10.1245/ASO.2005.04.003
Annals of Surgical Oncology 12:161-166 (2005)
© 2005 Society of Surgical Oncology
Immediate Reconstruction After Neoadjuvant Chemotherapy: Effect on Adjuvant Treatment Starting and Survival
Sebastien Gouy, MD1,
Roman Rouzier, MD1,2,
Marie-Christine Missana, MD1,
David Atallah, MD3,
Omar Youssef, MD4 and
Lise Barreau-Pouhaer, MD1
1 Breast Surgery Unit, Institut Gustave-Roussy, 39 Rue C. Desmoulins, 94805 Villejuif Cedex, France
2 Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Box 424, 1515 Holcombe Boulevard, Houston, Texas 77030
3 Department of Gynaecologic Surgery, Hotel-Dieu, PO Box 16-6830, Beirut, Lebanon
4 Department of Surgical Oncology, National Cancer Institute, Cairo, Egypt
Correspondence: Address correspondence and reprint requests to: Roman Rouzier, MD; E-mail: rrouzier{at}mdanderson.org.
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ABSTRACT
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Background: For patients treated with initial surgery, the safety of immediate breast reconstruction after mastectomy has been demonstrated. Some concerns exist after neoadjuvant chemotherapy because this sequence is proposed for patients with large tumors and for whom adjuvant therapies are considered cornerstones of treatment. In this study, we sought to determine whether reconstruction after neoadjuvant chemotherapy and mastectomy for large operable breast cancer affects the interval between surgery and adjuvant treatment and affects survival.
Methods: A single-institution retrospective analysis was performed by using the database of the Institut Gustave-Roussy.
Results: Forty-eight patients who had undergone mastectomy and immediate reconstruction (implant, 60%) followed by adjuvant chemotherapy were identified. They were compared with 181 patients who underwent mastectomy without reconstruction and with 32 patients who underwent mastectomy followed by delayed reconstruction (implant, 19%). No difference was found concerning the interval between surgery and adjuvant chemotherapy: 26 vs. 23 days for patients with immediate breast reconstruction and for patients treated with modified radical mastectomy followed or not by delayed reconstruction, respectively (P = .11). No difference was found concerning the onset of radiotherapy: 87 vs. 81 days (P = .22). Survival was not different in patients treated with immediate reconstruction compared with those with mastectomy alone.
Conclusions: Immediate breast reconstruction does not delay the starting of adjuvant therapy and has no significant effect on local relapse–free or distant disease–free survival. Additional data are needed concerning the use of flap for this indication.
Key Words: Breast cancer • Neoadjuvant chemotherapy • Immediate reconstruction • Survival
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INTRODUCTION
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As compared with modified radical mastectomy alone, immediate breast reconstruction (IR) after neoadjuvant chemotherapy (NC) does not delay the starting of adjuvant therapy and has no significant effect on local relapse–free or distant disease–free survival. Breast conservation has become the standard treatment for early breast carcinoma. For patients with large breast carcinoma at presentation, NC has been demonstrated to reduce tumor size, thus allowing breast preservation, in approximately 50% of cases, whereas mastectomy is still required for other patients.1,2 IR can be a viable option for these patients. Nevertheless, fear about delaying the onset of adjuvant treatment raised debate about this option, especially because systemic treatment has become a cornerstone in the management of patients with large breast carcinoma. The deleterious effect of irradiation on the cosmetic results and the possibility that radiotherapy could be less efficient after reconstruction are other problems that have been also raised.3 A consensus conference was held in Philadelphia in April 2003 to review the evidence to support NC.4 The experts stated that IR may be offered to women undergoing mastectomy after NC, but with several qualifiers, including a requirement for postoperative radiotherapy and adjuvant chemotherapy. They also stated that the technique of reconstruction should be adapted to postoperative treatment modalities. However, no references were cited to support these statements because of the lack of published data. The aims of this study were to compare the delay between surgery and adjuvant therapy and to evaluate local control and survival in a cohort of patients treated with NC followed by mastectomy with or without reconstruction.
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MATERIALS AND METHODS
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The database of the Institut Gustave-Roussy was reviewed to select 457 women with invasive T2 (
3 cm) to T4a–c breast carcinomas referred between January 1985 and October 1995. They received neoadjuvant anthracycline-based chemotherapy, followed by surgery and adjuvant chemotherapy, with or without radiotherapy. Subsequent surgery was a lumpectomy when the tumor was <3 cm in diameter or a mastectomy for tumors exceeding 3 cm and for bifocal tumors. Among the 457 patients, 261 patients underwent a mastectomy. This cohort of patients constitutes the study population: 181 patients underwent a mastectomy without reconstruction, 48 underwent a mastectomy and IR, and 32 underwent a mastectomy followed by delayed reconstruction (DR). Patient characteristics are listed in Table 1
. According to the International Union Against Cancer classification, 123 patients had T2 tumors, 101 had T3 tumors, and 37 had T4 tumors. One hundred three patients were clinically N0, and 148 were N1 or N2. Pathologic diagnosis and grading were performed on a tumor tissue sample obtained by a core needle biopsy performed before treatment. The tumors corresponded to infiltrating ductal carcinoma in 88% (n = 230) and infiltrating lobular carcinoma in 12% (n = 31). The histological grade was assessed according to the Scarff, Bloom, Richardson grade. Three (90 patients) or 4 cycles (171 patients) of preoperative chemotherapy were administered at 21-day intervals or longer, depending on the bone marrow recovery. Four chemotherapy regimens were used: AVCMF (Adriamycin [doxorubicin] 50 mg/m2, vincristine 1 mg/m2, cyclophosphamide 600 mg/m2, methotrexate 30 mg/m2, and 5-fluorouracil 900 mg/m2) in 127 patients; FAC 50 and FEC 50–60 (Adriamycin [doxorubicin] 50 mg/m2/epirubicin 50/60 mg/m2, cyclophosphamide 600 mg/m2, and 5-fluorouracil 900 mg/m2) in 17 and 86 cases, respectively; or FEC 100 (epirubicin 100 mg/m2, cyclophosphamide 1000 mg/m2, and 5-fluorouracil 1000 mg/m2) in 31 patients. The clinical response to chemotherapy was assessed by the oncologist and the surgeon. Patients in whom the initial breast tumor could not be identified on palpation were defined as complete responders. A regression >50% (International Union Against Cancer definition) was considered as a partial response. The disease was considered as progressive if the postchemotherapy size was >125% of the initial tumor size. All other patients were classified as having stable disease.
Three breast reconstruction techniques were used during the study period: latissimus dorsi myocutaneous flap with or without an implant, transverse rectus abdominis myocutaneous flap, and implant alone. The indication for and the choice of reconstruction procedure were based on patient and surgeon motivation (preference). Adjuvant chemotherapy consisted of two or three cycles of FAC 50 or FEC 50/60/100 for 214 patients. Forty-seven patients did not receive adjuvant chemotherapy because they had been included in a randomized trial. Radiotherapy to the chest wall was given to 250 patients: the dose was 45 Gy. Hormonal therapy (tamoxifen 20 mg/day) was prescribed for all postmenopausal patients and for premenopausal patients with estrogen receptor–positive tumors. After treatment, patients were seen alternately by the oncologist, the radiotherapist, and the surgeon. Capsular contracture was assessed with Spear and Baker’s classification.5
Frequency distributions were tested with the 
2 test. Analysis of variance or nonparametric Mann-Whitney U-tests were used for continuous variables, depending on the distribution of the variable. Survival curves were constructed with the Kaplan-Meier method. Survival curves were compared by using the log-rank test. All significance tests were two tailed, and differences were considered to be statistically significant at P < .05. Statistical analyses were performed with SPSS (SPSS Inc., Chicago, IL).
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RESULTS
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A modified radical mastectomy was performed for 213 patients; among them, 32 patients underwent a DR. Forty-eight patients underwent an IR. The three populations were similar according to T stage; nodal status; histological type; Scar., Bloom, and Richardson grade; estrogen receptor status; and chemotherapy regimen (Table 1
). Conversely, patients undergoing reconstruction were significantly younger than those who did not undergo reconstruction: 44 and 46 years (IR and DR, respectively) versus 51 years (P < .04). The number of preoperative chemotherapy courses was significantly different in the IR group compared with other groups. The distributions of clinical response rates were not statistically different among the three groups. Only three patients (one patient in each group) had a pathologic complete response (breast tissue without residual malignant epithelial cells, with residual invasive malignant epithelial cells without mitosis and representing <5% of the tumor mass or tumors with a strictly in situ malignant residual component). The methods of reconstruction are listed in Table 1. Patients who had undergone an IR underwent reconstruction significantly more frequently with an implant alone than patients who underwent a DR. Among the 48 patients who underwent an IR, 1 patient underwent reoperation in the early postoperative course (implant deflation). In the DR group, three patients underwent reoperation because of hematoma or flap necrosis.
The delays between surgery and the onset of adjuvant treatment are reported in Table 2. No difference was found concerning the interval between surgery and adjuvant chemotherapy: 26 vs. 23 days for patients who had an IR and for patients treated with modified radical mastectomy only, respectively (P = .11). The delays were also compared according to the technique of IR, and no significant differences were found. The mean interval before surgery and the onset of chemotherapy was 25 days for patients reconstructed with a simple implant or expander and 28 days for patients reconstructed with a myocutaneous flap (P = .23). Concerning the onset of radiotherapy, the mean delays were 88 and 82 days for the patients reconstructed with a simple implant and a flap, respectively (P = .58).
The local relapse–free survivals and distant disease–free survivals are represented in Figs. 1 and 2. The 5-year local relapse–free survivals were respectively 89%, 90%, and 93% for the IR, no-reconstruction, and DR groups, respectively (Fig. 1). There was no significant difference among the three groups. The 5-year distant disease–free survivals were 58%, 59%, and 80% for patients treated with no reconstruction, with IR, and with DR, respectively. The 10-year distant disease–free survivals were 43%, 48%, and 64% for patients treated with no reconstruction, IR, and DR, respectively (P = .04; Fig. 2).
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FIG. 1. Local relapse–free survival according to the surgical procedure: mastectomy without reconstruction (solid line), with immediate reconstruction (short dashed line), and with delayed reconstruction (long dashed line).
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FIG. 2. Distant disease–free survival according to the surgical procedure: mastectomy without reconstruction (solid line), with immediate reconstruction (short dashed line), and with delayed reconstruction (long dashed line).
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Concerning the outcome of reconstruction, 24 (50%) patients in the IR group and 16 (50%) in the DR group had additional surgery on the reconstructed breast (implant removal, flap amelioration, or both) during the first 2 years after the reconstruction surgical procedure. Twenty-five (64%) of the 39 patients who underwent IR with an implant (with or without a latissimus dorsi flap) developed a capsular contracture (Baker II to IV).
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DISCUSSION
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Breast reconstruction after mastectomy for treatment of cancer is becoming increasingly popular: approximately 15% of patients treated with mastectomy receive breast reconstruction.6,7 Historically, reconstructions were performed during a second surgical procedure after completion of adjuvant treatment and after a period of disease-free survival.8 During the last decade, surgical teams have demonstrated that IR has significant advantages over DR: psychological, esthetic, and financial benefits have been demonstrated.9,10 For patients treated with NC, few data are available in the literature. We demonstrate in this study that IR does not delay the start of adjuvant therapies and that it has no significant effect on local relapse–free or distant disease–free survival.
These results were achieved in a series of 261 women for whom initial clinical and follow-up data were prospectively registered in a database. There are obvious limitations in the interpretation of the retrospective study that must be acknowledged, however. Patients who underwent reconstruction (IR or DR) were significantly younger than patients who had mastectomy without reconstruction. Both patient and physician preferences can easily explain this findings: other authors have recognized the same trend.11,12 It is unlikely that differences in age could have introduced a bias, mainly because young age has been demonstrated to be a bad prognostic factor for both distant and local recurrences.13 Even if no statistical difference could be observed between the chemotherapy regimens used, heterogeneity of primary chemotherapy regimens is another limitation of this study. Patients who underwent IR were more likely to have received four courses of NC (50%) than were patients who did not have reconstruction (30%) or patients who had DR (34%). We did not find a clear explanation for this finding. However, the rates of clinical response were similar among the groups, and patients who underwent IR were more likely to have metastatic lymph nodes. It is therefore unlikely that the difference in the number of preoperative chemotherapy cycles may have counteracted a potential detrimental effect from the IR.
In a review of the literature, few studies were identified that address the question of whether IR delays the starting of adjuvant chemotherapy. Moreover, in series of patients with locally advanced breast cancer, most patients (40% to 100%) had not been treated with NC, thus precluding direct comparison with our study. In the study of Allweis et al.,14 49 patients were identified who had undergone mastectomy and IR followed by adjuvant chemotherapy. They were compared with 308 patients who underwent mastectomy without reconstruction. The time to chemotherapy was significantly longer in the group that received no reconstruction: 53 vs. 41 days (P = .039). In the series of Newman et al.,15 the median interval between surgery and postoperative chemotherapy was 35 days for the IR patients and 21 days for the patients not undergoing IR. This difference was marginally significant. To our knowledge, only two studies have evaluated the delay between surgery and adjuvant treatment in patients with operable large carcinoma treated with NC, mastectomy, and IR. However, in these two series, no comparison was made with patients treated without IR. In the series of Sultan et al.,16 which included 22 patients with locally advanced disease, the perioperative morbidity was 14%, but no patient experienced a delay in the resumption of chemotherapy. Deutsch et al.17 have reported a series of 31 patient treated by NC followed by mastectomy and IR with the transverse rectus abdominis musculocutaneous flap. Seventeen patients (55%) had postoperative complications, but only two patients (6%) had a delay in the resumption of chemotherapy. Our study is the first to compare the timing with control groups. In our series, the intervals between surgery and the onsets of adjuvant chemotherapy and radiotherapy were similar: 26 vs. 23 days for patients who had an IR and for patients treated with mastectomy without IR, respectively (P = .11). Data concerning the delay between IR by latissimus dorsi flap and chemotherapy are lacking. In our series, there was no significant difference, but the number of patients immediately reconstructed with flaps was low, and a type II statistical error cannot be excluded. Additional data concerning the use of flaps are needed for this indication.
Concerning the effect on survival, we found a significant difference in favor of patients who underwent a DR. In fact, patients with an early metastatic event were not offered a DR, thus explaining why in our study patients with DR had a longer survival than other patients (Fig. 2). To our knowledge, the survival rates according to reconstruction or not after NC and mastectomy have never been reported previously. The local relapse rate was not significantly higher in patients treated with breast reconstruction (IR or DR) than in those with mastectomy alone. No negative effect of IR on radiation efficiency could be suspected from our results. Our study also provides evidence that IR has no effect on disease-free survival.
In our study, most of the IRs were performed with implants. The method of reconstruction probably accounts for the low rate of complications in our series as compared with that of Deutsch et al.,17 in which all patients had a transverse rectus abdominis musculocutaneous flap breast reconstruction. Cosmetic results were not prospectively registered in our database; therefore, we did not include long-term cosmetic results in our study. Nevertheless, other authors have demonstrated that implant reconstruction deteriorates in a linear fashion, whereas reconstruction with flaps provides more stable cosmetic results. 15,18 Fifty percent of patients with IR underwent an additional procedure during the 2 years after the initial operation (mainly because of capsular contraction). This high rate of IR failure/early implant removal may be a cause for concern. The revisional surgery rate in this study is similar to that in previous reports,19 but one should keep in mind that metastasis developed in almost 30% of patients at 2 years in our series. Patients with metastatic disease are unlikely to have undergone reoperation, thus decreasing the revisional surgery rate. In fact, in our series, almost all patients received adjuvant radiotherapy, and it has been clearly demonstrated that IR failure and poor results are higher in patients who have received adjuvant radiotherapy.20 Some multidisciplinary teams recommend avoiding IR with implants in patients who will require postmastectomy radiotherapy. 3 For patients treated with NC, there is room for debate. The indication of chest wall irradiation mainly depends on two factors: tumor size and pathologic nodal status.21 The downstaging induced by NC interferes with these criteria: all patients receive chest wall radiation after NC because they are considered to have a potential nodal involvement before NC. For some of them, an initial surgical treatment would have resulted in a different adjuvant therapy: no irradiation would have been delivered in case of pathologically uninvolved nodes. It is likely that new radiological and surgical techniques, such as sentinel lymph node biopsy, realized before NC, could provide more accurate staging and give physicians more accurate information to tailor adjuvant radiotherapy and, therefore, facilitate the choice of IR.
We report in this study that immediate breast reconstruction with an implant, latissimus dorsi flap, or both does not delay the starting of adjuvant therapy and that it has no significant effect on local relapse–free or distant disease–free survival.
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ACKNOWLEDGMENTS
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Supported by the Association pour la Recherche sur le Cancer (RR).
Received for publication April 2, 2004.
Accepted for publication October 4, 2004.
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REFERENCES
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- Rouzier R, Extra JM, Carton M, et al. Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol 2001;19:3828–35.[Abstract/Free Full Text]
- Buchholz TA, Kronowitz SJ, Kuerer HM. Immediate breast reconstruction after skin-sparing mastectomy for the treatment of advanced breast cancer: radiation oncology considerations. Ann Surg Oncol 2002;9:820–1.[Free Full Text]
- Schwartz GF, Hortobagyi GN. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26–28, 2003, Philadelphia, Pennsylvania. Cancer 2004;100:2512–32.[CrossRef][Medline]
- Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg 1995;96:1119–23; discussion 1124.[Medline]
- Alderman AK, McMahon L Jr, Wilkins EG. The national utilization of immediate and early delayed breast reconstruction and the effect of sociodemographic factors. Plast Reconstr Surg 2003;111:695–703; discussion 704–5.[Medline]
- Polednak AP. How frequent is postmastectomy breast reconstructive surgery? A study linking two statewide databases. Plast Reconstr Surg 2001;108:73–7.[Medline]
- Spyrou GE, Titley OG, Cerqueiro J, Fatah MF. A survey of general surgeons’ attitudes towards breast reconstruction after mastectomy. Ann R Coll Surg Engl 1998;80:178–83.[Medline]
- Schain WS, Wellisch DK, Pasnau RO, Landsverk J. The sooner the better: a study of psychological factors in women undergoing immediate versus delayed breast reconstruction. Am J Psychiatry 1985;142:40–6.[Abstract/Free Full Text]
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- Reaby LL. Reasons why women who have mastectomy decide to have or not to have breast reconstruction. Plast Reconstr Surg 1998;101:1810–8.[Medline]
- de la Rochefordiere A, Asselain B, Campana F, et al. Age as prognostic factor in premenopausal breast carcinoma. Lancet 1993;341:1039–43.[CrossRef][Medline]
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- Newman LA, Kuerer HM, Hunt KK, et al. Feasibility of immediate breast reconstruction for locally advanced breast cancer. Ann Surg Oncol 1999;6:671–5.[Abstract]
- Sultan MR, Smith ML, Estabrook A, Schnabel F, Singh D. Immediate breast reconstruction in patients with locally advanced disease. Ann Plast Surg 1997;38:345–9; discussion 350–1.[Medline]
- Deutsch MF, Smith M, Wang B, Ainsle N, Schusterman MA. Immediate breast reconstruction with the TRAM flap after neoadjuvant therapy. Ann Plast Surg 1999;42:240–4.[Medline]
- Clough KB, O’Donoghue JM, Fitoussi AD, Nos C, Falcou MC. Prospective evaluation of late cosmetic results following breast reconstruction. I. Implant reconstruction. Plast Reconstr Surg 2001;107:1702–9.[CrossRef][Medline]
- Missana MC, Levy C, Barreau-Pouhaer L, Janin N. Radiotherapy and immediate breast reconstruction with myocutaneous flap in breast cancer of reserved prognosis (in French). Ann Chir Plast Esthet 2000;45:83–9.[Medline]
- Barreau-Pouhaer L, Le MG, Rietjens M, et al. Risk factors for failure of immediate breast reconstruction with prosthesis after total mastectomy for breast cancer. Cancer 1992;70:1145–51.[Medline]
- Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1539–69.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
