 26.1% (P ⫽ 0.001), and the proportions of patients with negative axillary nodes at the time of surgery were 50.8% versus 58.2% (P ⫽ 0.001) for AC alone and AC followed by docetaxel, respectively. Pathological primary tumor response was a significant predictor of pathological nodal status. The findings of this study provided evidence that the addition of four cycles of preoperative docetaxel after four cycles of preoperative AC significantly
110 increased the cCRs and pCRs for operable breast cancer patients. However, the recent presentation of the initial findings of this study at the 21st San Antonio Breast Cancer Symposium indicated no significant improvement in disease-free or overall survival rates with the addition of docetaxel, either pre- or postoperatively. However, after a median follow-up of 68 months, the study showed a significant reduction in the risk of recurrence. The detailed publication of the data in a peer-reviewed manuscript is anticipated to adequately evaluate the value of this approach.8
M.D. Anderson Cancer Center (MDACC) Randomized Neoadjuvant Chemotherapy Trials MDACC ID94-002 Study This study was designed to compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer.5 Patients received either paclitaxel 250 mg/m2 given as a 24-hour continuous infusion or FAC in the standard (M.D. Anderson) doses and schedule every 3 weeks. FAC chemotherapy consisted of fluorouracil 500 mg/m2 intravenously on days 1 and 4, cyclophosphamide 500 mg/m2 intravenously on day 1 only, and doxorubicin 50 mg/m2 given as a 72-hour continuous infusion through a central venous catheter. A total of 174 patients were registered on the study, with 87 patients randomized to each arm of the study. Approximately two thirds of patients had positive regional nodes on clinical examination, and 17% had stage IIIA disease. Major clinical responses (ie, complete and partial responses) were observed in 79.3% (21 cCRs and 48 cPR among 87 patients) following FAC therapy and 80.2% (23 cCRs and 46 cPR among 86 evaluable patients) after paclitaxel therapy (P ⫽ 0.85). Clinical objective response rates were similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel group had progressive disease. The extent of residual disease at the time of surgery by an intent-to-treat analysis was also similar in the two arms of the study. The pCRs were 17% and 8% for the FAC and paclitaxel arms of the study. A numerically higher number of patients (46%) in the paclitaxel arm of the study had breast preservation compared with the FAC arm (35%), but these differences were not significant (P ⫽ 0.30). The results of this prospective study demonstrated that singleagent neoadjuvant paclitaxel had significant antitumor activity, and this was clinically comparable to the results obtained with the long-established FAC regimen. Similar fractions of patients had clinical complete and partial responses, and very few patients failed to respond to either therapy. In this study, definitive local therapy was done after 12 weeks of therapy; however, in all our subsequent studies, all chemotherapy was delivered before local therapy, and the results of those studies are summarized below. MDACC ID98-240 Study The purpose of this study was to determine if a change in the schedule of paclitaxel from once every 3 weeks to weekly
A.U. Buzdar and G.N. Hortobagyi administration would impact on the pCR rate in patients with operable breast cancer treated with primary systemic chemotherapy.6 Patients with clinical stage I-IIIA breast cancer were randomized to receive paclitaxel either weekly (for a total of 12 doses of paclitaxel) or every 3 weeks (four cycles), followed by four cycles of FAC in standard doses given every 3 weeks. Two different doses of paclitaxel were used in the weekly schedule based on lymph node status defined by ultrasound and fine-needle aspiration. Patients that were deemed nodenegative received weekly paclitaxel at 80 mg/m2 administered as an intravenous infusion over 1 hour weekly for 12 weeks. Patients with lymph node metastasis (established cytologically by FNA) received dose-intense weekly paclitaxel therapy. These patients 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 randomized to this dose/schedule received two cycles of treatment. However, analysis of toxicity after the first cohort of patients revealed unacceptable grade 3 neurotoxicity (88.5%), and the dose of paclitaxel was reduced to 150 mg/m2, maintaining the same schedule. Evaluation of the second cohort of patients treated with high-dose paclitaxel 150 mg/m2 showed reduction in grade 3 neurotoxicity (50%), but an increasing number of patients had delay in delivery of their dose at week 4 because of neutropenia.2 Therefore, the schedule of paclitaxel was changed for this group. The remainder of the patients treated with high-dose weekly paclitaxel received 150 mg/m2 over 3 hours weekly for 3 weeks, followed by a 1-week rest. This constituted one cycle of therapy. Four cycles of paclitaxel were administered at this dose and schedule to the remainder of patients with positive lymph nodes randomized to receive weekly paclitaxel therapy. FAC chemotherapy was administered at the doses and schedules described above. FAC was administered every 21 days for 4 cycles to all patients after completion of all paclitaxel. All chemotherapy (paclitaxel ⫻ 4 and FAC ⫻ 4) was given before loco-regional therapy. A total of 258 patients were randomized to receive paclitaxel either weekly or every 3 weeks followed by FAC. Of these, 110 patients had histological lymph node involvement and 148 patients had clinically N0 disease. Weekly paclitaxel followed by FAC was given to 127 patients and paclitaxel every 3 weeks followed by FAC was given to 131 patients. cCRs to treatment were similar in the two groups (P ⫽ 0.08). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with every-3-week paclitaxel (15.7%; P ⫽ 0.02), resulting in improved breast-conservation rates (P ⫽ 0.05). The results of this study established that the change in schedule of paclitaxel from an every-3-week schedule to weekly administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes. The data from this study also demonstrated that the therapeutic index of paclitaxel could be significantly enhanced when the drug was given on a weekly schedule, and it increased the pCR rate by almost 100%. The two different doses of weekly paclitaxel evaluated in this study demonstrated that the lower
Neoadjuvant therapy of operable breast cancer
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Table 1 Summary of US Randomized Preoperative Chemotherapy in Patients With Operable Breast Cancer Design and Drugs NSABP Studies B-18 Protocol Preoper. AC vs AC adjuvant
B-27 Protocol Preop. AC vs AC ⴙ docetaxel vs preop. AC-surgery - docetaxel
MDACC Studies MDACC ID94-002 Study Clinical & pathological response Paclitaxel ⴛ 4 vs FAC ⴛ 4 MDACC ID98-240 Study Weekly paclitaxel ⴛ 2 weeks; Followed by FAC ⴛ 4 vs Q 3 weeks paclitaxel; Followed by FAC ⴛ 4 MDACC ID99-146 Study Paclitaxel ⴛ 4 > FAC ⴛ 4 vs same chemotherapy ⴙ 24 weeks of trastuzumab
Primary Objectives
Findings
Preoperative effect on breast preservation
Higher rates of lumpectomy; similar effect on disease-free or overall survival
Effect on cCR and pCR rates
Increased clinical and pathological ER rates with addition of docetaxel; no effect on disease-free or overall survival
Compare cCRs & pCRs of two therapies
Similar clinical responses High pCRs with FAC
Compare pCR by schedule of paclitaxel
Significantly high pCR rates with weekly paclitaxel
To determine effect of trastuzumab on pCR and safety of this combination
Significantly higher pCR Safety—no clinical congestive heart failure
dose of paclitaxel (80 mg/m2) provided improved efficacy with decreased toxicity; this schedule was recommended for further clinical use. The impact of weekly paclitaxel (as compared with every3-weeks paclitaxel) on disease-free and overall survival rates remains to be defined. However, similar results were observed in a prospective randomized trial conducted in patients with metastatic breast cancer. In that study, patients treated with weekly paclitaxel achieved a higher cCR rate compared with those treated with once every-3-weeks schedule. MDACC ID99-146 Trial The primary objective of this prospective study was to compare the pCR rates following chemotherapy alone to the same chemotherapy combined with trastuzumab in the neoadjuvant setting.7 Patients with operable, HER-2 positive (either immunohistochemistry (IHC) 3⫹, or fluorescence in situ hybridization (FISH)-positive) breast cancer (stage II or IIIA) were included in the study. Preoperative chemotherapy consisted of 4 cycles of paclitaxel (administered at 225 mg/m2 as a 24-hour continuous intravenous infusion) repeated every 3 weeks for 4 cycles. Following 4 cycles of paclitaxel, 4 cycles of 5-fluorouracil 500 mg/m2 intravenously on days 1 and 4, cyclophosphamide 500 mg/m2 intravenously on day 1 only, and epirubicin 75 mg/m2 on day 1 only were administered. In the experimental arm, patients received trastuzumab weekly simultaneously with the administration of chemotherapy, with the first dose at 4 mg/kg intravenously on day 1, then 2 mg/kg intravenously weekly for a total of 24 weeks. After completing all chemotherapy, patients had local therapy. This trial was designed to compare the complete pCR
between the two arms of the study; the projected pCR rate with the standard arm was estimated to be 21%, and the study was planned to detect a 20% improvement in that rate to 41%. Accrual of 164 patients was planned. With that number of patients, the study would have had 80% power to detect a 20% difference. pCR was defined as the absence of invasive cancer in the breast and in the lymph nodes. The Institutional Data Monitoring Committee reviewed the results obtained by the first 34 patients. The findings indicated that the 18 patents treated with chemotherapy and trastuzumab had a 66.7% pCR rate, whereas 25% of those treated with chemotherapy alone had pCRs (n ⫽ 16). The Institutional Data Monitoring Committee recommended closure of the trial because there was evidence of superiority in the pCRs in the trastuzumab and chemotherapy arm compared with the chemotherapy alone arm. This decision was based largely on the findings that if accrual continued to 164 patients, there would be a 95% probability that the trastuzumab with chemotherapy arm would be superior. The final results based on the 42 patients (chemotherapy alone, n ⫽ 19; and chemotherapy and trastuzumab, n ⫽ 23) randomized into this study based on an intent-to-treat analysis showed pCR rates of 26.3% and 65.2% for the chemotherapy alone and chemotherapy and trastuzumab arms, respectively (P ⫽ 0.016). To date, no clinical cardiac dysfunction has been observed; however, ⬎10% decreases in ejection fraction were observed in a small number of patients in both arms of the study, but none of the patients had any evidence of clinical congestive heart failure. Since these data became available, the protocol has been amended and additional patients were treated with chemotherapy and trastuzumab. Longer
A.U. Buzdar and G.N. Hortobagyi
112 follow-up of these and subsequent patients will provide additional safety and efficacy data and evidence as to whether this approach will result in improved disease-free and overall survival.
Discussion In the past two decades, use of preoperative chemotherapy has steadily increased. Preoperative chemotherapy provides important prognostic information, and this approach provides the data regarding the tumor’s sensitivity to systemic therapeutic agents. The extent of residual disease in the nodes and breast following preoperative chemotherapy still provides important prognostic information. Patients with persistent disease in the lymph nodes or large-volume residual tumor in the breast are at an increased risk of recurrence, and the risk is proportional to the number of nodes containing cancer. Patients who have not responded to initial therapy could be offered alternate therapies to evaluate the impact of this additional intervention on the clinical course of this disease. A couple of small studies have already provided validation of this approach. However, this approach needs to be validated in appropriately designed large randomized trials. The data of B-27 didn’t fully support the observation of the Aberdeen study regarding the addition of alternate noncross-resistant therapy with taxanes following an initial anthracycline-cyclophosphamide– containing drug regimen.9 There is a number possible explanations for this discrepancy. In the B-27 trial, all hormone receptor–positive patients received tamoxifen concomitant with chemotherapy. Simultaneous combination of tamoxifen with adjuvant chemotherapy has been shown to result in inferior relapse-free and overall survival rates compared with sequential administration. Therefore, this aspect of the design of B-27 might have compromised the outcome. B-27 also included a more favorable subset of patients, and it is possible that additional follow-up and more events are needed to confirm the value of additional taxane therapy. The preoperative chemotherapy model also provides an avenue to rapidly evaluate new promising agents with significant antitumor activity in patients with metastatic disease. This is highlighted by the initial positive results of the MDACC ID99-146 study. Trastuzumab is under evaluation in the adjuvant setting in over 12,000 patients, but so far no efficacy data are available. The data of our preoperative study suggest that the addition of trastuzumab to adjuvant chemotherapy will result in significant improvement in the longterm outcome of patients with HER-2–positive breast cancer. With this approach, one doesn’t need large numbers of patients or long observation periods to determine the effect of new therapies on the disease. The availability of tumor tissue before, during, and at the completion of therapy (if residual disease is still present) also
provides important information to further study the biology of the disease. This approach also identifies the subset of patients in whom currently available therapies have had little impact, as documented by large-volume residual disease left in the breast and or in the regional nodes. Novel therapies could be offered and evaluated in this very high-risk population before recurrence. These studies would require smaller numbers of patients and a much shorter follow-up time to evaluate newer agents. The role of preoperative chemotherapy in patients with operable breast cancer remains an area of discussion. However, at our institute we consider that if a patient with histologically confirmed breast cancer satisfies the indications for adjuvant chemotherapy, then we prefer the preoperative administration of chemotherapy. Patients not responding after 6 to 9 weeks of preoperative therapy are offered alternate therapies before local therapy. With this approach, patients are not continued on ineffective therapies, and thus the toxicities of ineffective therapies are avoided.
References 1. Hortobagyi GN: Comprehensive management of locally advanced breast cancer. Cancer 66:1387-1391, 1990 2. Jacquillat C, Weil M, Baillet F, et al: Results of neoadjuvant chemotherapy and radiation therapy in the breast-conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer 66:119-129, 1990 3. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18 [see comments]. J Clin Oncol 15:2483-2493, 1997 4. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:41654174, 2003 5. Buzdar AU, Singletary SE, Theriault RL et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412-3417, 1999 6. Green MC, Buzdar AU, Smith T, et al: Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr) 7. Buzdar AU, Hunt K, Smith T, et al: Significantly higher pathological complete remission (PCR) rate following neoadjuvant therapy with trastuzumab (H), paclitaxel (P), and anthracycline-containing chemotherapy (CT): Initial results of a randomized trial in operable breast cancer (BC) with HER/2 positive disease. Proc Am Soc Clin Oncol 23:7a, 2004 (abstr) 8. Bear HD, Anderson S, Smith RE, et al: A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: results of NSABP B-27. Breast Cancer Res Treat 88:S16, 2004 (suppl) 9. Smith IC, Heys SD, Hutcheon AW, et al: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20:1456-1466, 2002
P
rimary systemic chemotherapy has become an integral part of the treatment of patients with locally advanced or borderline inoperable cancer.1,2 One of the most significant advantages of neoadjuvant chemotherapy is that it allows monitoring the response of the primary tumor to treatment. This is important because long-term outcome significantly correlates with clinical and, more importantly, pathological tumor response. Preoperative chemotherapy also has resulted in an increased rate of breast-conservation therapy in
Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Aman U. Buzdar, MD, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 424, Houston, TX 77030. E-mail: [email protected]
108
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.009
patients with larger tumors who would otherwise require mastectomy.3 Over the past 2 decades, multiple pilot or single-arm clinical trials have documented the clinical and pathological effects of neoadjuvant chemotherapy in locally advanced and large operable breast cancer. Such trials showed that chemotherapy was effective in the great majority of primary breast cancers, resulting in major regressions of primary tumors and regional lymph node deposits. Various combinations including anthracyclines, alkylating agents, vinca alkaloids, taxanes, platinum salts, and fluoropirymidines have been used, with most showing substantial efficacy. However, uncontrolled studies do not provide reliable information about the relative efficacy of a treatment regimen or informative data about time to progression or survival. Therefore, we focused this review on the few reported ran-
Neoadjuvant therapy of operable breast cancer domized trials on the subject of neoadjuvant chemotherapy conducted in the United States (Table 1). A companion paper reviews the European experience in this issue. Randomized trials provided evidence that systemic neoadjuvant therapy did not improve survival compared with the same chemotherapy regimen given as adjuvant treatment. The results of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 illustrated that preoperative chemotherapy was similar in efficacy to postoperative chemotherapy. The disease-free and overall survival rates of the two treatment arms were identical. With the established safety of preoperative chemotherapy, its use has been extended to patients with operable breast cancer. The objective of this manuscript was to review the US experience of preoperative chemotherapy in patients with operable breast cancer. The focus of this paper will be to include data from only randomized trials; the objective of this review is to determine what has been clearly established from these data and what areas of uncertainties remain.
Review of Data NSABP Studies NSABP B-18 Protocol This prospective study was designed to determine whether preoperative doxorubicin cyclophosphamide (AC) would permit more lumpectomies to be performed and decrease the incidence of positive lymph nodes in women with primary breast cancer.3 The study included 1523 patients; of these, 759 eligible women received postoperative AC, whereas 747 had preoperative AC. Tumor response to preoperative therapy was clinically evaluated as clinical complete response (cCR), partial response (cPR), stable disease (cSD), or progressive disease (cPD). The entire surgical specimen from patients with cCR was evaluated for pathological complete response (pCR), defined as no residual invasive breast cancer within the involved breast. In this study, breast tumor size was reduced by more than 50% in 80% of the patients after preoperative chemotherapy, and 36% achieved clinical complete response; tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with cCR had pCR. Clinical nodal response occurred in 89% of node-positive patients; 73% of these had a cCR, and 44% of those achieved a pCR. There was a 37% increase in the incidence of pathologically negative nodes in the patients treated with preoperative chemotherapy. Overall, 12% more lumpectomies were performed in the preoperative group of women with tumors ⱖ5.1 cm than in the group treated with surgery first. The data from this landmark study established that preoperative chemotherapy reduces the size of most operable breast tumors and decreases the incidence of positive nodes. Furthermore, there was an increase in lumpectomy rates after preoperative chemotherapy in patients with tumors ⬎5 cm. Approximately 13% of primary breast carcinoma cases exhibited both a cCR and a pCR to preoperative AC. An additional 7% of patients exhibited a pCR in the absence of cCR.
109 A pCR occurred in 38% of those determined to have achieved cCR. Poor nuclear grade of tumor cells determined in the pre-entry fine-needle aspiration (FNA) or true-cut specimens significantly predicted pCR. In this study, detailed evaluation of the lymph nodes was also correlated with outcome. Patients with micrometastases (⬍2 mm) or mini-micrometastases (⬍1 mm) detected by immunohistochemistry and true negative lymph node status (not converted to positive nodes by immunohistochemical studies) had different prognoses.4 Those with mini-micrometastases had significantly worse overall survival compared with those with true negative lymph node status (P ⫽ 0.0007). Disease-free survival was worse for the patients with micrometastases and mini-micrometastases compared with those with negative nodes, although it was better than that for patients with macrometastases (P ⫽ 0.02). The follow-up of this study illustrated that there were no significant differences in disease-free survival, distant disease-free survival, or overall survival among patients treated with preoperative chemotherapy and those who received the same therapy in the adjuvant setting. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy. Rates of ipsilateral breast tumor recurrences after lumpectomy were similar between the two groups (7.9% and 5.8%, respectively; P ⫽ 0.23). The outcome was better for women who had a pCR than for those with cPR or cNR. The authors of this study concluded that preoperative chemotherapy was an effective approach and as effective as postoperative chemotherapy; however, preoperative chemotherapy resulted in more lumpectomies for patients with stage I and stage II disease. It was further noted that combined modality therapy that includes preoperative chemotherapy was a good model for studying breast cancer biology. NSABP B-27 NSABP B-27 protocol was designed to determine the effects of adding docetaxel after four cycles of preoperative AC on cCR, pCR, and disease-free and overall survival of women with operable breast cancer.4 This study included 2411 women with operable breast cancer. Patients were randomly assigned to either 4 cycles of preoperative AC followed by surgery (n ⫽ 804) or 4 cycles of AC followed by 4 cycles of docetaxel followed by surgery (n ⫽ 805) or 4 cycles of AC followed by surgery and then 4 cycles of docetaxel (n ⫽ 802). cCRs and pCRs to preoperative chemotherapy were assessed. The addition of docetaxel increased the cCR rate from 40.2% to 63.6% (P ⫽ 0.001). Overall cCRs were 85.7% versus 90.7% for preoperative AC and preoperative AC and docetaxel, respectively (P ⫽ 0.001). pCR rates for the same two groups were 13.7% versus 26.1% (P ⫽ 0.001), and the proportions of patients with negative axillary nodes at the time of surgery were 50.8% versus 58.2% (P ⫽ 0.001) for AC alone and AC followed by docetaxel, respectively. Pathological primary tumor response was a significant predictor of pathological nodal status. The findings of this study provided evidence that the addition of four cycles of preoperative docetaxel after four cycles of preoperative AC significantly
110 increased the cCRs and pCRs for operable breast cancer patients. However, the recent presentation of the initial findings of this study at the 21st San Antonio Breast Cancer Symposium indicated no significant improvement in disease-free or overall survival rates with the addition of docetaxel, either pre- or postoperatively. However, after a median follow-up of 68 months, the study showed a significant reduction in the risk of recurrence. The detailed publication of the data in a peer-reviewed manuscript is anticipated to adequately evaluate the value of this approach.8
M.D. Anderson Cancer Center (MDACC) Randomized Neoadjuvant Chemotherapy Trials MDACC ID94-002 Study This study was designed to compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer.5 Patients received either paclitaxel 250 mg/m2 given as a 24-hour continuous infusion or FAC in the standard (M.D. Anderson) doses and schedule every 3 weeks. FAC chemotherapy consisted of fluorouracil 500 mg/m2 intravenously on days 1 and 4, cyclophosphamide 500 mg/m2 intravenously on day 1 only, and doxorubicin 50 mg/m2 given as a 72-hour continuous infusion through a central venous catheter. A total of 174 patients were registered on the study, with 87 patients randomized to each arm of the study. Approximately two thirds of patients had positive regional nodes on clinical examination, and 17% had stage IIIA disease. Major clinical responses (ie, complete and partial responses) were observed in 79.3% (21 cCRs and 48 cPR among 87 patients) following FAC therapy and 80.2% (23 cCRs and 46 cPR among 86 evaluable patients) after paclitaxel therapy (P ⫽ 0.85). Clinical objective response rates were similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel group had progressive disease. The extent of residual disease at the time of surgery by an intent-to-treat analysis was also similar in the two arms of the study. The pCRs were 17% and 8% for the FAC and paclitaxel arms of the study. A numerically higher number of patients (46%) in the paclitaxel arm of the study had breast preservation compared with the FAC arm (35%), but these differences were not significant (P ⫽ 0.30). The results of this prospective study demonstrated that singleagent neoadjuvant paclitaxel had significant antitumor activity, and this was clinically comparable to the results obtained with the long-established FAC regimen. Similar fractions of patients had clinical complete and partial responses, and very few patients failed to respond to either therapy. In this study, definitive local therapy was done after 12 weeks of therapy; however, in all our subsequent studies, all chemotherapy was delivered before local therapy, and the results of those studies are summarized below. MDACC ID98-240 Study The purpose of this study was to determine if a change in the schedule of paclitaxel from once every 3 weeks to weekly
A.U. Buzdar and G.N. Hortobagyi administration would impact on the pCR rate in patients with operable breast cancer treated with primary systemic chemotherapy.6 Patients with clinical stage I-IIIA breast cancer were randomized to receive paclitaxel either weekly (for a total of 12 doses of paclitaxel) or every 3 weeks (four cycles), followed by four cycles of FAC in standard doses given every 3 weeks. Two different doses of paclitaxel were used in the weekly schedule based on lymph node status defined by ultrasound and fine-needle aspiration. Patients that were deemed nodenegative received weekly paclitaxel at 80 mg/m2 administered as an intravenous infusion over 1 hour weekly for 12 weeks. Patients with lymph node metastasis (established cytologically by FNA) received dose-intense weekly paclitaxel therapy. These patients 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 randomized to this dose/schedule received two cycles of treatment. However, analysis of toxicity after the first cohort of patients revealed unacceptable grade 3 neurotoxicity (88.5%), and the dose of paclitaxel was reduced to 150 mg/m2, maintaining the same schedule. Evaluation of the second cohort of patients treated with high-dose paclitaxel 150 mg/m2 showed reduction in grade 3 neurotoxicity (50%), but an increasing number of patients had delay in delivery of their dose at week 4 because of neutropenia.2 Therefore, the schedule of paclitaxel was changed for this group. The remainder of the patients treated with high-dose weekly paclitaxel received 150 mg/m2 over 3 hours weekly for 3 weeks, followed by a 1-week rest. This constituted one cycle of therapy. Four cycles of paclitaxel were administered at this dose and schedule to the remainder of patients with positive lymph nodes randomized to receive weekly paclitaxel therapy. FAC chemotherapy was administered at the doses and schedules described above. FAC was administered every 21 days for 4 cycles to all patients after completion of all paclitaxel. All chemotherapy (paclitaxel ⫻ 4 and FAC ⫻ 4) was given before loco-regional therapy. A total of 258 patients were randomized to receive paclitaxel either weekly or every 3 weeks followed by FAC. Of these, 110 patients had histological lymph node involvement and 148 patients had clinically N0 disease. Weekly paclitaxel followed by FAC was given to 127 patients and paclitaxel every 3 weeks followed by FAC was given to 131 patients. cCRs to treatment were similar in the two groups (P ⫽ 0.08). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with every-3-week paclitaxel (15.7%; P ⫽ 0.02), resulting in improved breast-conservation rates (P ⫽ 0.05). The results of this study established that the change in schedule of paclitaxel from an every-3-week schedule to weekly administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes. The data from this study also demonstrated that the therapeutic index of paclitaxel could be significantly enhanced when the drug was given on a weekly schedule, and it increased the pCR rate by almost 100%. The two different doses of weekly paclitaxel evaluated in this study demonstrated that the lower
Neoadjuvant therapy of operable breast cancer
111
Table 1 Summary of US Randomized Preoperative Chemotherapy in Patients With Operable Breast Cancer Design and Drugs NSABP Studies B-18 Protocol Preoper. AC vs AC adjuvant
B-27 Protocol Preop. AC vs AC ⴙ docetaxel vs preop. AC-surgery - docetaxel
MDACC Studies MDACC ID94-002 Study Clinical & pathological response Paclitaxel ⴛ 4 vs FAC ⴛ 4 MDACC ID98-240 Study Weekly paclitaxel ⴛ 2 weeks; Followed by FAC ⴛ 4 vs Q 3 weeks paclitaxel; Followed by FAC ⴛ 4 MDACC ID99-146 Study Paclitaxel ⴛ 4 > FAC ⴛ 4 vs same chemotherapy ⴙ 24 weeks of trastuzumab
Primary Objectives
Findings
Preoperative effect on breast preservation
Higher rates of lumpectomy; similar effect on disease-free or overall survival
Effect on cCR and pCR rates
Increased clinical and pathological ER rates with addition of docetaxel; no effect on disease-free or overall survival
Compare cCRs & pCRs of two therapies
Similar clinical responses High pCRs with FAC
Compare pCR by schedule of paclitaxel
Significantly high pCR rates with weekly paclitaxel
To determine effect of trastuzumab on pCR and safety of this combination
Significantly higher pCR Safety—no clinical congestive heart failure
dose of paclitaxel (80 mg/m2) provided improved efficacy with decreased toxicity; this schedule was recommended for further clinical use. The impact of weekly paclitaxel (as compared with every3-weeks paclitaxel) on disease-free and overall survival rates remains to be defined. However, similar results were observed in a prospective randomized trial conducted in patients with metastatic breast cancer. In that study, patients treated with weekly paclitaxel achieved a higher cCR rate compared with those treated with once every-3-weeks schedule. MDACC ID99-146 Trial The primary objective of this prospective study was to compare the pCR rates following chemotherapy alone to the same chemotherapy combined with trastuzumab in the neoadjuvant setting.7 Patients with operable, HER-2 positive (either immunohistochemistry (IHC) 3⫹, or fluorescence in situ hybridization (FISH)-positive) breast cancer (stage II or IIIA) were included in the study. Preoperative chemotherapy consisted of 4 cycles of paclitaxel (administered at 225 mg/m2 as a 24-hour continuous intravenous infusion) repeated every 3 weeks for 4 cycles. Following 4 cycles of paclitaxel, 4 cycles of 5-fluorouracil 500 mg/m2 intravenously on days 1 and 4, cyclophosphamide 500 mg/m2 intravenously on day 1 only, and epirubicin 75 mg/m2 on day 1 only were administered. In the experimental arm, patients received trastuzumab weekly simultaneously with the administration of chemotherapy, with the first dose at 4 mg/kg intravenously on day 1, then 2 mg/kg intravenously weekly for a total of 24 weeks. After completing all chemotherapy, patients had local therapy. This trial was designed to compare the complete pCR
between the two arms of the study; the projected pCR rate with the standard arm was estimated to be 21%, and the study was planned to detect a 20% improvement in that rate to 41%. Accrual of 164 patients was planned. With that number of patients, the study would have had 80% power to detect a 20% difference. pCR was defined as the absence of invasive cancer in the breast and in the lymph nodes. The Institutional Data Monitoring Committee reviewed the results obtained by the first 34 patients. The findings indicated that the 18 patents treated with chemotherapy and trastuzumab had a 66.7% pCR rate, whereas 25% of those treated with chemotherapy alone had pCRs (n ⫽ 16). The Institutional Data Monitoring Committee recommended closure of the trial because there was evidence of superiority in the pCRs in the trastuzumab and chemotherapy arm compared with the chemotherapy alone arm. This decision was based largely on the findings that if accrual continued to 164 patients, there would be a 95% probability that the trastuzumab with chemotherapy arm would be superior. The final results based on the 42 patients (chemotherapy alone, n ⫽ 19; and chemotherapy and trastuzumab, n ⫽ 23) randomized into this study based on an intent-to-treat analysis showed pCR rates of 26.3% and 65.2% for the chemotherapy alone and chemotherapy and trastuzumab arms, respectively (P ⫽ 0.016). To date, no clinical cardiac dysfunction has been observed; however, ⬎10% decreases in ejection fraction were observed in a small number of patients in both arms of the study, but none of the patients had any evidence of clinical congestive heart failure. Since these data became available, the protocol has been amended and additional patients were treated with chemotherapy and trastuzumab. Longer
A.U. Buzdar and G.N. Hortobagyi
112 follow-up of these and subsequent patients will provide additional safety and efficacy data and evidence as to whether this approach will result in improved disease-free and overall survival.
Discussion In the past two decades, use of preoperative chemotherapy has steadily increased. Preoperative chemotherapy provides important prognostic information, and this approach provides the data regarding the tumor’s sensitivity to systemic therapeutic agents. The extent of residual disease in the nodes and breast following preoperative chemotherapy still provides important prognostic information. Patients with persistent disease in the lymph nodes or large-volume residual tumor in the breast are at an increased risk of recurrence, and the risk is proportional to the number of nodes containing cancer. Patients who have not responded to initial therapy could be offered alternate therapies to evaluate the impact of this additional intervention on the clinical course of this disease. A couple of small studies have already provided validation of this approach. However, this approach needs to be validated in appropriately designed large randomized trials. The data of B-27 didn’t fully support the observation of the Aberdeen study regarding the addition of alternate noncross-resistant therapy with taxanes following an initial anthracycline-cyclophosphamide– containing drug regimen.9 There is a number possible explanations for this discrepancy. In the B-27 trial, all hormone receptor–positive patients received tamoxifen concomitant with chemotherapy. Simultaneous combination of tamoxifen with adjuvant chemotherapy has been shown to result in inferior relapse-free and overall survival rates compared with sequential administration. Therefore, this aspect of the design of B-27 might have compromised the outcome. B-27 also included a more favorable subset of patients, and it is possible that additional follow-up and more events are needed to confirm the value of additional taxane therapy. The preoperative chemotherapy model also provides an avenue to rapidly evaluate new promising agents with significant antitumor activity in patients with metastatic disease. This is highlighted by the initial positive results of the MDACC ID99-146 study. Trastuzumab is under evaluation in the adjuvant setting in over 12,000 patients, but so far no efficacy data are available. The data of our preoperative study suggest that the addition of trastuzumab to adjuvant chemotherapy will result in significant improvement in the longterm outcome of patients with HER-2–positive breast cancer. With this approach, one doesn’t need large numbers of patients or long observation periods to determine the effect of new therapies on the disease. The availability of tumor tissue before, during, and at the completion of therapy (if residual disease is still present) also
provides important information to further study the biology of the disease. This approach also identifies the subset of patients in whom currently available therapies have had little impact, as documented by large-volume residual disease left in the breast and or in the regional nodes. Novel therapies could be offered and evaluated in this very high-risk population before recurrence. These studies would require smaller numbers of patients and a much shorter follow-up time to evaluate newer agents. The role of preoperative chemotherapy in patients with operable breast cancer remains an area of discussion. However, at our institute we consider that if a patient with histologically confirmed breast cancer satisfies the indications for adjuvant chemotherapy, then we prefer the preoperative administration of chemotherapy. Patients not responding after 6 to 9 weeks of preoperative therapy are offered alternate therapies before local therapy. With this approach, patients are not continued on ineffective therapies, and thus the toxicities of ineffective therapies are avoided.
References 1. Hortobagyi GN: Comprehensive management of locally advanced breast cancer. Cancer 66:1387-1391, 1990 2. Jacquillat C, Weil M, Baillet F, et al: Results of neoadjuvant chemotherapy and radiation therapy in the breast-conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer 66:119-129, 1990 3. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18 [see comments]. J Clin Oncol 15:2483-2493, 1997 4. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:41654174, 2003 5. Buzdar AU, Singletary SE, Theriault RL et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412-3417, 1999 6. Green MC, Buzdar AU, Smith T, et al: Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr) 7. Buzdar AU, Hunt K, Smith T, et al: Significantly higher pathological complete remission (PCR) rate following neoadjuvant therapy with trastuzumab (H), paclitaxel (P), and anthracycline-containing chemotherapy (CT): Initial results of a randomized trial in operable breast cancer (BC) with HER/2 positive disease. Proc Am Soc Clin Oncol 23:7a, 2004 (abstr) 8. Bear HD, Anderson S, Smith RE, et al: A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: results of NSABP B-27. Breast Cancer Res Treat 88:S16, 2004 (suppl) 9. Smith IC, Heys SD, Hutcheon AW, et al: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20:1456-1466, 2002