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Journal of Clinical Oncology, Vol 17, Issue 7 (July), 1999: 2006
© 1999 American Society for Clinical Oncology

Outcomes of High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in Stage IIIB Inflammatory Breast Cancer

D. Adkins, R. Brown, K. Trinkaus, R. Maziarz, S. Luedke, C. Freytes, B. Needles, D. Wienski, P. Fracasso, T. Pluard, W. Moriconi, T. Ryan, K. Hoelzer, S. Safdar, T. Rearden, G. Rodriguez, H. Khoury, R. Vij, J. DiPersio

From the Divisions of Bone Marrow Transplantation and Stem Cell Biology, Medical Oncology, and Biostatistics, Washington University School of Medicine, Midwest Hematology/Oncology Group, Inc, Hematology/Oncology Associates, Inc, Midwest Hematology/Oncology Consultants, Inc, Missouri Cancer Care, PC, Medical Oncology/Hematology, PC, Hematology/Oncology Consultants, Inc, and University Hematology/Oncology, St Louis, MO; Division of Hematology/Medical Oncology, Oregon Health Sciences University, Portland, OR; Division of Hematology, University of Texas Health Sciences Center, San Antonio, TX; and Hematology/Oncology at St John's Pavilion, Springfield, and Illinois Oncology Associates, Belleville, IL.

Address reprint requests to Douglas R. Adkins, MD, Division of Bone Marrow Transplantation, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8007, St Louis, MO 63110-1093; email dadkins{at}imgate.wustl.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the disease-free survival (DFS) and overall survival (OS), prognostic factors, and treatment-related mortality of women with stage IIIB inflammatory breast cancer (IBC) treated with combined modality therapy (CMT) and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation.

PATIENTS AND METHODS: Between 1989 and 1997, 47 consecutive patients with stage IIIB IBC were treated with CMT and HDCT and were the subject of this retrospective analysis. Chemotherapy was administered to all patients before and/or after definitive surgery. Neoadjuvant and adjuvant chemotherapy was administered to 33 and 34 patients, respectively, and 20 patients received both. All patients received HDCT with autologous stem-cell transplantation, and 41 patients received locoregional radiation therapy. Tamoxifen was prescribed to patients with estrogen receptor (ER)–positive cancer.

RESULTS: The mean duration of follow-up from diagnosis was 30 months (range, 6 to 91 months) and from HDCT was 22 months (range, 0.5 to 82 months). At 30 months, the Kaplan-Meier estimates of DFS and OS from diagnosis were 57.7% and 59.1%, respectively. At 4 years, the Kaplan-Meier estimates of DFS and OS from diagnosis were 51.3% and 51.7%, respectively. In a multivariate analysis, the only factors associated with better survival were favorable response to neoadjuvant chemotherapy (P = .04) and receipt of tamoxifen (P = .06); however, the benefit of tamoxifen was only demonstrated in patients with ER-positive breast cancer. At last follow-up, 28 patients (59.6%) were alive and disease-free. Seventeen patients (36.2%) developed recurrent breast cancer. Seventeen patients died: 15 from disease recurrence and two (4.2%) from treatment-related mortality due to HDCT.

CONCLUSION: In this analysis, the early results of treatment with CMT and HDCT compare favorably with other series of patients with stage IIIB IBC treated with CMT alone. These outcomes must be confirmed with longer follow-up and controlled studies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
INFLAMMATORY BREAST cancer (IBC) represents only 1% to 6% of all cases of breast cancer, but is distinguished from non-IBC by its uniformly aggressive clinical course.1 Although surgery or radiation therapy alone or in combination provides effective local therapy in many patients with IBC, it is not curative.1-6 Non-randomized clinical trials demonstrated that the addition of chemotherapy to surgery and radiation therapy (defined as combined modality therapy [CMT]) improved outcomes over local treatment alone7-18; however, most patients treated with CMT ultimately relapsed and died of their disease.

High-dose chemotherapy (HDCT) administered with autologous stem-cell transplantation results in high response rates in metastatic breast cancer,19,20 and in one controlled study, it improved progression-free survival and overall survival (OS) when compared with conventional dose chemotherapy.21 Ongoing controlled trials are evaluating the role, if any, of HDCT in women with high-risk, early (stage II, IIIA) breast cancer treated with CMT, but preliminary data suggest a benefit of HDCT in patients with >= 10 involved axillary nodes.22 Because most patients with stage IIIB IBC who are treated with CMT ultimately relapse at distant sites, the preliminary encouraging outcomes with the addition of HDCT to CMT in other subsets of patients with breast cancer provide the rationale for evaluating this strategy in women with IBC. Since 1989, 47 consecutive patients with stage IIIB IBC have been treated with CMT and HDCT at three university institutions. This report describes a retrospective analysis of the outcomes of these patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population and Pretreatment Evaluation
Between October 1989 and April 1997, 47 consecutive patients with stage IIIB IBC were treated with CMT and HDCT at three institutions. Since 1989, the investigators at each institution consistently treated patients with stage IIIB IBC with CMT and HDCT. The study became a collective effort of the three universities after 1994. All patients participated on clinical trials approved by the institutional review board at each site, and all patients gave written informed consent. The number of patients enrolled onto these trials at Washington University, Oregon Health Sciences University at Portland, and University of Texas Health Science Center at San Antonio were 35, nine, and three, respectively.

All patients had stage IIIB IBC, defined by the presence of one or more clinical characteristics of this disease.1 Dermal lymphatic involvement on histologic specimens may or may not have been present. A pathologist at each institution reviewed stained slides of the primary tumor and/or mastectomy specimen. Physical examination, chest radiograph, abdominal computed tomography, and bone scan performed at diagnosis documented no gross evidence of distant disease. Computed tomography of the chest and bone marrow biopsy were not required at diagnosis. Minimal criteria for eligibility to proceed with HDCT included Karnofsky performance status >= 80%, age <= 65 years, left ventricular ejection fraction greater than 45% as documented by cardiac radionuclide gated pool scanning (multiple gated acquisition) or echocardiogram, and adequate hepatic (serum bilirubin level <= 2.0 mg/dL and AST and ALT levels <= three times normal) and pulmonary (diffusion capacity >= 40% of predicted) function. Computed tomography of the brain and chest radiograph showed no metastatic lesions. Computed tomography of the abdomen (or chest), bone scan, and bone marrow biopsy were not routinely performed, nor were they required, after pre-HDCT treatment and before HDCT.

Pre-HDCT Treatment
Surgery consisted of modified radical mastectomy in 46 patients and quadrantectomy in one. All patients underwent axillary node dissection. Chemotherapy was administered to all patients before (neoadjuvant) and/or after (adjuvant) definitive surgery. The decision to perform immediate surgery or to administer neoadjuvant chemotherapy before surgery was made jointly by the physician and the patient and was based on practical issues such as patient preference and technical issues, including variables that could affect the ability to achieve adequate negative surgical margins (such as tumor size). However, the physician recommended neoadjuvant chemotherapy. Any standard chemotherapy regimen was acceptable, but all patients received doxorubicin (-based) regimens. Neoadjuvant chemotherapy was administered to 33 patients: 28 received cyclophosphamide and doxorubicin with or without fluorouracil; one received doxorubicin, fluorouracil, and methotrexate; and four received doxorubicin alone. The mean number of cycles of neoadjuvant chemotherapy was four (range, two to nine). Adjuvant chemotherapy was administered to 34 patients and consisted of either cyclophosphamide and doxorubicin with or without fluorouracil in 20; doxorubicin or cyclophosphamide alone in seven; paclitaxel in four; or cyclophosphamide, methotrexate, and fluorouracil in three. The mean number of cycles of adjuvant chemotherapy was three.1-8 Both neoadjuvant and adjuvant chemotherapy were administered to 20 patients.

Definitions of Response to Neoadjuvant Chemotherapy
Response to neoadjuvant chemotherapy was determined by clinical and pathologic examination. By clinical examination, response to neoadjuvant chemotherapy included complete response (CR; resolution of all inflammatory signs and of the primary tumor mass and any associated enlarged axillary lymph nodes), partial response (PR; >= 50% reduction of the measurable inflammatory signs and of the primary tumor mass and any associated enlarged axillary nodes), or minor response (MR; 25% to 49% reduction of the measurable inflammatory signs and of the primary tumor mass and any associated enlarged axillary nodes). Stable disease was defined as either no change or less than 25% reduction of the measurable inflammatory signs and of the primary tumor mass and any associated enlarged axillary nodes. By pathologic examination, response to neoadjuvant chemotherapy included pathologic CR (clinical CR and no microscopic evidence of residual carcinoma at mastectomy), microscopic PR (clinical CR but microscopic evidence of persistent residual carcinoma at mastectomy), gross PR (clinical PR and gross and microscopic evidence of residual carcinoma at mastectomy), and MR (clinical MR and gross and microscopic evidence of residual carcinoma at mastectomy). Pathologic stable disease was defined as clinical stable response and gross and microscopic evidence of residual carcinoma at mastectomy.

Stem Cell Procurement
Stem cells were collected from the peripheral blood (PBSCs) in 37 patients, from the bone marrow in six, and from both in four. Stem cells were collected and stored using standard techniques.23 PBSCs were mobilized with colony-stimulating factors alone or with chemotherapy, based on institutional preferences.

HDCT Consolidation
Five different HDCT regimens were used, with choices based on institutional protocols. HDCT regimens included melphalan, etoposide, and carboplatin24 in 22 patients; cyclophosphamide and thiotepa25 alone or with carboplatin26 in 12 patients; cyclophosphamide, carmustine, and cisplatin27 in five patients; and busulfan, melphalan, and thiotepa28 in eight patients.

Autologous bone marrow stem cells (six patients), PBSCs (37 patients), or both (four patients) were reinfused on transplant day 0. Prophylactic and therapeutic antibiotics, posttransplant colony-stimulating factors, and blood product and nutritional support were determined by standard institutional practices.

Radiation Therapy
Radiation therapy to the chest wall and draining lymphatics (axilla, supraclavicular fossa, with or without internal mammary) at a dose of approximately 50.4 Gy (with a boost of approximately 9 Gy to the mastectomy scar/chest wall) was administered to 41 patients before (n = 4) or after (n = 37) HDCT. Radiation therapy was administered at the patient's referral facility or at one of the three institutions according to community standards. Six patients did not receive radiation therapy: four because of patient or physician choice and two because of death from HDCT.

Hormone Therapy
Tamoxifen (20 mg/d) was prescribed for patients with either estrogen receptor (ER)– or progesterone receptor (PGR)–positive breast cancer. Of the 21 patients with ER- and/or PGR-positive breast cancer, 17 received tamoxifen and four did not. The latter patients did not receive tamoxifen because of patient or physician choice in three and death from HDCT in one. Of the 26 patients with ER- and PGR-negative breast cancer, one received tamoxifen and 25 did not.

Posttreatment Follow-Up
Patients were re-evaluated by the primary referral physician and/or the institution at regular intervals upon completion of CMT and HDCT. Scheduled visits every 3 to 4 months included physical examination, blood counts, and chemistries. Yearly mammograms, chest radiographs, computed tomography scan of the abdomen, and bone scan were also performed.

Statistical Methods
Data were summarized as the mean or median ± SD or range for continuous variables and as frequencies and percents for categoric variables. The last follow-up date was April 6, 1998. Outcomes examined included OS and disease-free survival (DFS) and were calculated from diagnosis and from HDCT. OS was defined as time to death from any cause. DFS was defined as time to recurrence of breast cancer or death from treatment-related toxicities. The Kaplan-Meier (KM) product-limit method was used to obtain 22-month, 30-month, and 4-year estimates for DFS and OS.29

Univariate and multivariate KM survival analyses were performed to identify factors associated with DFS and OS from diagnosis. Factors examined included age (< 50 v >= 50 years), tumor size (<= 5 cm v > 5 cm), positive axillary node number (zero, one to nine, or >= 10), ER and PGR status (positive v negative), neoadjuvant chemotherapy (yes v no), response to neoadjuvant chemotherapy by clinical examination (CR and PR v MR/stable), response to neoadjuvant chemotherapy by pathologic examination (CR, microscopic PR, and gross PR v MR/stable), adjuvant chemotherapy (yes v no), neoadjuvant and adjuvant chemotherapy (yes v no), duration (months) from diagnosis to HDCT, and treatment with tamoxifen (yes v no). Multivariate analysis was performed using the factors identified to be potentially significant (P <= .15) in the univariate analysis. Proportional hazards modeling of survival was performed using these candidate variables. Primary tumor size and number of involved axillary nodes were compared among patients who received neoadjuvant chemotherapy and those who underwent immediate mastectomy at diagnosis (and did not receive neoadjuvant chemotherapy) using the Wilcoxon rank sum test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Forty-seven patients with stage IIIB IBC were treated with CMT and HDCT from August 1989 to April 1997. Patient characteristics are listed in Table 1. The mean age of the patients was 44 years (range, 25 to 61 years). The mean size of primary tumors at presentation was 8.2 cm (range, 1.3 to 23.0 cm) based on either gross pathologic (for 14 patients who underwent immediate definitive surgery) or clinical (for 33 patients who received neoadjuvant chemotherapy after biopsy) examination. In 30 patients, the primary tumor measured more than 5 cm. The mean number of axillary nodes involved by metastatic carcinoma was 12 (range, zero to 31), with 27 patients (57%) having >= 10 involved axillary nodes. The mean number of involved axillary nodes in patients who underwent immediate definitive surgery was 10 (range, zero to 28) versus 17 (range, six to 31) in patients who received neoadjuvant chemotherapy. Tumors were ER- and PGR-positive in 17 and 20 patients, respectively.


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  		Table 1. Patient Characteristics
 

Response to Neoadjuvant Chemotherapy
Thirty-three patients received neoadjuvant chemotherapy before modified radical mastectomy. By clinical examination, response to neoadjuvant chemotherapy included nine CRs, 18 PRs, five MRs, and one stable disease. By pathologic examination, response to neoadjuvant chemotherapy included one pathologic CR, three microscopic PRs, 21 gross PRs, seven MRs, and one stable disease.

Patients who received neoadjuvant chemotherapy had larger primary tumors and greater number of involved axillary nodes compared with those who underwent immediate mastectomy at diagnosis. The mean primary tumor size at diagnosis was 9.0 cm (range, 1.3 to 23.0 cm) and 6.3 cm (range, 1.3 to 23.0 cm) in patients who did or did not receive neoadjuvant chemotherapy, respectively (P = .03). Primary tumor size at diagnosis was determined by pathologic examination for patients who underwent immediate mastectomy and by clinical examination for patients who received neoadjuvant chemotherapy. The mean number of involved axillary nodes in patients who did nor did not receive neoadjuvant chemotherapy was 17 (range, six to 31) and 10 (range, zero to 28), respectively (P = .008).

HDCT
The mean duration from diagnosis to administration of HDCT was 8 months (range, 3 to 20 months). Forty-four patients underwent HDCT within 12 months of diagnosis: 19 patients within 6 months and 25 patients between 6 and 12 months from diagnosis. Two patients (4.2%) died of HDCT treatment-related mortality. One patient died on posttransplant day 12 of sepsis syndrome and CNS hemorrhage, and another patient died on posttransplant day 75 of corticosteroid-refractory diffuse interstitial pneumonitis, likely secondary to carmustine treatment.

Survival
All patients were assessable for DFS and OS. The mean duration of follow-up from diagnosis was 30 months (range, 6 to 91 months) and from HDCT was 22 months (range, 0.5 to 82 months). At last follow-up, 28 patients (59.6%) were alive and disease-free. At 30 months, the KM estimates of DFS and OS from diagnosis were 57.7% and 59.1%, respectively (Figs 1 and 2). At 4 years, the KM estimates of DFS and OS from diagnosis were 51.3% and 51.7%, respectively. At 22 months, the KM estimates of DFS and OS from HDCT were 56.4% and 59.4%, respectively. At 4 years, the KM estimates of DFS and OS from HDCT were 56.4% and 54.4%, respectively.




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  		Fig 1. DFS from (A) diagnosis and (B) HDCT, determined by the KM product-limit method.

 



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  		Fig 2. OS from (A) diagnosis and (B) HDCT, determined by the KM product-limit method.

 

Seventeen patients (36.2%) developed recurrent breast cancer. Recurrent breast cancer occurred at locoregional sites (n = 5), distant sites (n = 11), or both (n = 1). The mean duration to development of recurrent breast cancer was 258 days (range, 52 to 656 days) after transplantation; 14 patients developed recurrent disease within 1 year after transplantation. Fifteen of 17 patients with recurrent disease died; 80% of these patients died within 1 year of disease relapse.

At last follow-up, 17 patients (36.2%) had died. Causes of death included disease recurrence in 15 (31.9%) and complications of HDCT in two (4.2%).

Prognostic Factors
Several variables were evaluated by univariate and multivariate KM survival analyses to identify factors associated with DFS and OS from diagnosis. Of the variables examined by univariate analysis, the only factors associated with better survival from diagnosis were receipt of tamoxifen and favorable response to neoadjuvant chemotherapy (Table 2). Patients who received tamoxifen demonstrated better DFS and OS than those who did not receive tamoxifen (P = .07 and .05, respectively, by log-rank test). Patients whose tumors achieved at least a gross pathologic PR (CR + microscopic PR + gross PR) to neoadjuvant chemotherapy demonstrated better OS (P = .05) but not DFS (P = .91) than did those whose tumor responded less favorably (MR + stable disease) to neoadjuvant chemotherapy. Patients whose tumors achieved at least a clinical PR (CR + PR) to neoadjuvant chemotherapy demonstrated a trend toward better OS (P = .11) but not DFS (P = .67) than did those whose tumors responded less favorably (MR + stable disease). Patients who underwent HDCT within 6 months of diagnosis also demonstrated a trend toward better DFS (P = .09), but not OS (P = .33), than did those who underwent HDCT after 6 months from diagnosis.


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  		Table 2. Univariate Analysis of Prognostic Factors for DFS and OS From Diagnosis
 

The results of a multivariate analysis of factors identified in the univariate analysis to be potentially predictive (P <= .15) of DFS or OS are summarized in Table 3. In the proportional hazards model, receipt of tamoxifen (P = .07) and <= 6 months from diagnosis to HDCT (P = .09) retained borderline statistical significance as independent predictors of longer DFS. Only favorable clinical response (CR + PR) to neoadjuvant chemotherapy (P = .04) and receipt of tamoxifen (P = .06) retained statistical significance as independent predictors of longer OS.


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  		Table 3. Multivariate Analysis* of Factors Identified in the Univariate Analysis to Be Potentially (P <= .15) Predictive of DFS or OS
 

A KM survival model was used to examine further the relationship between hormone receptor status and receipt of tamoxifen. In the cohort of 21 patients with ER- and/or PGR-positive breast cancer, the DFS and OS of the 17 patients who received tamoxifen were significantly longer than those of the four patients who did not receive tamoxifen (P = .0001, log-rank test for both survival outcomes). In the cohort of 29 patients who did not receive tamoxifen, the DFS and OS of the 25 patients with ER- and PGR-negative breast cancer were significantly longer than those of the four patients with ER- and/or PGR-positive breast cancer (P = .03 and .0011 for DFS and OS, respectively). No significant difference in survival outcomes was observed between the 17 patients with ER- and/or PGR-positive breast cancer who received tamoxifen and the 25 patients with ER- and PGR-negative breast cancer who did not receive tamoxifen. Thus, the benefit of tamoxifen was demonstrated only in patients with ER- and/or PGR-positive breast cancer. This observation must be interpreted cautiously because only four of the 21 patients who had hormone receptor–positive breast cancer did not receive tamoxifen.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Conventional treatment of stage IIIB IBC consists of CMT, including local therapy with surgery and/or radiation and systemic therapy with chemotherapy with or without hormonal agents.1 The optimal sequencing of these modalities is unclear. Ayash et al30 summarized the outcomes of CMT in four large retrospective series,2,7,13,31 each with >= 100 patients with stage IIIB IBC. The median DFS and OS durations were 21 and 40 months, respectively. The 4 (or 5)-year DFS and OS rates were 33% and 40%, respectively. Of these four series, the best outcomes with CMT were reported in 79 patients who were treated with the sequence of chemotherapy/radiation therapy/chemotherapy.7 In these patients, the 4-year DFS and OS rates were 46% and 66%, respectively. Long-term (15 to 20 years) follow-up of patients with stage IIIB IBC who were treated with CMT demonstrated that 15% to 27% of patients have durable remissions and are likely to be cured with this therapeutic approach.17,18 Thus, although CMT may be curative, most patients with stage IIIB IBC experience recurrence and die of their disease, usually within 4 or 5 years of diagnosis.

In this retrospective analysis of 47 patients with stage IIIB IBC who were treated with CMT and HDCT, the KM estimates of DFS and OS at 4 years from diagnosis were 51.3% and 51.7%, respectively. The mean follow-up duration from diagnosis was 30 months (range, 6 to 91 months). The KM estimates of DFS and OS at 30 months were 57.7% and 59.1%, respectively. These early results compare favorably with the summarized outcomes of the aforementioned four large retrospective series of patients treated with CMT alone.2,7,13,31 However, comparisons among these studies are not entirely valid because of potential or actual differences in patient selection, treatment design, and follow-up. Only controlled studies will define the benefit, if any, of the addition of HDCT to CMT in the treatment of this disease. However, given the low frequency of this form of breast cancer, controlled trials to address this question may not be feasible. Notably, nonrandomized comparisons of data from patient cohorts treated with either local therapy alone or with chemotherapy were used to establish the benefit of CMT in this disease.1 Physicians currently must provide treatment recommendations to patients based on a summary analysis of the available data, which consists mostly of noncontrolled and/or retrospective comparisons of a variety of treatment approaches.

The survival outcomes observed in this study of 47 patients with stage IIIB IBC treated with CMT and HDCT compare similarly to those observed in four other series of 22 to 260 patients also treated with HDCT (Table 4).30,32-34 The largest of these series was a retrospective analysis of 260 patients reported to the Autologous Blood and Marrow Transplant Registry between 1989 and 1995.32 An analysis of the characteristics of these patients and the pre- and post-HDCT treatment was not described in this report; however, the 3-year progression-free survival and OS were 42% and 52%, respectively. All other series consisted of less than 50 patients. Ayash et al30 reported 42 patients with stage IIIB IBC treated prospectively and homogeneously with four biweekly cycles of doxorubicin followed by HDCT with cyclophosphamide, thiotepa, and carboplatin and autologous transplantation. Posttransplant therapy consisted of mastectomy and radiotherapy, and tamoxifen if indicated. The 2.5-year estimates of DFS and OS were 64% and 89%, respectively. The other two series by Cagnoni et al33 and Somlo et al34 reported similar results but consisted of only 22 to 30 patients each. These four series and the current report are all limited by relatively short follow-up duration. In addition, in most series, the therapy was not consistent among patients and, in at least one series,34 patient selection may have influenced outcomes in that patients who were eligible for HDCT must have achieved at least a PR to neoadjuvant chemotherapy, if given. Notably, the DFS and OS curves reported in these series do not yet demonstrate a plateau. Longer follow-up is required to determine if the early favorable outcomes observed in patients with stage IIIB IBC treated with CMT and HDCT are durable.


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  		Table 4. Series With 22+ Patients With Stage IIIB IBC Treated With HDCT
 

It may be argued that selection of more favorable patients with stage IIIB IBC may have contributed to the early encouraging outcomes of CMT and HDCT compared with those of CMT alone. This concern has been expressed in trials of HDCT in women with non-IBC.35 In one retrospective study of a small number of patients, extensive pretransplant evaluation identified occult metastatic disease in 23% of patients with high-risk, early-stage non-IBC, rendering these patients ineligible for a randomized trial comparing the addition of HDCT to standard adjuvant therapy.36 These results should be cautiously interpreted because this finding has not been confirmed in larger numbers of patients. HDCT trials also may exclude patients whose tumor progresses while receiving conventional-dose chemotherapy. However, tumor progression during conventional-dose chemotherapy is uncommon in patients with stage IIIB IBC, reported in only 2% to 4% of patients.1 Other investigators have also presented reasonable arguments refuting the relative importance of patient selection bias in these cohorts of patients with high-risk, early-stage breast cancer.37

Of the variables examined in this study, only receipt of tamoxifen and response to neoadjuvant chemotherapy were associated with OS in the multivariate model. In patients with ER- and/or PGR-positive breast cancer, both DFS and OS were significantly longer in patients who received tamoxifen compared with those who did not receive tamoxifen. These results suggest, but do not conclusively prove, that tamoxifen improved survival in this cohort of women with hormone receptor–positive stage IIIB IBC who were treated with HDCT in addition to CMT. Additional studies with larger numbers of patients are required to confirm this observation. The role of adjuvant hormone therapy in women with stage IIIB IBC is unclear. In contrast to early-stage non-IBC,38 the benefit, if any, of adjuvant hormonal therapy in women with stage IIIB IBC treated with CMT alone has not been evaluated adequately by controlled, randomized trials.1 In this study, favorable clinical response to neoadjuvant chemotherapy was associated with better OS but not DFS. Ayash et al30 and Cagnoni et al33 observed better DFS in women with stage IIIB IBC treated with CMT and a single cycle of HDCT who achieved a favorable pathologic response to neoadjuvant chemotherapy. Neoadjuvant chemotherapy administered in multiple cycles of HDCT may increase the response of the primary tumor in women with IBC. Preliminary data from one trial reported high clinical and pathologic CR rates in women with IBC who received six sequential cycles of high-dose cyclophosphamide (3 to 6 g/m2) and doxorubicin (75 mg/m2) supported with autologous stem-cell transplantation before mastectomy.39

In the cohort that did not receive tamoxifen in the present study, survival of patients with ER- and/or PGR-positive breast cancer was significantly shorter than that of the patients with ER- and/or PGR-negative breast cancer. This unexpected observation may be a result of statistical sampling error or to cohort imbalances in other potential prognostic factors not examined in this study, such as tumor grade,40,41 thymidine-labeling index,42,43 or c-erbB-2 amplification.44 A randomized trial of three doses of a doxorubicin-containing adjuvant chemotherapy regimen in women with node-positive, early-stage breast cancer demonstrated that patients whose tumors overexpressed c-erbB-2 derived the greatest benefit from higher doses of chemotherapy, whereas no benefit occurred with dose intensification in patients with no or low c-erbB-2 expression.44 The results of this randomized trial that used more conventional doses of chemotherapy support further investigation of whether c-erbB-2 expression is a significant prognostic factor in women with stage IIIB IBC who are treated with CMT and HDCT.

HDCT and autologous transplantation are associated with significantly greater morbidity and mortality compared with CMT alone. In our series, two patients (4.2%) died of treatment-related mortality from HDCT. In data on autologous transplants for breast cancer reported to the Autologous Blood and Marrow Transplant Registry, Antman et al32 observed a decline in the 100-day mortality from 22% to 5% between 1989 and 1995. Serious confounding medical illnesses or advanced age in some patients with stage IIIB IBC may preclude the option of HDCT in addition to CMT because of the greater risk of HDCT-related morbidity and mortality in these patients.

In this retrospective analysis of patients with stage IIIB IBC, the early results of treatment with CMT and HDCT compare favorably with those of other series of patients treated with CMT alone.2,7,13,31 Although these outcomes must be confirmed with longer follow-up and controlled, preferably randomized studies, the early results are encouraging and support further trials to evaluate this treatment strategy.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Jaiyesimi IA, Buzdar AU, Hortobagyi G: Inflammatory breast cancer: A review. J Clin Oncol 10:1014-1024, 1992[Abstract]

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Submitted June 5, 1998; accepted March 12, 1999.


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