Adjuvant and Neoadjuvant Breast Cancer Treatment: Where Are We Going?
Scientific Editor: C. D. Buckner M.D.
Taxanes in Adjuvant Breast Cancer Treatment
The incorporation of taxanes into standard adjuvant chemotherapy for breast cancer has been hotly debated over the past several years. Preliminary results have been reported for two trials, CALGB 9344 and NSABP B-28, that evaluate adjuvant Adriamycin® and Cytoxan® (AC) with or without the sequential use of Taxol®. Interim analysis of NSABP B-28 has shown no difference in overall survival with the addition of Taxol® to AC. 1 However, analysis of CALGB 9344 with four years of follow-up shows a 3% improvement in relapse-free and overall survival for the AC==>T arm. 2 To date, several other trials evaluating taxanes in the adjuvant setting have completed accrual, but results are still pending. Preliminary results of a trial using concurrent Taxotere® in the adjuvant setting were presented by Dr. Nabholtz and colleagues at the 2002 ASCO meeting. 3< /SUP>
In this study, Dr. Nabholtz presents a planned interim analysis of a phase III trial comparing TAC (Taxotere®, Adriamycin®, Cytoxan®) with FAC (5-fluorouracil, Adriamycin®, Cytoxan®) as adjuvant therapy in women with lymph node-positive breast cancer. The study enrolled 1,491 patients who were stratified by enrolling center and number of lymph nodes. The two patient groups were well balanced with regard to tumor size, menopausal status, and hormone receptor status. Chemotherapy doses were FAC 500/50/500 and TAC 75/50/500 given every 3 weeks for a total of 6 cycles. All 6 cycles of therapy were completed in 91% of patients receiving TAC and 97% of patients in the FAC arm.
The current analysis was performed with a median of 33 months of follow-up. Disease-free survival (DFS) was 82% and 74% for TAC and FAC, respectively (RR=0.68, p=0.0011). Overall survival at 33 months was 92% and 87% for TAC and FAC, respectively (RR 0.76, p=0.11). However, additional planned analysis of DFS by lymph node status showed the DFS difference to be statistically significant only in the group of patients with 1-3 positive lymph nodes (RR=0.50, p=0.0002), but not in the subset with > 4 positive lymph nodes (RR=0.86, p=0.33). DFS advantage for TAC was significant, regardless of ER or HER-2/neu status. Although febrile neutropenia and grade 3-4 anemia were significantly higher in the TAC arm, infection rates were similar and no septic deaths occurred in either group. Although these early results are encouraging, analysis of these data with longer follow-up is required to determine whether the advantage in DFS for TAC will translate into a survival advantage.
The use of primary, or neoadjuvant, chemotherapy in breast cancer patients has been increasing over the past several years. Trials that compare neoadjuvant with adjuvant chemotherapy, such as NSABP B-18, have shown equivalent survival with the two strategies, but with an increased rate of breast conservation. Multiple neoadjuvant regimens and schedules have been evaluated. In one study, treatment with dose-dense Adriamycin® and Taxotere® (50/75) given every 2 weeks for 4 cycles resulted in a pathologic complete response (pCR) rate of 9.7%. 4 Another trial showed a pCR rate of 12.8% with a dose-dense regimen of sequential Adriamycin® and Taxotere® as primary chemotherapy. 5
A study reported at the 2002 ASCO meeting by Dr. von Minckwitz compared the above regimen to sequential Adriamycin® and Cytoxan® (AC) followed by Taxotere®. The primary endpoint was comparison of pCR rates between the two regimens. A total of 913 patients with operable breast cancer (T2-3, N0-2, M0) were enrolled in this study and randomized to four cycles of ADOC (Adriamycin® 50, Taxotere 75) every 2 weeks or 4 cycles each of sequential AC (60/600) q21 days and Taxotere® (100) q 21d (AC-DOC). Nolvadex® was administered concurrently with chemotherapy in ER+ patients. Patient groups were well balanced with regard to age, tumor size (median 3-4 cm) and lymph node status (38-42% LN+).
Clinical evaluation of tumor response rate revealed an increased response rate in the sequential (AC-DOC) arm versus the dose-dense (ADOC) arm (86.8% vs 77.2%). Differences in pathologic complete response rates (shown below) led to premature closure of this trial.
Toxicity rates were acceptable in both arms and the major grade 3-4 toxicity was neutropenia, which occurred in 44.7% of patients in the ADOC group and 66.7% of patients in the AC-DOC group. However, the ADOC patients received prophylactic GCSF support. A higher dropout rate was observed in the AC-DOC arm versus the ADOC arm (22.3% vs 7.6%), primarily due to toxicity; this rate was probably higher because of the longer treatment period in the sequential arm.
These results suggest that cell kill percentage may not be increased with dose dense chemotherapy. However, it may contribute to the argument that longer chemotherapy regimens are more efficacious than shorter regimens. This has also been suggested by the results of NSABP B-27, showing a significant improvement in pCR rate with the addition of Taxotere® to AC, a difference that could be due to increased duration of therapy rather than a difference in regimens.
Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy
A study presented by Dr. Mamounas and colleagues analyzed the effectiveness and reliability of sentinel lymph node biopsy (SNB) after neoadjuvant chemotherapy. 6 To this point, studies evaluating this technique after neoadjuvant chemotherapy have involved small numbers of patients and have led to widely varying reports of sentinel lymph node identification and efficacy. Of 2,411 patients enrolled in NSABP B-27, 420 underwent sentinel lymph node biopsy at the time of surgery. Chart review revealed the sentinel lymph node identification rate in this group of patients to be 85%. Identification rate was significantly higher when radioisotope (with or without lymphazurin blue dye) was used. Identification rate did not vary with age, clinical lymph node status, or initial tumor size.
In this review, 340 patients with an identified SLN then underwent a full axillary lymph node dissection, allowing evaluation of the accuracy of SNB. The sentinel lymph node was positive in 125 of these patients, and was the only positive lymph node in 56% of patients. The false negative rate in this series was 7% (15 patients). The false negative rate was associated with increased tumor size and with the use of blue dye without radioisotope. The authors pointed out that the limitations of this study included that it was a retrospective review without a set protocol for SNB. Also, surgeons in this trial had varying levels of experience with the SNB procedure. However, the false negative rate of 11% is comparable to that seen in other studies. This is the largest of such trials to date and suggests that SNB is a reasonable procedure in selected patients after primary chemotherapy.
1.NIH consensus development conference, Nov. 2000.
2.Henderson I, Berry D, Demetri G, et al. Improved disease-free survival and overall survival from the addition of sequential Taxol® but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Proceedings from the 34th Annual Meeting of the American Society of Clinical Oncology. 1998; 17:101a (Abstract 390A).
3.Nabholtz J.-M., Pienkowski T, Mackey J, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proceedings from the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:36a (Abstract 141).
4.von Minckwitz G, Costa SD, Raab G, et al. Journal of Clinical Oncology. 2001;19:3506-3515.
5.Miller KD, McCaskill-Stevens W, Sisk J, et al. Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: a randomized pilot trial of the Hoosier Oncology Group. Journal of Clinical Oncology. 1999;17:3033-3037.
6.Mamounas EP, Brown A, Smith R, et al. Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: updated results from NSABP B-27. Proceedings from the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:36a (Abstract 140).