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© 2003 American Society for Clinical Oncology Is Surgery Necessary After Complete Clinical Remission Following Neoadjuvant Chemotherapy for Early Breast Cancer?From the Royal Marsden Hospital, London, United Kingdom. Address reprint requests to Ian E. Smith, MD, Breast Unit, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: ian.smith{at}rmh.nthames.nhs.uk.
Purpose: This retrospective analysis aimed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission (cCR) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery. Patients and Methods: One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospectively maintained database of 453 patients. Of these, 67 patients had undergone surgery as their primary locoregional therapy, and 69 patients had radiotherapy alone. Outcome was assessed in relation to local recurrence-free survival, disease-free survival, and overall survival. Results: Median follow-up was 63 months in the surgery group and 87 months in the no surgery group. Prognostic characteristics were well balanced between the two groups. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% v 76%; 10-year, 60% v 70%, P = .9) between the two groups. There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group (21% v 10% at 5 years; P = .09), but no long-term failures of local control. Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8%. Conclusion: In patients achieving a cCR to neoadjuvant chemotherapy, radiotherapy alone achieve survival rates as good as with surgery, but with higher local recurrence rates. Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospective trial.
SURGERY IS the mainstay of early breast cancer management. In recent years, it has become accepted that conservative surgery is as effective as mastectomy,1,2 but the concept of avoiding surgery altogether is novel. Neoadjuvant chemotherapy is increasingly used in the management of patients with large operable breast cancers, reducing the need for mastectomy and using the primary tumor as an in vivo measure of chemosensitivity.3 Randomized trials comparing neoadjuvant chemotherapy with postoperative adjuvant chemotherapy have shown similar rates of local control and overall survival, and a lower mastectomy rate with the neoadjuvant approach.3–6 After neoadjuvant chemotherapy, patients usually undergo either conservative surgery or mastectomy, depending on the site and size of the residual tumor. Around 30% of patients achieve a complete clinical remission (cCR) following neoadjuvant chemotherapy, with a reported range of 16% to 66%, depending on the study population, the treatment schedule, and the agents used.6–10 cCR correlates with improved disease-free survival (DFS),3,6,11 and the question arises whether surgery before radiotherapy is necessary at all in this subgroup. In the past, some studies have included patients who did not undergo surgery following neoadjuvant chemotherapy, but these reported little in the way of survival data as compared with similar groups undergoing surgery.7,12–19 At the Royal Marsden, we have a prospectively maintained database of patients with large, operable breast cancer treated with neoadjuvant chemotherapy since 1986. Initially, patients who achieved a cCR were often offered the option of standard radiotherapy without surgery. This policy stopped in 1995 following an audit and subsequent publication suggesting a high local recurrence rate.12 We have now expanded this analysis to compare the survival and local recurrence rates between patients achieving a cCR who had surgery and those who did not, over a more extended period and with a median follow-up of 7.3 years in the no surgery group.
Patient Selection A sequential and prospectively maintained database was retrospectively searched, for patients who received neoadjuvant chemotherapy for operable breast carcinoma. Neoadjuvant chemotherapy was given for cytologically or histologically proven breast cancer with a tumor size  3 cm. (Occasionally patients with smaller cancers were also included.) Metastatic disease was excluded using chest x-ray, CBC, and biochemical liver and bone profiles; further investigations were only carried out if clinically indicated. Patients were excluded if they had inflammatory breast carcinoma or locally advanced breast cancer (defined as inoperable according to the Haagensen criteria20), or if they refused surgery or radiotherapy. Only patients who achieved a clinically complete remission were selected for inclusion in this analysis. Patient characteristics, including clinical staging, type of chemotherapy and number of courses, treatment to the breast and axilla, endocrine treatment, and pathological response in breast and axilla, were recorded. Data available as of December 1, 2002, were used for this analysis.
Treatment Following chemotherapy, patients received surgery (conservative or mastectomy) or no surgery. Initially, the Unit often offered the option of no surgery to patients who achieved a cCR, until an internal audit in 1995 suggested a higher local recurrence rate. Subsequently, all patients were routinely offered surgery. All patients undergoing breast conserving surgery, and all nonsurgery patients were given breast radiotherapy. The range of doses given to the breast was 46 to 50 Gy, with boosts to the tumor bed at 11.1 to 17.5 Gy. Our policy was also to give radiotherapy to the axilla if surgically untreated (dose range, 46 to 50 Gy), and to the supraclavicular fossa (dose range, 46 to 50 Gy) where axillary node status was positive or unknown. Radiotherapy was also given to patients with involved axillary nodes after mastectomy. Tamoxifen 20 mg was given to patients whose tumors were estrogen receptor-positive or unknown.
Definition of cCR
Follow-Up
Statistical Analysis
Patient Characteristics Of 453 patients identified for neoadjuvant chemotherapy between 1986 and 1999, 136 (30%) had a cCR, 67 underwent surgery as their primary locoregional treatment modality, and 69 had no surgery but had radiotherapy alone. Patient characteristics, including age, menopausal status, T-stage, and N-stage, are presented in Table 1  . There were no significant differences between the two groups in terms of baseline characteristics, although in the no surgery group, there were nonsignificant trends toward larger tumors and more premenopausal patients. The diagnosis was made on the basis of core biopsy in 58 (87%) of 67 of the surgery patients and 58 (84%) of 69 of the no surgery patients. The remainder of the patients was diagnosed on cytology alone. Treatment details, including types of chemotherapy, cycles administered, cycles to cCR, and local management of the breast and nodal areas, are presented in Table 2. In those patients undergoing surgery, 17 (25%) achieved a pathological complete remission (no residual in situ or invasive disease in the breast or regional lymph nodes), and in 19 (28%), residual tumor was detected in the axillary lymph nodes. Median follow-up differs between the two groups, reflecting the change in policy with regards to surgery, and was 63 months (range, 21 to 134 months) in the surgery group, and 87 months (range, 13 to 180 months) in the no surgery group.
DFS and Overall Survival There were no significant differences in DFS between patients who underwent surgery and those who underwent radiotherapy alone (64% v 61% at 5 years, and 52% v 46% at 10 years; P = .7; Fig 1 ). Similarly, there were no differences in metastasis-free survival between the two groups (70% v 75% at 5 years; P = .6; Fig 2). Overall survival at 5 years was 74% in those undergoing surgery and 76% in those without surgery. These results were maintained at 10 years follow-up (60% v 70%; P = .9; Fig 3). In patients who had surgery after chemotherapy, the extent of surgery (mastectomy v conservative) did not effect DFS or overall survival (data not shown).
Local Relapse No significant difference was seen in rates of locoregional only (breast or axilla, no metastatic disease) recurrence free-survival, but there was a trend toward higher recurrence rates for the no surgery group than for the surgery group (locoregional only recurrence rate, 21% v 10% at 5 years; P = .09; Fig 4 ). Likewise, there was a nonsignificant trend toward a higher overall locoregional recurrence rate for the no surgery group compared with the surgery group (25% v 17%; P = .2; Fig 5). The patterns of relapse are shown in Table 3. Sixteen patients in the no surgery group had isolated locoregional recurrences; in 15 cases these were in the breast alone, and one patient had a recurrence in both the breast and axilla. In these 16 patients, locoregional recurrences were successfully managed with surgery in 15 patients (11 mastectomy, four conservative surgery), and in one patient, with chemotherapy followed by mastectomy. No further failures of local control occurred in any of these patients.
Ultrasound In 51 of the 69 patients who were treated without surgery, ultrasound examinations were performed following completion of primary chemotherapy. Eighteen (35%) of patients had no evidence of residual disease on ultrasound examination (uCR); the remainder had either a residual mass or parenchymal distortion despite there being no clinically detectable disease. In this small subgroup, there was a nonsignificant trend to lower rates of local relapse in patients achieving a uCR, compared with those who had an ultrasound-detected residual mass or parenchymal distortion (8% v 21% at 5 years, P = .4, Fig 6 ). Ultrasound was available for 50 (75%) of the 67 patients who underwent surgery. Thirteen (26%) of these 50 had a uCR. Of the 13 patients who had a uCR, 7 (54%) had a pathological complete remission at the time of surgery.
This retrospective analysis of patients achieving a complete clinical remission following neoadjuvant chemotherapy is nonrandomized, but compares well-matched populations who were all treated at a single institution. The small size of the study would only allow the detection of differences in DFS and overall survival of at least 25%. Nonetheless the data as presented show no evidence for survival detriment out to 7.3 years and no increased risk of distant metastases for no surgery compared with surgery. However the results also demonstrate a trend toward increased local recurrence in the no surgery group that would probably have become significant with larger numbers. Our 5-year local recurrence rate of 25% in the no surgery group is similar to that reported in other studies where radiotherapy was used as sole locoregional therapy. Scholl et al23 demonstrated a 5-year local recurrence rate of 30% in 45 patients who achieved a cCR to primary chemotherapy and were treated with radiotherapy alone. Similarly Mauriac et al7 treated 44 women who achieved a cCR with primary chemotherapy with irradiation to the breast and nodal areas alone. After a median follow-up of 124 months, 15 local relapses were reported. Both of these studies showed a trend toward higher locoregional recurrence rates in those patients having radiotherapy without surgery, compared with those who underwent surgery. The recurrence rate in our surgically treated group is similar to those reported in other studies, indicating that this is a valid comparator group. In the National Surgical Adjuvant Breast and Bowel Project B18 (NSABP-B18) trial, 1,523 women with operable breast cancer were randomly assigned to preoperative or postoperative anthracycline-based chemotherapy.6 Patients in NSABP-B18 had better baseline prognostic features than patients in the current analysis, with fewer T3 and T4 tumors (13% v 42%), and with fewer node-positive patients (26% v 49%). In the 504 assessable women who received preoperative chemotherapy followed by lumpectomy and radiotherapy, 13.6% had an ipsilateral breast tumor recurrence, or other local or regional recurrence as their first reported site of treatment failure. Local failure rates may have been lower in those patients achieving a cCR before surgery (5.3% ipsilateral breast tumor recurrence alone), but details of nodal and other local failure were not presented. Our data are comparable with 5-year overall and isolated locoregional recurrence rates in those undergoing surgery of 17% and 10%, respectively. Conventional wisdom argues that higher local recurrence rates are associated with adverse long-term survival. Our results do not support this, with a median follow-up of 7.3 years for patients treated without surgery. Two recent reports on major trials from the NSABP and the Milan Cancer Institute with 20 years of follow-up likewise suggest that higher local recurrence rates associated with less intensive local therapy may not impact survival.1,2 The avoidance of surgery altogether would eliminate common postoperative problems including chronic arm morbidity, pain, seroma formation, and wound infections.24,25In addition, some of the psychological and cosmetic impact of surgery might be avoided. Rare anesthetic problems and complications such as thromboembolic disease would also not occur, and considerable inpatient resource savings would be made. It could be argued, therefore, that no surgery remains an option that some patients might wish to take following the achievement of a complete clinical remission, on the basis that most will not relapse, and those who do will have no survival disadvantage or long-term local control problems. One downside of such an approach, however, is that recurrences in an irradiated breast will usually require mastectomy, and the opportunity for conservative surgery will be lost. We have previously shown in patients with a complete clinical remission to neoadjuvant chemotherapy, that the presence of a residual ultrasound abnormality is not necessarily indicative of residual cancer.26 In the current study, the locoregional relapse-free survival in patients with an ultrasound-confirmed CR was more than 90%, and was comparable to that seen in the those patients undergoing surgery. In this subgroup of patients, it may be legitimate to withhold surgery and offer radiotherapy alone. Such an approach would also circumvent the practical issue of where to direct surgery in these patients with no residual lesion identifiable on ultrasound. In the future, contrast-enhanced magnetic resonance imaging may also prove to be useful in response assessment, as residual tumor size on magnetic resonance imaging has been shown to correlate well with pathological findings following neoadjuvant chemotherapy.27,28 These current observations are based on small numbers of patients analyzed retrospectively, and therefore are no more than hypothesis-generating. A prospective randomized trial addressing the need for surgery after cCR would seem reasonable in patients with ultrasound or magnetic resonance imaging-defined complete remissions.
The authors indicated no potential conflicts of interest.
1. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241, 2002
2. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227–1232, 2002 3. Smith IE, Lipton L: Preoperative/neoadjuvant medical therapy for early breast cancer. Lancet Oncology 2:561–570, 2001[CrossRef][Medline]
4. Powles TJ, Hickish TF, Makris A, et al: Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 13:547–552, 1995 5. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial S6. Eur J Cancer 5:645–652, 1994 6. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672–2685, 1998[Abstract]
7. Mauriac L, MacGrogan G, Avril A, et al: Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: A unicentre randomized trial with a 124-month median follow-up — Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol 10:47–52, 1999
8. Smith IE, Walsh G, Jones A, et al: High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. J Clin Oncol 13:424–429, 1995
9. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in operable breast cancer: Eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93–100, 1998
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12. Ellis P, Smith I, Ashley S, et al: Clinical prognostic and predictive factors for primary chemotherapy in operable breast cancer. J Clin Oncol 16:107–114, 1998 13. Calais G, Descamps P, Chapet S, et al: Primary chemotherapy and radiosurgical breast-conserving treatment for patients with locally advanced operable breast cancers. Int J Radiat Oncol Biol Phys 26:37–42, 1993[Medline] 14. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507–2516, 1988[CrossRef][Medline] 15. Touboul E, Lefranc JP, Blondon J, et al: Multidisciplinary treatment approach to locally advanced non-inflammatory breast cancer using chemotherapy and radiotherapy with or without surgery. Radiother Oncol 25:167–175, 1992[CrossRef][Medline] 16. 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[CrossRef][Medline] 17. Hery M, Namer M, Moro M, et al: Conservative treatment (chemotherapy/radiotherapy) of locally advanced breast cancer. Cancer 57:1744–1749, 1986[CrossRef][Medline] 18. Schaake-Koning C, van der Linden EH, Hart G, et al: Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: A randomized clinical study. Int J Radiat Oncol Biol Phys 11:1759–1763, 1985[Medline] 19. Baillet F, Rozec C, Ucla L, et al: Treatment of locally advanced breast cancer without mastectomy: 5- and 10-year results of 135 tumors larger than 5 centimeters treated by external beam therapy, brachytherapy, and neoadjuvant chemotherapy. Ann N Y Acad Sci 698:264–270, 1993[CrossRef][Medline] 20. Haagensen CD, Stout AP: Carcinoma of the breast: Criteria of operability. Ann Surg 118:859–870, 1943[Medline] 21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 22. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: Analysis and examples. Br J Cancer 35:1–39, 1977[Medline] 23. Scholl SM, Pierga JY, Asselain B, et al: Breast tumour response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer 31:1969–1975, 1995[CrossRef] 24. Tasmuth T, von Smitten and Kalso E: Pain and other symptoms during the first year after radical and conservative surgery for breast cancer. Br J Cancer 74:2024–2031, 1996[Medline] 25. Woodworth PA, McBoyle MF, Helmer SD, et al: Seroma formation after breast conservation surgery: Incidence and predicting factors. Am Surg 66:444–450, 2000[Medline] 26. Seymour MT, Moskovic EC, Walsh G, et al: Ultrasound assessment of residual abnormalities following primary chemotherapy for breast cancer. Br J Cancer 76:371–376, 1997[Medline]
27. Partridge SC, Gibbs JE, Lu Y, et al: Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. AJR Am J Roentgenol 179:1193–1199, 2002 28. Cheung YC, Chen SC, Su MY, et al: Monitoring the size and response of locally advanced breast cancers to neoadjuvant chemotherapy (weekly paclitaxel and epirubicin) with serial enhanced MRI. Breast Cancer Res Treat 78:51–58, 2003[CrossRef][Medline] Submitted May 30, 2003; accepted October 10, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher’s exact test for categoric variables and the Mann-Whitney nonparametric test for continuous and ordered categoric variables. DFS was defined as the date of treatment to date of first relapse at any site, or appearance of a second primary breast cancer. Overall survival was measured from the date of first treatment to death from any cause or last follow-up. Locoregional recurrence was defined as tumor arising in the treated breast, chest wall, or regional lymph nodes. Survival curves were calculated using the Kaplan-Meier method, and differences were assessed by the log-rank statistic.
