Neoadjuvant Chemotherapy for Operable Breast Cancer: Is This the Future?

Neoadjuvant Chemotherapy for Operable Breast Cancer: Is This the Future? Eleftherios P. Mamounas Abstract The idea of using preoperative or neoadjuvant chemotherapy in patients with operable breast cancer originated from experimental and clinical observations as well as theoretical hypotheses on tumor cell growth and dissemination. Initially, nonrandomized studies demonstrated considerable rates of clinical tumor response, low rates of pathologic complete response (pCR), and increased rates of breast-conserving procedures. However, nonrandomized studies could not address the relative efficacy of neoadjuvant versus adjuvant chemotherapy on disease-free and overall survival. Similarly, earlier randomized trials were not designed as straightforward comparisons of neoadjuvant versus adjuvant chemotherapy and therefore could not adequately address the relative efficacy of neoadjuvant versus adjuvant chemotherapy on outcome. These answers were eventually provided by larger randomized trials that directly compared neoadjuvant with adjuvant chemotherapy, which are reviewed in more detail in this article. Potential advantages and disadvantages of the neoadjuvant approach and surgical considerations in the breast and axilla after neoadjuvant chemotherapy are also discussed. Finally, several recently reported trials of neoadjuvant therapy incorporating newer agents such as taxanes in sequence with anthracycline-containing regimens have shown further increases in pCR rates. Although outcome data are not available yet from these studies, it is hoped that the observed increase in pCR rates will be associated with improved outcome. If the previously observed significant correlation between the achievement of pCR and improved outcome continues to be demonstrated with these newer regimens, it will substantially strengthen the rationale for using neoadjuvant rather that adjuvant chemotherapy in the clinical setting as well as in future research studies. Clinical Breast Cancer, Vol. 4, Suppl. 1, S10-S19, April 2003 Key words: Anthracyclines, Preoperative systemic therapy, Radiation therapy, Surgery, Taxanes

Introduction The clinical rationale for considering preoperative or neoadjuvant chemotherapy in patients with operable breast cancer originated from studies in patients with locally advanced disease, in whom excellent clinical response rates could be documented with this approach.1-3 In addition, the establishment of lumpectomy as the surgical treatment of choice for the majority of patients with early-stage breast cancer4-8 and the demonstration of significant improvements in disease-free and overall survival with adjuvant chemotherapy in patients with positive or negative axillary nodes9,10 provided further clinical justification for considering neoadjuvant chemotherapy in this setting. In addition, several preclinical and clinical observations provided biologic rationale as to why such an intervention may have an advantage over the administration of chemotherapy in the conventional postoperative fashion.11-14

Nonrandomized Studies Evaluating Neoadjuvant Chemotherapy Results from several nonrandomized studies evaluating neoadjuvant chemotherapy in patients with operable breast cancer have shown that various chemotherapeutic regimens administered preoperatively resulted in high rates of clinical response (47%-88%) but generally low rates of pathologic complete response (pCR; 4%-30%).15-21 Some of these studies have also shown that, because primary tumor size is reduced by neoadjuvant chemotherapy, more breast-conserving procedures can be performed.15,16 Although the relative efficacy of preoperative versus postoperative chemotherapy on diseasefree and overall survival could not be evaluated in nonrandomized studies, these studies did provide useful information on the downstaging effect of neoadjuvant chemotherapy on primary breast tumors and involved axillary nodes.

Northeastern Ohio Universities College of Medicine, Rootstown; Cancer Center, Aultman Health Foundation, Canton, Ohio

Randomized Trials Comparing Neoadjuvant with Adjuvant Chemotherapy

Submitted: Nov 18, 2002; Revised: Jan 17, 2003; Accepted: Jan 24, 2003

Some of the early randomized trials22-26 that compared neoadjuvant with adjuvant chemotherapy, by the nature of their design, were not able to adequately evaluate the 2 modalities in terms of outcome results (Table 122-31).

Address for correspondence: Eleftherios P. Mamounas, MD, Cancer Center, Aultman Health Foundation, 2600 6th Street, Canton, OH 44710 Fax: 330-363-7367; e-mail: [email protected]

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Table 1

Randomized Trials Comparing Neoadjuvant with Adjuvant Chemotherapy in Patients with Operable Breast Cancer

Clinical Trial

Tumor Number of Patients Stage/Size

Chemotherapy Regimen

ORR

cCR

pCR

DFS Benefit*

OS Benefit*

Mauriac et al22

272

> 3 cm

NADJ EVM/MTV vs. ADJ EVM/MTV except for node-negative or ER-positive patients

NR

NR

NR†

No

Yes

Scholl et al23,24

414

T2/3 N0/1

NADJ CAF vs. ADJ CAF except for node-negative patients at surgery

65%

NR

NR†

No

Yes

Powles et al25 Makris et al26

309

Operable

NADJ and ADJ MM ± M + Tam vs. ADJ MM ± M + Tam

84%

22%

10%

No

No

Fisher et al27,28 Wolmark et al29

1523

Operable

NADJ AC vs. ADJ AC

80%

36%

13%

No

No

Van der Hage et al30

698

T1c-T3, T4b N0/1

NADJ FEC vs. ADJ FEC

49%

7%

2%

No

No

Gianni et al31

892

Operable

NADJ doxorubicin/paclitaxel/CMF vs. ADJ doxorubicin/paclitaxel/CMF vs. ADJ A/CMF

NR

52%

23%

NR

NR

*Benefit for neoadjuvant versus adjuvant therapy. † Patients underwent radiation therapy after chemotherapy. Abbreviations: A = doxorubicin; AC = doxorubicin/cyclophosphamide; ADJ = adjuvant; CAF = cyclophosphamide/doxorubicin/5-fluorouracil; cCR = clinical complete response; CMF = cyclophosphamide/methotrexate/5-fluorouracil; DFS = disease-free survival; ER = estrogen receptor; EVM/MTV = epirubicin/vincristine/ methotrexate/methotrexate/thiotepa/vinblastine; FEC = 5-fluorouracil/epirubicin/cyclophosphamide; MM ± M = methotrexate/mitoxantrone ± mitomycin-C; NADJ = neoadjuvant; pCR = pathologic complete response; NR = not reported; Tam = tamoxifen

In 2 French trials, all patients randomized to the neoadjuvant arms received chemotherapy but some patients did not receive chemotherapy on the adjuvant arms.22-24 In a British trial, patients assigned to the neoadjuvant arm received 4 cycles of chemotherapy before surgery, followed by another 4 cycles of the same chemotherapy after surgery, whereas patients assigned to the adjuvant arm received 8 cycles of chemotherapy after surgery.25,26 Thus, none of these trials was a pure comparison between neoadjuvant and adjuvant chemotherapy.

National Surgical Adjuvant Breast and Bowel Project B-18 Trial The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial was the first large randomized trial designed to directly compare adjuvant with neoadjuvant chemotherapy in patients with operable breast cancer (Figure 1).27,28 After diagnosis of breast cancer by fine-needle aspiration or core-needle biopsy (CNB), patients were stratified according to their age, clinical tumor size, and clinical nodal status and then randomized to receive either surgery (lumpectomy and axillary node dissection or modified radical mastectomy) followed by 4 cycles of adjuvant chemotherapy (AC [doxorubicin/cyclophosphamide] every 21 days) or chemotherapy followed by surgery. All patients ≥ 50 years of age were also given tamoxifen 10 mg twice daily for 5 years after chemotherapy. Patients treated with lumpectomy also received breast radiation. Between 1988 and 1993, 1523 patients were accrued into the trial. Results on the effect of neoadjuvant chemotherapy on tumor response indicate that 36% of patients experienced clinical complete response (cCR) and 44% of patients obtained a clinical partial response

(cPR), for an overall response rate of 80%.27 Seventeen percent of patients were classified as having stable disease and 3% as having progressive disease. More importantly, 9% of the patients were found to have no tumor present on pathologic examination of the lumpectomy or mastectomy specimen and another 4% were found to have only noninvasive tumors, for an overall pCR of 13%. Neoadjuvant chemotherapy resulted in significant pathologic downstaging of involved axillary lymph nodes. Whereas 57% of the patients receiving adjuvant chemotherapy were found at surgery to have pathologically involved axillary nodes, this finding occurred in only 41% after neoadjuvant chemotherapy. This difference was statistically significant (P < 0.001) and amounted to axillary nodal downstaging in 16% of all patients receiving preoperative chemotherapy or in 28% of patients presumed to be nodepositive at the time of administration of neoadjuvant chemotherapy. Patients who received neoadjuvant chemotherapy were significantly more likely to undergo lumpectomy than

Figure 1 Treatment Schema of the NSABP B-18 Trial

Operable breast cancer

Stratification • Age • Clinical tumor size • Clinical nodal status

AC for 4 cycles Surgery

Surgery AC for 4 cycles

This trial compared preoperative (neoadjuvant) AC to postoperative (adjuvant) AC in patients with operable breast cancer. Abbreviations: AC = doxorubicin/cyclophosphamide; NSABP = National Surgical Adjuvant Breast and Bowel Project

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Neoadjuvant Chemotherapy in Operable Breast Cancer Figure 2 Outcome Results from Survival in NSABP B-18 Trial According to Clinical and Pathologic Breast Tumor Response A

Disease-Free Survival

Percent of Patients

100 80 60 40 20

0

pCR pINV cPR cNR 2

B

4

Years

6

8

10

Overall Survival

100

Percent of Patients

P = 0.00005

80 60 40 20

0

pCR pINV cPR cNR 2

P = 0.0008 4

6

8

10

Years Abbreviations: cNR = clinical nonresponse; cPR = clinical partial response; NSABP = National Surgical Adjuvant Breast and Bowel Project; pCR = pathologic complete response; pINV = clinical complete response with residual invasive tumor on pathologic examination Adapted with permission from Wolmark N, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from NSABP B-18. J Natl Cancer Inst Monogr 2001; 30:96-102.

were patients who received adjuvant chemotherapy (67% vs. 60%; P = 0.002).27 When the 2 treatment groups were compared in terms of outcome, there were no significant differences in disease-free survival, distant disease-free survival, or overall survival.28 There was, however, evidence of a significant correlation between pathologic tumor response after neoadjuvant chemotherapy and patient outcome. Patients in whom pCR was achieved had significantly superior disease-free and overall survival compared to those who had cCR but had residual invasive carcinoma in the breast specimen (pINV) or those who had cPR or clinical nonresponse (cNR). When the prognostic effect of pCR was examined after adjusting for other known clinical prognostic factors such as clinical nodal status, clinical tumor size, and age, pCR remained a significant independent predictor of disease-free survival and overall survival.28 Recently updated outcome results from the NSABP B-18 study demonstrate that the equivalence in outcome between neoadjuvant and adjuvant chemotherapy and the significant correlation between pCR and outcome have persisted through 9 years of fol-

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low up (Figure 2).29 At 9 years, the disease-free survival rate for patients in whom pCR was achieved was 75%, compared with 58% for patients with pINV. The respective overall survival rates were 85% in patients in whom pCR was achieved and 73% in patients with pINV. Overall primary tumor responses graded as pCR, pINV, cPR, or cNR were strongly associated with all outcome measures (overall survival, P = 0.0008; disease-free survival, P = 0.00005; relapse-free survival, P = 0.0002). Similar to previously reported results, these significant associations persisted after adjustment for clinical tumor size, clinical nodal status, and age at randomization. The results further demonstrated that primary tumor response in the breast contributed additional prognostic information beyond pathologic nodal status (overall survival, P = 0.06; disease-free survival, P = 0.006; relapse-free survival, P = 0.004).

European Organization for Research and Treatment of Cancer Trial The European Organization for Research and Treatment of Cancer 10902 trial was similar in design to the NSABP B18 trial and compared surgery followed by 4 cycles of adjuvant FEC (5-fluorouracil/epirubicin/cyclophosphamide) with 4 cycles of neoadjuvant FEC followed by surgery.30 A total of 698 patients with stages T1c, T2, T3, or T4b N0/1 M0 breast cancer were enrolled. Overall, clinical response was observed in 49% of the patients randomized to the neoadjuvant chemotherapy regimen (7% complete and 42% partial responses). Of the 23 patients who experienced cCR, only 6 did not have any invasive tumor left (pCR: 3%). There was some evidence of axillary nodal downstaging with neoadjuvant chemotherapy: 38% of patients were found to have negative nodes in the neoadjuvant chemotherapy group compared to 32% in the adjuvant chemotherapy group. Although 23% of patients receiving neoadjuvant chemotherapy were converted from mastectomy to a breast-conserving procedure, 18% of patients underwent mastectomy instead of the planned breast-conserving procedure. With a median follow-up of 56 months, there was no significant difference between the 2 groups in terms of overall survival, progression-free survival, and time to locoregional recurrence.

European Cooperative Trial in Operable Breast Cancer The European Cooperative Trial in Operable Breast Cancer (ECTO) randomized patients with tumors > 2 cm to 4 cycles of adjuvant doxorubicin followed by 4 cycles of adjuvant intravenous CMF (cyclophosphamide/methotrexate/ 5-fluorouracil; A/CMF) or 4 cycles of adjuvant doxorubicin/paclitaxel followed by 4 cycles of CMF or doxorubicin/paclitaxel/CMF as neoadjuvant therapy.31 Of 892 fully evaluable patients, 270 received neoadjuvant chemotherapy. Neoadjuvant doxorubicin/paclitaxel/CMF produced cCR in 52% of the patients (27% after doxorubicin/paclitaxel and 25% after CMF). The rate of pCR was 23%. Similar to what has been reported previously from the NSABP neoadjuvant trials, pCR in the breast was associated with histologically negative nodes in 87% of cases. The rates of breast-conserving surgery were significantly improved with

Eleftherios P. Mamounas neoadjuvant chemotherapy (71%) compared to adjuvant chemotherapy (35%; P < 0.0001). The percentage of patients who had histologically negative nodes at the time of surgery was also significantly increased in patients who received neoadjuvant chemotherapy (61%) compared to those who had surgery first (38%; P = 0.0001).

Potential Advantages of Neoadjuvant Chemotherapy Increase in the Rate of Breast-Conserving Surgery As described earlier, the potential for increasing the rates of breast-conserving surgery has provided most of the clinical justification for evaluating neoadjuvant chemotherapy in patients with operable breast cancer. Results from nonrandomized and randomized trials have clearly demonstrated that the administration of neoadjuvant chemotherapy significantly increases the rates of breast-conserving surgery without significantly increasing the rate of ipsilateral breast tumor recurrence. It is hoped that the development of more-effective chemotherapeutic regimens will further increase the rates of breast-conserving surgery, even though recently reported results from a large randomized trial evaluating taxane-based chemotherapy (described later in this article) do not support this argument.

Correlation Between Tumor Response and Outcome The resulting separation of patients into different outcome groups according to the achievement of pCR might provide a significant clinical advantage in patient management, after neoadjuvant chemotherapy. If this association persists with the use of more-effective chemotherapy regimens, pCR could be used as an intermediate endpoint in determining the value of new chemotherapy regimens or new drugs administered after well-established regimens.32 Because this intermediate endpoint can be achieved within weeks from the start of neoadjuvant chemotherapy, new regimens could be evaluated promptly, and useful conclusions could be drawn without a 5- to 10-year waiting period as is currently the case with the use of adjuvant chemotherapy. Thus, in the future, patients might be spared from repeated administration of ineffective regimens if these do not translate into prompt tumor response in the neoadjuvant setting. Of course, before such an approach can be widely adopted, nonrandomized and randomized studies have to convincingly demonstrate that the correlation between pathologic tumor response and outcome seen with anthracycline-containing regimens (eg, AC, FAC [5-fluorouracil/doxorubicin/cyclophosphamide])27,33 and non–anthracycline-containing regimens (eg, CMF) 17 is also demonstrated with new taxane-based regimens.

Correlation Between Biomarker Expression and Tumor Response/Outcome Evaluation of many of the proven, as well as putative, prognostic tumor markers, such as estrogen receptors, proges-

terone receptors, ploidy, S phase, erbB-2, p53, and other tumor oncogenes and growth factors, in material obtained by needle biopsy before and after neoadjuvant chemotherapy allows the potential correlation of the expression of such biomarkers (either individually or in combination), as well as changes in the biomarkers, with clinical and pathologic tumor response and eventually with outcome. Thus, if pCR is validated as an intermediate endpoint, the manner in which new tumor markers are developed and evaluated may change. Moreover, it might be possible in the future to use such biomarkers to identify patients among those with cCR who have a high likelihood of pCR and for whom further local therapy in the form of surgical resection and/or breast radiation therapy might be avoided.32 Furthermore, by serially monitoring biomarker changes during and after neoadjuvant chemotherapy, one might gain biologic insight into the nature and function of such biomarkers and the mechanism(s) of action of novel chemotherapeutic regimens or new treatment modalities.

Potential Disadvantages of Neoadjuvant Chemotherapy Risk of False-Positive Results of Fine-Needle Aspiration Biopsy Although the rate of false-positive results of fine-needle aspiration biopsy (FNAB) for breast cancer diagnosis is very low, invasive and noninvasive carcinoma cannot be readily differentiated by this technique. This is a potential weakness when it comes to using preoperative chemotherapy because neoadjuvant chemotherapy may end up being administered in some patients with noninvasive tumors. In the adjuvant arm of the NSABP B-18 trial, the false-positive rate of FNAB in the diagnosis of cancer was 0.3%, but the false-positive rate in the administration of appropriate preoperative chemotherapy was 2%. However, the development and widespread use of the CNB technique, which results in minimal tumor perturbation while providing important diagnostic information (similar to that obtained by open biopsy), has essentially eliminated the problem of false-positive diagnoses. This technique is rapidly becoming the method of choice for the histologic diagnosis of breast cancer, particularly in patients who are being considered as candidates for neoadjuvant chemotherapy.

Potential Loss of Prognostic Information from Pathologic Tumor Characteristics One of the concerns surrounding the use of preoperative chemotherapy relates to the potential for unnecessary chemotherapy treatment of some patients who may not need adjuvant chemotherapy based on pathologic tumor and nodal characteristics that are not available before surgery. The use of CNB rather than FNAB usually provides enough material for the evaluation of most important prognostic and predictive tumor markers, such as estrogen/progesterone receptors, erbB-2, ploidy, and S-phase. In addition, with the demonstration of benefit from adjuvant chemotherapy in patients with breast cancer irrespective of nodal status,9,10 knowledge of

Clinical Breast Cancer Supplement April 2003 • S13

Neoadjuvant Chemotherapy in Operable Breast Cancer pathologic nodal status is usually not a requirement when the decision whether to use adjuvant chemotherapy is made, except in patients with small tumors (< 1 cm), in whom a slight benefit from chemotherapy may not justify its use, and in patients with other comorbid conditions, in whom the use of chemotherapy might be contraindicated. Recent studies have shown that, in patients with stage III disease, the presence of positive nodes after preoperative chemotherapy continues to provide important prognostic information, with patients who have ≥ 4 positive nodes having a very high risk for recurrence.33 Conversely, clearance of tumor cells by neoadjuvant chemotherapy in patients with confirmed histologic or cytologic involvement of axillary nodes confers excellent prognosis.34 Finally, some have argued that patients who are found to have 1-3 involved axillary nodes after neoadjuvant chemotherapy might have started with ≥ 4 involved nodes before chemotherapy and therefore might still be at substantial risk for local recurrence and should undergo locoregional radiation therapy after mastectomy. Although the data regarding rates of locoregional recurrence after neoadjuvant chemotherapy are sparse, one publication has suggested that such patients do indeed have significant risk for local recurrence and should probably be offered locoregional radiation therapy.35 As more information on this subject becomes available from the completed and ongoing clinical trials of neoadjuvant chemotherapy, this issue will be adequately addressed, and it is therefore unlikely that it will represent a disadvantage for the use of neoadjuvant chemotherapy in the future.

Issues Relating to Cost and Patient Convenience Although there is no difference in cost between chemotherapy in the neoadjuvant and adjuvant settings, additional expense, as well as inconvenience, may be encountered in the neoadjuvant setting as a result of the patient having to make additional visits to the surgeon during chemotherapy for the purpose of monitoring tumor response and operability. In addition, the additional cost of mammograms and procedures that might be necessary in cases of cCR (such as titanium clip placement and wire localization) should also be taken into account. However, when considered in relation to the potential benefit of avoiding a mastectomy and obtaining information that can be used for further patient management, such cost and inconvenience issues should be considered minor.

Local Therapy Considerations in Patients Who Receive Neoadjuvant Chemotherapy Surgical Management of the Primary Breast Tumor The first issue that requires careful consideration before neoadjuvant chemotherapy begins relates to the ability to identify the exact tumor location if a cCR occurs after neoadjuvant chemotherapy. In most of these cases, residual mammographic abnormalities remain, making wire localization and tumor removal fairly straightforward. However, in

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some patients in whom cCR is achieved, there is no residual abnormality on mammographic evaluation. Therefore, it is always prudent in a patient who is about to receive neoadjuvant chemotherapy to consider marking the exact tumor location by inserting a titanium clip under mammographic or sonographic guidance. This can be performed either at the time of the initial core biopsy or at a subsequent time when there is clinical evidence of response. In the latter situation, the patient should be monitored closely by physical examination, and the corresponding mammographic abnormality should be promptly marked when a clinical response first becomes evident. In cases in which the primary tumor is poorly visible mammographically because of dense breast parenchyma, the placement of the surgical clip should precede initiation of preoperative chemotherapy and, in such cases, the clip can usually be placed under sonographic guidance. Clip placement is crucial in cases of pCR because it allows the pathologist to focus his/her attention on that particular area in search of residual tumor. In cases in which titanium clip placement is unavailable or infeasible, tattooing the skin of the breast in 4 quadrants around the edge of the tumor before initiating chemotherapy is an easy, albeit less accurate, alternative. The second surgical issue relates to the amount of breast tissue that needs to be removed during lumpectomy in patients who respond to neoadjuvant chemotherapy. In this circumstance, the question is whether the tissue removal should account for the original tumor size or whether it should be limited to an adequate margin around the residual tumor after response to chemotherapy. The answer to this question generally depends on the original tumor configuration (ie, on whether the original tumor is well-circumscribed or irregular with projections), the presence or absence of suspicious microcalcifications that would indicate an extensive intraductal component, and the breast/tumor ratio and potential for compromise of the cosmetic outcome if a wide excision based on the original tumor size were to be performed. It is reasonable to plan the lumpectomy on the basis of the residual tumor size after chemotherapy; however, the status of the surgical margins must be carefully assessed and the surgeon must be prepared to perform additional resection if the margins are found on pathologic evaluation to be compromised.

Surgical Management of Axillary Nodes Because sentinel node biopsy (SNB) is rapidly evolving as an alternative to axillary node dissection for axillary staging of patients with stage I/II breast cancer, and because neoadjuvant chemotherapy continues to be employed increasingly in this setting, the question of whether SNB is feasible and accurate after neoadjuvant chemotherapy becomes one of great importance. As previously discussed, neoadjuvant chemotherapy has been shown to downstage axillary lymph nodes in a significant proportion of patients (approximately 30% in the NSABP B-18 study). Thus, if SNB is accurate after neoadjuvant chemotherapy, patients who present with involved axil-

Eleftherios P. Mamounas lary nodes at the time of diagnosis may potentially be spared from axillary dissection if the sentinel node is found to be negative after neoadjuvant chemotherapy. However, there are some unique questions relative to the performance of SNB after neoadjuvant chemotherapy. Does tumor response to chemotherapy cause tissue scarring that affects the lymphatic drainage pattern? Does neoadjuvant chemotherapy have the same effect in noninvolved sentinel nodes as it does in involved sentinel nodes? Until recently, only small single-institution studies have examined the efficacy of lymphatic mapping and the accuracy of SNB after neoadjuvant chemotherapy.36-41 These studies generally included patients with operable and locally advanced breast cancer and have reported significant variability in the success rate of sentinel node identification as well as in the rate of false-negative SNB results. This is primarily because of the small size of most of these studies, with numbers of patients ranging between 13 and 51. More importantly, numbers of patients with positive nodes in these studies range between 9 and 25. Sentinel node identification rates were reported between 84% and 94%, which is comparable to the identification rates achieved in studies of SNB before systemic therapy.42,43 Sentinel node identification rates were generally higher when radiocolloid was used for the lymphatic mapping than when blue dye alone was used. The rates of false-negative SNB results were quite variable (0%33%), leading to different conclusions regarding the accuracy of the procedure in this setting. However, the small size of these studies can easily account for the wide variability of the estimates. When one examines all these studies combined, the average identification rate of 86.7% and the average false-negative rate of 14.0% are within the range of rates reported in the earlier studies of SNB before systemic therapy.42-45 The variability in the efficacy and accuracy of SNB after neoadjuvant chemotherapy documented in the small singleinstitution series underscores the importance of evaluating this approach in larger cohorts of patients. The largest report to date comes from the NSABP B-27 trial, in which > 400 patients underwent an attempt for SNB and complete axillary node dissection after neoadjuvant chemotherapy.46 The NSABP B-27 trial evaluated the effect of neoadjuvant or adjuvant docetaxel after 4 cycles of neoadjuvant AC chemotherapy. Although a level I and II axillary dissection was mandated in this study, some participating surgeons performed SNB before the required axillary node dissection. There was no predefined protocol dictating the method of lymphatic mapping or the approach to SNB. Among 2411 patients accrued to this trial, there were 428 in whom lymphatic mapping was performed and an attempt at sentinel node identification and removal was made before the required axillary node dissection. Lymphatic mapping was performed with radioactive colloid (15%), lymphazurin blue dye alone (30%), or both (55%). The identification rate was 85% and was significantly higher when radiocolloid was used for lymphatic mapping compared to when lymphazurin blue dye alone was used (90% with radiocolloid alone, 88% with the combination, and 77% with lymphazurin blue dye alone; P = 0.01).

Of the 363 patients in whom at least 1 sentinel node was identified and removed, 20 patients (5.5%) did not undergo the required axillary node dissection, leaving 343 patients in whom the accuracy of the sentinel node in correctly staging the axilla could be assessed. The sentinel node accurately predicted axillary nodal status in 328 of 343 patients with SNB (overall accuracy rate, 96%), in 125 of 140 node-positive patients (sensitivity, 89%; false negative rate, 11%), and in 203 of 218 patients with negative SNB results (negative predictive value, 93%). The false-negative rate was not associated with clinical or pathologic tumor response but, because patients experiencing a pCR in the breast have the lowest rate of axillary nodal involvement (approximately 13%), the accuracy of SNB was higher among pathologic complete responders than in those with pINV and those with any other type of clinical response. However, these differences were not statistically significant. The results with SNB from the B-27 trial are comparable with those obtained from multicenter studies evaluating SNB before systemic therapy and are encouraging because they suggest that the sentinel node concept can be applicable and useful in patients with breast cancer who have received neoadjuvant chemotherapy.

Locoregional Radiation Therapy After Neoadjuvant Chemotherapy and Surgery The indications for locoregional radiation therapy for patients who receive neoadjuvant chemotherapy followed by surgery are still evolving as more data on local recurrence rates become available from large neoadjuvant therapy trials. The indications for radiation therapy are generally similar to those for patients who undergo surgery first, followed by adjuvant chemotherapy. Postlumpectomy radiation therapy is recommended after neoadjuvant chemotherapy irrespective of original primary tumor size or tumor response. There are no definitive data, however, on the incidence of ipsilateral breast tumor recurrence in patients in whom pCR is achieved after neoadjuvant chemotherapy. Similarly, there are few data on the incidence of chest wall recurrence after mastectomy in patients who receive neoadjuvant chemotherapy and who experience pCR or other types of response.35 In general, most clinicians decide to add postmastectomy chest wall radiation therapy based on the original clinical tumor size before neoadjuvant chemotherapy. Regarding the administration of radiation therapy to regional lymph nodes as well, there is significant controversy. There is general agreement that patients with ≥ 4 positive nodes after neoadjuvant chemotherapy are at substantial risk for recurrence and would benefit from the addition of locoregional radiation therapy. Similarly, there is general agreement that patients with negative nodes after neoadjuvant chemotherapy are at low risk and therefore could be spared from regional radiation therapy. For patients with 1-3 positive nodes after neoadjuvant chemotherapy, there is continuing debate because such patients might have started with > 4 positive nodes before neoadjuvant chemotherapy. Data from one study support that such patients have a substantial

Clinical Breast Cancer Supplement April 2003 • S15

Neoadjuvant Chemotherapy in Operable Breast Cancer 5-year rate of locoregional recurrence (17%), justifying the consideration of locoregional radiation therapy.35 Definitive information on this subset of patients from larger data sets will hopefully be available in the future.

Randomized Trials Comparing Different Neoadjuvant Chemotherapy Regimens The results from the early randomized trials of neoadjuvant chemotherapy strengthened the biologic and clinical rationales for continuing to evaluate its role in patients with operable breast cancer.32 Because response to neoadjuvant chemotherapy correlated with patient outcome in the early trials, it was hypothesized that more-active neoadjuvant chemotherapy regimens can further increase the pCR rates and improve outcome in terms of disease-free and overall survival. In addition, more-active chemotherapy regimens could further reduce the extent of locoregional therapy in the breast and/or axilla. If higher pCR rates with more-effective regimens indeed continue to predict improved outcome, pCR could be used as an intermediate endpoint in testing new chemotherapy regimens or new drugs administered after standard regimens. The demonstration of significant antitumor activity with taxanes in patients with advanced breast cancer provided the opportunity to test some of the aforementioned hypotheses in the clinical setting. At the 2001 San Antonio Breast Cancer Symposium, the NSABP reported the preliminary results of protocol B-27, a randomized trial that evaluated the worth of docetaxel when administered in the preoperative or postoperative setting after 4 cycles of preoperative AC chemotherapy (Figure 3).47 Patients were randomized into 3 groups. Group 1 was to receive 4 cycles of neoadjuvant AC followed by surgery, group 2 was to receive 4 cycles of neoadjuvant AC followed by 4 cycles of neoadjuvant docetaxel and then surgery, and group 3 was to receive 4 cycles of preoperative AC followed by surgery and 4 cycles of postoperative docetaxel. All patients received tamoxifen 20 mg a day orally beginning on day 1 of the first AC course and continuing for 5 years. The preliminary results from this trial relative to the comparison of response rates between patients treated with neoadjuvant AC and those treated with neoadjuvant AC followed by neoadjuvant docetaxel demonstrated that the group receiving docetaxel experienced significantly higher rates of clinical response and pCR. The addition of preoperative docetaxel to preoperative AC also resulted in significant downstaging of axillary lymph nodes. However, in contrast to what was observed in the NSABP B-18 trial, the increase in clinical and pathologic response rates with preoperative docetaxel did not translate to a significant increase in the rate of breast conservation. Disease-free and overall survival data are not available yet. An obvious question regarding the sequential administration of neoadjuvant sequential anthracycline/taxane regimens is whether the observed improvement in clinical and pathologic response rates is the result of administration of additional cycles of chemotherapy in the experimental group

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Figure 3 Treatment Schema of NSABP B-27 Trial

Operable breast cancer

R A N D O M I Z E

AC for 4 cycles Tam for 5 years

Surgery

AC for 4 cycles Tam for 5 years

Docetaxel for 4 cycles

AC for 4 cycles Tam for 5 years

Surgery

Surgery Docetaxel for 4 cycles

This trial compared neoadjuvant AC to neoadjuvant AC followed by neoadjuvant docetaxel and to neoadjuvant AC followed by adjuvant docetaxel in patients with operable breast cancer. Abbreviations: AC = doxorubicin/cyclophosphamide; NSABP = National Surgical Adjuvant Breast and Bowel Project; Tam = tamoxifen

(8 cycles vs. 4 cycles) or the result of administration of potentially non–cross-resistant regimens. A recently reported study attempted to address this particular question by randomizing patients with operable or locally advanced breast cancer who experienced clinical response after 4 cycles of a neoadjuvant anthracycline-containing regimen (cyclophosphamide/vincristine/doxorubicin/prednisolone) to receive either 4 additional cycles of the same regimen or 4 cycles of docetaxel.48 Results showed that, in terms of clinical and pathologic response rates, switching to a potentially non–cross-resistant regimen by randomization improved the antitumor efficacy, even when the total number of cycles between the 2 groups was the same. Interestingly, despite the significant improvement in clinical and pathologic response rates with the docetaxel-containing regimen, no significant differences were observed in axillary nodal downstaging between the 2 groups48-53 (Table 247-53). A subsequent update of this study, presented at the 24th Annual San Antonio Breast Cancer Symposium, demonstrated that the increase in clinical and pathologic response rates with docetaxel has translated to early significant improvements in disease-free and overall survival.49 However, given the small number of patients included in this comparison (approximately 50 per group), more data are needed before such an association is firmly established. At the 38th Annual Meeting of the American Society of Clinical Oncology, results from 5 randomized trials31,50-53 evaluating neoadjuvant chemotherapy in all or some arms of the studies were presented (Table 2). These studies evaluated various taxane-based regimens as neoadjuvant therapy and have provided useful observations regarding the activity of these regimens in terms of their ability to induce pCR in the breast and axillary nodes. However, no diseasefree or overall survival data are available for any of these trials as of yet. In the ECTO study, patients with tumors > 2 cm were randomized to either 4 cycles of adjuvant doxorubicin followed by 4 cycles of adjuvant intravenous CMF (A/CMF), 4 cycles of adjuvant doxorubicin/paclitaxel followed by 4 cycles of CMF (doxorubicin/paclitaxel/CMF), or doxorubicin/

Eleftherios P. Mamounas Table 2

Randomized Trials Comparing Neoadjuvant Chemotherapy Regimens in Patients with Operable Breast Cancer

Clinical Trial NSABP47

Smith et al48 Hutcheon et al49

50

Green et al

Untch et al51

von Minckwitz et al52

Evans et al53

Number of Patients

Tumor Stage/Size

Chemotherapy Regimen

Operable T1c-T3 N0 T1-3 N1

AC for 4 cycles vs. AC for 4 cycles, TXT for 4 cycles

14%

2411

145

Operable T1c-T3 N0 T1-3 N1

CVAP for 8 cycles vs. CVAP for 4 cycles, TXT for 4 cycles

15%

Operable

TXL weekly for 3 of 4 weeks for 4 cycles, FAC for 4 cycles vs. weekly TXL for 12 weeks, FAC for 4 cycles

258

631

913

362

pCR

Primary tumor > 3 cm or inflammatory

E for 3 cycles, TXL for 3 cycles every 2 weeks (dose-dense) vs. ETXL for 4 cycles

Operable

AC for 4 cycles, TXT for 4 cycles vs. AT for 4 cycles (dose-dense) every 2 weeks

Locally advanced, operable

AC for 6 cycles vs. AT for 6 cycles

26%

31%

DFS Benefit

OS Benefit

NR

NR

Yes*

Yes*

NR

NR

NR

NR

NR

NR

NR

NR

14% 29% 18% 10% 22% 12% 12% 8%

*Benefit for CVAP-TXT versus CVAP. Abbreviations: AC = doxorubicin/cyclophosphamide; AT = doxorubicin/docetaxel; CVAP = cyclophosphamide/vincristine/doxorubicin/prednisolone; DFS = disease-free survival; E = epirubicin; ETXL = epirubicin/paclitaxel; FAC = 5-fluorouracil/doxorubicin/cyclophosphamide; NR = not reported; NSABP = National Surgical Adjuvant Breast and Bowel Project; pCR = pathologic complete response; TXL = paclitaxel; TXT = docetaxel

paclitaxel/CMF as neoadjuvant therapy.31 Results on the efficacy of the neoadjuvant doxorubicin/paclitaxel/CMF regimen on locoregional disease were described previously in this article and in Table 1.22-31 Outcome results on the comparison between the neoadjuvant doxorubicin/paclitaxel/ CMF regimen and the 2 adjuvant regimens (A/CMF and doxorubicin/paclitaxel/CMF) are not available as of yet. One study explored different schedules of administering neoadjuvant paclitaxel in 258 patients with operable breast cancer.50 Patients were randomized to receive either weekly paclitaxel or standard paclitaxel given every 3 weeks to determine if different schedules or dose densities of paclitaxel improve pCR rates. The doses of weekly paclitaxel varied based on the clinical status of axillary lymph nodes. Patients with clinically negative axillary nodes received 80 mg/m2/ week for 12 weeks. Patients with clinically involved axillary nodes received 150 mg/m2/week for 3 weeks followed by a 1week break (1 cycle) for 4 cycles. Standard paclitaxel was given as a 24-hour continuous infusion at 225 mg/m2 every 3 weeks for 4 cycles. After completion of paclitaxel, all patients received 4 cycles of neoadjuvant FAC. Rates of pCR were significantly higher in patients who received the weekly paclitaxel regimen (28% for clinically node-positive patients and 29% for clinically node-negative patients) than in those who received the standard paclitaxel regimen (13.7% for clinically node-positive patients and 13% for clinically node-negative patients).

Another neoadjuvant trial was designed to compare the frequency of breast-conserving surgery, response rates, and safety between 2 neoadjuvant epirubicin/paclitaxel regimens given either in a dose-dense sequential fashion (epirubicin 150 mg/m2 every 2 weeks for 3 cycles followed by paclitaxel 250 mg/m2 every 2 weeks for 3 cycles with colony-stimulating factor support) or in combination at standard doses (epirubicin 90 mg/m2 plus paclitaxel 175 mg/m2 every 3 weeks for 4 cycles).51 After surgery, all patients received 3 cycles of adjuvant CMF. A total of 631 patients enrolled in the study, of whom response and safety information was available in 475. Results demonstrated increased efficacy with the sequential dose-dense regimen. The rate of breastconserving surgery was significantly increased in patients treated with the dose-dense regimen (66% vs. 55 %; P = 0.016), as was the rate of pCR (18 % vs. 10 %; P = 0.030). There was also a nonsignificant increase in the proportion of patients with histologically negative nodes among those treated with the dose-dense regimen compared to those treated with the combination (51% vs. 42%; P = 0.098). A study of similar design was reported by another German group.52 This neoadjuvant study compared a dose-dense combination regimen of (AT) doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 2 weeks for 4 cycles to a sequential regimen of neoadjuvant AC followed by neoadjuvant docetaxel as used in the NSABP B-27 trial. A total of 913 patients were randomized. The study was stopped early by the

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Neoadjuvant Chemotherapy in Operable Breast Cancer data-monitoring committee when it became apparent that there was an advantage in favor of the sequential arm compared to the dose-dense combination arm relative to the primary endpoint of the study, which was pCR rate. Last, a study conducted in the United Kingdom compared 2 combination regimens given as neoadjuvant therapy for 6 cycles each.53 A total of 362 patients with operable or locally advanced breast cancer were randomized to receive either AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2) or AT. Clinical response rates for 184 evaluable patients at the time of presentation of results were 78% for AC and 88% for doxorubicin/paclitaxel (P = 0.11). At surgery, pathologic involvement of axillary nodes was present in 63% of patients treated with AC and 64% of patients treated with doxorubicin/paclitaxel, and pCR in the breast was seen in 12% of patients treated with AC versus 8% of patients treated with doxorubicin/paclitaxel (P = 0.26). The authors concluded that there were no differences in efficacy between these 2 neoadjuvant regimens but, because only two thirds of the patients in the study have completed neoadjuvant therapy, the results are considered preliminary. Although the results of most of the recently disclosed neoadjuvant studies are preliminary and could change with time, and although no disease-free and overall survival data are available yet, these data are beginning to point out some general trends regarding the activity of various taxanebased regimens relative to the achievement of pCR in the breast and axillary nodes. It appears that the sequential regimens of an anthracycline followed by a taxane produce generally higher pCR rates than the combination regimens of an anthracycline plus a taxane. This may be the result of the longer duration of therapy typically seen with sequential regimens, but it is possible that it is partially related to the addition of cyclophosphamide. Combination regimens of an anthracycline and a taxane produced similar response rates to those achieved by AC. Finally, no information exists on pCR rates with the neoadjuvant administration of the triple combination of an anthracycline, a taxane, and cyclophosphamide, a combination that showed promising activity in the adjuvant setting based on the preliminary results of a randomized adjuvant trial.54

Unanswered Questions and Future Directions with Neoadjuvant Chemotherapy Despite significant progress with neoadjuvant chemotherapy, several unanswered questions remain. The most pressing one from a research standpoint is whether the higher pCR rates observed with the taxane-containing chemotherapy regimens will translate to an overall survival improvement. Provided that the correlation between pathologic response and outcome is confirmed in these studies, the neoadjuvant setting will be valuable in the rapid evaluation of novel chemotherapy regimens (such as docetaxel/capecitabine and other combinations with potential synergistic effects)55-57 as well as in the evaluation of different promising

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ways of administering existing chemotherapy regimens (such as in a dose-dense fashion).58 A remaining important question with clinical and research implications is whether there will be a role for additional adjuvant chemotherapy in patients who are found to have residual disease in the breast and/or axillary nodes after neoadjuvant chemotherapy. Regarding the effects of neoadjuvant chemotherapy on locoregional disease, it remains to be determined conclusively whether more-effective neoadjuvant chemotherapy regimens will be able to further reduce the extent of surgery in the breast and—perhaps more importantly—in the axilla by causing additional tumor downstaging. The indications for locoregional radiation therapy for patients with involved nodes after neoadjuvant chemotherapy need to be further refined. Finally, the more important and provocative question is whether tumor response could be used in the future as a guide for selecting optimal sequential neoadjuvant chemotherapy regimens that will eventually lead to improvement in overall survival compared to the standard adjuvant approach. Although answers to some of these questions will be forthcoming from recently completed and currently ongoing neoadjuvant trials, the last question can be answered only by designing innovative trials that will compare a tailored neoadjuvant approach to predefined standard adjuvant chemotherapy regimens.

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