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Journal of Clinical Oncology, Vol 22, No 20 (October 15), 2004: pp. 4067-4074 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.068 Long-Term Follow-Up for Locally Advanced and Inflammatory Breast Cancer Patients Treated With Multimodality TherapyFrom the Cancer Therapeutics Branch, Medical Oncology Clinical Research Unit, Biostatistics and Data Management Section, and Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and Department of Medicine, University of Michigan, Ann Arbor, MI Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bldg 8, Rm 5101, 8901 Wisconsin Ave, Bethesda, MD 20889-5015; e-mail: swains{at}mail.nih.gov
PURPOSE: To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. PATIENTS AND METHODS: Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. RESULTS: OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. CONCLUSION: Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.
Locally advanced breast cancer (LABC) was originally characterized as inoperable breast cancer by Haagensen and Stout.1 Inoperable LABC has features such as skin ulceration, tumor fixation to the chest wall, satellite nodules, and palpable supraclavicular lymph nodes, as well as the findings used to describe inflammatory breast cancer (IBC), such as rapidly progressive breast erythema, warmth, edema, and induration.2 Today, LABC usually includes operable larger tumors (> 5 cm) as well as those traditionally considered inoperable because of the primary role neoadjuvant chemotherapy plays in their treatment. Neoadjuvant or primary chemotherapy is used to improve the operability of LABC and IBC, which are known to have a worse prognosis than early-stage breast cancer because of the high likelihood that the disease has already micrometastasized. IBC, often considered a subset of LABC, has a distinct clinicopathologic history3 and an associated poorer prognosis. Previously published data on the prognosis of patients with IBC and LABC is mostly limited to single-institution studies and case series. Fewer studies have been published about the long-term prognosis of LABC than IBC, at least partially because of the poor prognosis of these patients and also because of the heterogeneity of this classification. LABC includes patients with slower-growing neglected breast cancers as well as more rapidly growing cancers in poor locations such as chest wall, skin, or axilla, or with evidence of local spread, such as to the regional lymph nodes. In general, these features are understood to herald a poorer prognosis than breast cancers diagnosed at an earlier stage. Survival rates will depend on the mixture of these patients in a particular published series and the particular modes of therapy with which these patients are treated. Single-institution series of locally advanced breast cancer patients have reported 10-year survivals of 20% to 50%4-7 and 15-year survival data has not been previously reported. The largest database of IBC is the Surveillance, Epidemiology, and End Results registry, which reported a 3-year survival of 42% for IBC.8 Other institutions reporting large series of IBC patients treated with multimodality therapy have had 3- to 5-year survival rates of 20% to 74%,5 ,6 ,9-13 reflecting the variability in the criteria for diagnosing these patients and variation of therapy available to these patients over the last 30 years. Long-term data on IBC has been published by the M.D. Anderson Cancer Center14 (10- and 15-year survivals of 33% and 29%, respectively) and 10-year survivals in the range of 13% to 47% have been published by other institutions.5 ,6 ,15-20 At the National Cancer Institute, 107 stage III patients, including 46 IBC patients, were treated with multimodality therapy on a clinical trial consisting of primary and adjuvant doxorubicin-containing chemotherapy with hormonal synchronization and local therapy consisting of radiation therapy with or without mastectomy based on response to chemotherapy. The response to therapy and 5-year local recurrence information about these patients has been previously reported by Swain et al in 198721 and Pierce et al in 1992.22 It was reported that 31 (29%) of the initial 107 patients achieved pathologic complete response, and 5-year overall survival was 61% for stage IIIA patients, 36% for IBC patients, and 31% for stage IIIB non-IBC (NIBC) patients. Stage IIIA patients had a 12% local-regional recurrence rate compared with 36% for IBC patients at 5 years.22 Most of these patients, in addition to other patients treated on a separate protocol, were also included in an analysis of local therapy after neoadjuvant therapy.23 At the time of that study with a median follow-up of 8.3 years, local-regional recurrence rates among NIBC were lower (18.8%) than in IBC (36.4%). Although the National Cancer Institute has had significant experience with this rare disease, we have not previously reported our long-term experience with these IBC and LABC patients. We now present survival and recurrence data for these patients enrolled onto a single clinical trial with more than 16 years of median follow-up time.
Enrollment Patients were classified according to 1983 American Joint Committee on Cancer breast cancer staging criteria and Haagensen's criteria for IBC.2 Briefly, patients with stage IIIA breast cancer had tumors of any size (T0 to T3) with fixed axillary nodes (N2) or had tumors of greater than 5 cm (T3) with any axillary nodal status (N0 to N2). Stage IIIB patients had tumors of any size (T0 to T3) with supraclavicular or infraclavicular nodes or arm edema (N3) or had tumors with direct extension to the chest wall or skin, edema of skin, ulceration, or satellite skin nodules (T4). All stage III patients did not have evidence of metastatic disease on chest x-ray, liver-spleen and bone scans, or bone marrow biopsy before enrollment. IBC is defined by Haagensen as breast carcinoma with clinical findings of mottled erythema over one third of the breast, warmth, peau d'orange lymphedema, and ridges dividing areas of induration and more normal areas of skin.2 Patients gave informed consent approved by the National Cancer Institute institutional review board and were registered for protocol 84-C-0216, except for one patient who gave consent for standard care and was registered and treated similarly to enrolled patients. This clinical trial also enrolled stage IV patients without prior chemotherapy, and these patients were treated similarly to the stage III patients. These patients are not included in the analysis discussed in this article.
Protocol Schema
The first 12 patients were randomly assigned to receive chemotherapy with or without hormonal synchronization. They received cyclophosphamide 750 mg/m2 intravenously (IV) on day 1, doxorubicin 30 mg/m2 IV on day 1, methotrexate 40 mg/m2 IV on day 8, and fluorouracil 500 mg/m2 IV on day 8. In addition, half of the patients received tamoxifen 20 mg orally on days 2 through 6 and conjugated estrogens 0.625 mg orally every 12 hours on days 7 and 8. Because patients receiving hormonal synchronization had better responses than those who did not,24 the subsequent 95 patients received hormonal synchronization, and the chemotherapy doses were slightly modified to cyclophosphamide 500 mg/m2 IV on day 1, doxorubicin 30 mg/m2 IV on day 1, methotrexate 300 mg/m2 IV on day 8, fluorouracil 500 mg/m2 IV on day 8, leucovorin 10 mg/m2 orally every 6 hours for six doses beginning on day 9, tamoxifen 40 mg by mouth on days 2 through 6, and conjugated estrogens 0.625 mg every 12 hours on days 7 and 8. Radiation therapy to the intact breast consisted of 44 to 54 Gy of tangential-field radiation to the breast with boost to the original tumor site, with a median dose of 60 Gy delivered to the original tumor volume. Postmastectomy patients received a median dose of 54 Gy of radiation to the chest wall, internal mammary nodes, and supraclavicular fossa. Patients with IBC had bolus applied to the chest wall or intact breast every other day as tolerated. Details of radiation therapy are reported by Pierce et al.22 Adjuvant cyclophosphamide, methotrexate, fluorouracil, tamoxifen, and conjugated estrogens were given concurrently with radiation therapy. An additional six cycles of cyclophosphamide, doxorubicin, methotrexate, fluorouracil, tamoxifen, and conjugated estrogens was given after completion of local therapy, with the total doxorubicin dose not exceeding 525 mg/m2. In an amendment to the protocol in 1984, IBC patients who achieved complete response or could be rendered disease-free surgically could be randomly assigned to receive high-dose melphalan 60 mg/m2/d for 3 days and autologous bone marrow transplantation. Thirteen of the 28 patients who were eligible refused randomization for bone marrow transplantation. Eight patients were randomly assigned to no transplantation. Two patients were found to have residual disease in bone marrow after randomization. In total, five of the 46 IBC patients underwent autologous bone marrow transplantation.
Statistical Methods
Characteristics of patients were compared according to stage using the
Patients One hundred seven patients with stage III breast cancer were enrolled at the National Cancer Institute between April 1980 and April 1988. Forty-six had IBC, 48 had stage IIIA breast cancer, and 13 had stage IIIB NIBC. All patients commenced primary chemotherapy and had at least two cycles of therapy, with a median number of five cycles for IBC patients, five cycles for stage IIIA patients, and four cycles for stage IIIB NIBC patients as neoadjuvant therapy. Patient characteristics are listed in Table 1. The median follow-up time of live patients was 16.8 years.
Outcome Median OS and EFS for all patients and actuarial 10-year and 15-year survival rates are listed in Table 2. OS and EFS curves for all patients, as well as stratified into stage IIIA, stage IIIB IBC, and NIBC, are shown in Figure 2. Patients with stage IIIA disease lived longer than those with either IIIB IBC (P = .0046) or IIIB NIBC (P = .018). Similarly, the EFS for stage IIIA exceeded that of IIIB IBC (P = .0060) and NIBC (P = .016). Four of the five patients who received high-dose chemotherapy with stem-cell transplantation experienced disease recurrence and died of their disease within 1 to 7 years of their diagnosis; the fifth patient developed acute myeloid leukemia 10 years after transplantation.
Although most patients have relapsed or died within the first 5 years of their diagnosis, our cohort contains seven patients (four stage IIIA, two IBC, and one NIBC) who relapsed 5 or more years from their original treatment period. Nineteen (18%) of the patients died more than 5 years after treatment. Four patients whose disease recurred after their original treatment period remained alive more than 15 years later. Although none of our patients relapsed after 10 years, eight patients (7%) have died after 10 years. The rate of local-regional relapse as the sole first site of relapse was 4% in stage IIIA patients, 17% in IBC patients, and 15% in stage IIIB NIBC patients (Table 3). Local-regional recurrence as a component of the first relapse was present in 15% of stage IIIA, 28% of stage IIIB IBC, and 23% of IIIB NIBC patients. Local-regional recurrence as a component of first relapse was compared between pathologic complete responders and those who had clinical or pathologic residual disease (Table 4). All stages had a higher local recurrence rate as a component of first relapse in patients who had a pathologic response (10 of 32; 31%) than those with residual disease who underwent mastectomy (13 of 75; 17%), but this was not statistically significant. Pathologic response also was not associated with improved overall survival among either stage IIIA patients (P = .078) or IBC patients (P = .29; Fig 3).
OS was examined in IBC patients with and without dermal lymphatic invasion. Forty of 46 IBC patients underwent skin punch biopsy before therapy. A negative skin punch biopsy was one without dermal lymphatic invasion. Patients with dermal lymphatic invasion did not have a significantly different survival than those with clinical signs of IBC only (P > .80; Fig 4).
Overall survival was also compared for estrogen receptor status and menopausal status at time of diagnosis. No significant differences were seen between the survival times of estrogen receptor–positive versus estrogen receptor–negative patients, nor between pre- and postmenopausal patients (data not shown).
The study of the natural course of breast cancer requires extended follow-up to assess the outcome of this disease.26 ,27 In this report, we summarize the OS and EFS for patients treated between 16 and 24 years ago for their stage III disease. Our study indicates not only that longer follow-up captures additional recurrences and deaths, but also that there is a quantifiable population of long-term survivors with poorest-prognosis stages of breast cancer. Possibly because of the poor prognosis of these patients, follow-up longer than 3 to 5 years is rarely reported. Studies reporting 10- and 15-year follow-up for IBC and LABC patients are listed in Table 5. In the only other series of published 15-year follow-up in IBC, Ueno et al14 summarized patients from four different protocols treated over a 20-year period to give 10- and 15-year overall survival. However, 40% of these patients had been enrolled onto protocol less than 10 years before the publication date of the article, and median follow-up time was 7.4 years. At the time that report was published, only the two of the four cohorts, or 63 of the 178 patients, had achieved a median of 15 years of potential follow-up. Thus it is difficult to determine whether the 28% of patients who are disease-free at 15 years is representative of their entire population of IBC patients.
Complete pathologic response has been associated with improved prognosis in a large, randomized neoadjuvant chemotherapy trial (National Surgical Adjuvant Breast and Bowel Project Trial B-18), suggesting that quantifying breast tumor response to preoperative therapy may serve as an intermediate estimate of the effectiveness of preoperative chemotherapy on micrometastatic disease.28 Because of the small sample size of our study, we did not and were not likely to see a significant improvement in overall survival for stage IIIA patients and IBC patients who had a pathologic complete response to neoadjuvant therapy. An alternative explanation is that the difference in treatment between patients without evidence of disease after preoperative chemotherapy and those with residual disease obscured the survival benefit. Patients in this trial with complete pathologic response underwent radiation therapy with adjuvant chemotherapy without mastectomy. Finally, the assessment of complete pathologic response was made with needle biopsies and incisional biopsies, which are not considered the standard of care today and may not adequately define the extent of residual disease. False-negatives were most likely more prevalent than with current methods used to determine pathologic response such as lumpectomy and node dissection, and the pathologic complete response rate may be overestimated in our cohort. The role of mastectomy in IBC has been controversial, with recommendations against surgical intervention in IBC29 in part based on Haagensen's findings that surgery alone did not improve survival in IBC patients.1 Randomized trials to include or avoid mastectomy as part of management of IBC have not been done, and surveys of historical series are confounded by prognostic factors that also influence operability. A review of M.D. Anderson patients by Fleming et al30 suggested that the addition of mastectomy improved disease-free survival and OS in patients with a clinical response to chemotherapy. Some limitations to the generalization of our study are common to other studies analyzing the long-term survival of IBC and LABC. These patients were referred and recruited to a National Cancer Institute study and may not be representative of the population at large. This is a single-institution study containing nonrandomized cohorts of stage III patients that by their nature would be expected to have different clinical prognoses. Although there remains no standard therapy for the treatment of LABC and IBC, this study uses a chemotherapy regimen that is not commonly used today. In addition, the hormonal synchronization approach that was used in this study has not been shown to improve survival and is not standard of care. Use of concurrent chemotherapy and radiation therapy, as was done in this study, is also not commonly practiced. However, several of the principles of treatment, such as using an anthracycline-containing neoadjuvant regimen to best response, followed by locoregional therapy, remain standard. Because these patients met clinical trial entry criteria and were treated on one protocol, they represent a more homogeneous group than have been previously reported in other single-institution case series. The long-term prognosis of patients with IBC and stage III disease is poor, but not uniformly fatal. Our data quantify the long-term prognosis from IBC and LABC and provide a benchmark for future therapies for these poor-prognosis diseases.
The authors indicated no potential conflicts of interest.
We thank Jo Anne Zujewski, MD, for her assistance in the management and follow-up of these patients.
Preliminary portions of this work were presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002 (abstract 251). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Mehta's version of Fisher's exact test
