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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1839-1848 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.147 Prognostic Indicators and Survival in Patients With Stage IIIB Inflammatory Breast Carcinoma After Dose-Intense ChemotherapyFrom the Departments of Medical Oncology and Therapeutics Research, Biostatistics, Hematology/Bone Marrow Transplantation, and Anatomic Pathology, City of Hope Comprehensive Cancer Center, Duarte; Kaiser Permanente Southern California, Los Angeles; and University of California San Francisco, San Francisco, CA; and The Good Samaritan Bone Marrow Transplant Unit, Phoenix, AZ. Address reprint requests to George Somlo, MD, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010; e-mail: gsomlo{at}coh.org
PURPOSE: To improve treatment outcome for patients presenting with inflammatory breast cancer (IBC), we have sequentially developed and tested single and tandem dose-intense chemotherapy regimens (DICT). Tumor- and treatment-related factors were analyzed to generate a prognostic model. PATIENTS AND METHODS: Between May 1989 and April 2002, 120 patients received conventional-dose chemotherapy, surgery, and sequentially developed single- or tandem-cycle DICT. Disease- and treatment-specific features were subjected to univariate and multivariate analysis to correlate with outcome. RESULTS: At a median follow-up of 61 months (range, 21 to 161 months), estimated 5-year relapse-free survival (RFS) and overall survival (OS) were 44% (95% CI, 34% to 53%) and 64% (95% CI, 55% to 73%), respectively. In an age-adjusted multivariate analysis, RFS was better in patients with estrogen receptor (ER)/progesterone receptor (PR)–positive tumors (P = .002), for patients with fewer than four involved axillary nodes before DICT (P = .01), and in patients treated with radiation therapy (P = .001) and tandem DICT (P = .049). OS was improved in patients with ER/PR-positive tumors (P = .002), in those with fewer than four involved axillary nodes before DICT (P = .03), and in patients treated with radiation therapy (P = .002). CONCLUSION: This retrospective analysis suggests that either single or tandem DICT can be administered safely and may benefit selected patients with stage IIIB IBC. Those with receptor-negative IBC and with four or more involved axillary nodes before DICT need improved neoadjuvant and postadjuvant intensification therapy. A prospective randomized trial of single versus tandem DICT would be required to confirm the potential benefit of tandem DICT in the setting of IBC.
Fewer than 3% of patients with newly diagnosed breast cancer present with inflammatory breast cancer (IBC).1 Conventional treatment includes neoadjuvant chemotherapy, definitive surgery (most frequently consisting of modified radical mastectomy), adjuvant chemotherapy, local-regional radiation therapy, and, if indicated, antiestrogen therapy. Relapse-free survival (RFS) and overall survival (OS) remain unsatisfactory, with approximately 30% of patients alive at 5 years.1,2 We previously reported the long-term outcome of patients treated at the City of Hope National Medical Center (COHNMC) after conventional therapy for IBC. Five-year projected survival was 30% in IBC patients treated with nontaxane-containing neoadjuvant and adjuvant therapy.3 We have also described our results in patients with high-risk primary breast cancer (defined as the presence of  10 involved axillary lymph nodes, > 5 cm tumors with any number of involved axillary nodes, or with the features of IBC) after high-dose or dose-intense chemotherapy (DICT); in that cohort, projected 7-year overall survival for the group of 23 patients with IBC was 48%.4 Here we report on the outcome of a large cohort of 120 patients with IBC who were treated on sequentially developed single- and tandem-cycle DICT trials. Tumor- and treatment-related features for IBC patients entered onto these prospective studies were analyzed to generate a model of prognostic and predictive factors of outcome.
All 120 patients participating in DICT trials approved by institutional review boards (IRB) gave their written, voluntary informed consent for study participation. Patients were treated on clinical protocols developed at the COHNMC. Most of the patients were treated at the COHNMC (116 patients). Collaborating institutions included the Good Samaritan Hospital/City of Hope Bone Marrow Transplant Unit in Phoenix, Arizona (three patients), and the University of California, San Francisco (one patient). The majority of patients received standard neoadjuvant and adjuvant, doxorubicin-containing chemotherapy from their primary oncologists either in the community or at the center delivering DICT. Doxorubicin-containing neoadjuvant and/or adjuvant chemotherapy was received by 119 patients (99%). A taxane was administered either as part of neoadjuvant or adjuvant therapy to 40% of the patients in this report, including 11 patients participating in the most recent COHNMC tandem DICT protocol (IRB no. 96139) who received 96-hour continuous intravenous infusions (CIVI) of doxorubicin 75 mg/m2 every 2 weeks for two to three doses, followed by two doses of 96-hour CIVI of paclitaxel 140 mg/m2 as their neoadjuvant therapy. Eighty-eight patients (73%) received neoadjuvant chemotherapy. Patients underwent definitive surgery which, in the great majority, consisted of modified radical mastectomy (98%) or breast preservation and axillary node dissection. The median time from diagnosis to DICT was 7 months (range, 4 to 12 months).
Characteristics of patients are listed in Table 1. Eligible patients had IBC defined by the presence of inflammatory changes involving one third or greater of the breast surface area, with or without pathologic evidence of dermal lymphatic invasion. Patients were
Patients were to undergo peripheral-blood progenitor cell procurement followed by DICT within 12 months from diagnosis. All sequentially developed single-cycle DICT protocols have been described earlier and consisted of cyclophosphamide and etoposide and either doxorubicin or cisplatin (CCVP)4; doxorubicin, cyclophosphamide, and paclitaxel (ACT)5; carboplatin, thiotepa, and cyclophosphamide7; or CCCT.8 When both a doxorubicin- and a nondoxorubicin-containing study were open for accrual, the former was considered higher priority for those patients with a cumulative total exposure of less than 240 mg/m2 of doxorubicin. Patients were accrued continuously to ongoing DICT trials depending on which trial was available at their particular time of evaluation. However, with the development of tandem DICT trials, and especially from 1996 on, patients were preferentially enrolled onto tandem-cycle DICT trials consisting first of IRB no. 91088, two cycles of melphalan and cisplatin9; IRB no. 94098, CCVP followed by carboplatin, ifosfamide, and paclitaxel10; and, more recently, IRB no. 96139, ACT followed by melphalan and cisplatin.11 There was no significant difference in characteristics among patients treated with single-cycle versus tandem-cycle DICT, except for age and prior exposure to taxanes (data not shown). Table 2 describes each regimen and protocol in a tabulated form, detailing accrual. Although 44 of the 120 patients were enrolled onto tandem DICT protocols, only 31 patients actually received both cycles.
All DICT cycles were supported by granulocyte colony-stimulating factor 10 µg/kg–mobilized peripheral-blood progenitor cells (targeted to procure > 2 x 106 CD34 + cells/kg/cycle), except for patients treated with ACT and melphalan with cisplatin, whose progenitor cells were mobilized using paclitaxel 140 mg/m2 over 96 hours given as a CIVI and followed by granulocyte colony-stimulating factor 10 µg/kg daily, until reaching the target. Details on progenitor cell mobilization and procurement and supportive care have been reported previously.4,6
Post-DICT Therapy
Posttreatment Follow-Up
Histopathologic Analysis
Statistical Methods
Univariate and multivariate Cox regression analyses were carried out to assess potential prognostic (inherent to the primary tumors) and predictive indicators (treatment-related variables) of RFS and OS. These features included tumor size ( Age-adjusted multivariate analysis resulted in a final model of two prognostic and three predictive variables for RFS and two prognostic and two predictive variables for OS. Models generated based on the presence or absence of these variables were then constructed to assess relative risk of relapse and death. Standard Kaplan-Meier12 and Cox13 regression methods were applied for survival analysis using the SAS (SAS Institute, Cary, NC)/STAT14 and S-Plus software (Statistical Science, Seattle, WA). All significance testing was two-sided (log-rank statistics and Wald statistics were used in univariate and multivariate analysis, respectively). The last follow-up date was August 13, 2003.
Patient Characteristics Between May 1989 and April 2002, 120 patients with IBC underwent DICT. Patient characteristics are listed in Table 1. The median age at diagnosis was 47 years (range, 30 to 63 years); four patients were 60 years old. Five patients presented with simultaneous bilateral breast cancer, two patients presented with noninvasive synchronous breast tumors, and five patients had a history of prior ipsilateral or contralateral breast cancer. Eighty-eight patients (73%) underwent neoadjuvant therapy, and 98% underwent modified radical mastectomy as their definitive surgical treatment. The median tumor size was 5.5 cm (range, 1.1 to 20 cm); a median of nine axillary lymph nodes (range, 0 to 37 nodes) were involved. Fifty-seven percent of tumors were ER- and/or PR-positive, and 65% were high-grade tumors. HER-2 status was available on 62% of tumors, 39% of which were 2 +, 3+, or fluorescent in situ hybridization–positive. The median duration from diagnosis to DICT was 7 months (range, 4 to 12 months). Of those patients treated with neoadjuvant chemotherapy, seven were in pathologic complete remission at the time of their definitive surgery. Sixteen patients (13%) still had residual tumor involving the final surgical margin after modified radical mastectomy. All patients received adjuvant chemotherapy. Ninety-nine percent of patients received doxorubicin, and 40% received a taxane as part of neoadjuvant or adjuvant chemotherapy before DICT. Ninety-three percent of patients received local-regional radiation treatment, including draining lymph-node areas according to community standards, and 60% of patients received tamoxifen, whereas 2% of patients received anastrozol.
Therapeutic Outcome
Table 3 lists single sites and multiple sites of relapse. The predominant sites of relapse were local-regional or contralateral soft tissue (26%), bone, brain and lung. Seven patients developed new contralateral invasive breast cancers, five of whom went on to develop systemic recurrence either simultaneously or shortly thereafter. One patient was diagnosed with contralateral carcinoma-in-situ.
Toxicities All patients developed grade 4 pancytopenias requiring RBC and platelet transfusions and broad-spectrum antibiotic coverage as indicated. Other grade 3 and 4 toxicities were regimen-specific and primarily consisted of mucositis (worse for ACT, less with the combination of carboplatin, thiotepa, and cyclophosphamide and CCCT), ototoxicity (CCVP), and electrolyte abnormalities (all regimens). Detailed accounts of the toxicities associated with each regimen were reported earlier.4–11,15 Of the 44 patients scheduled to undergo tandem DICT, 31 patients (70%) received both cycles. The reasons for not receiving the second cycle of DICT were as follows: one patient refused, one patient experienced mild, reversible decrease in creatinine clearance to 56 mL/min, six patients were found to have a decrease in their left ventricular ejection fraction (mean, 47%; range, 46% to 49%), one patient with preexisting Wolff-Parkinson-White syndrome required cardioversion because of ventricular tachycardia/hypotension, one patient experienced grade 3 paresthesias, one patient required intubation for alveolar hemorrhage after the first cycle of DICT, and in one patient the insurance company did not authorize the second cycle. One patient treated on a protocol consisting of ACT followed by melphalan and cisplatin died of enteritis-related gastric perforation and septic complications after ACT. There were no long-term organ toxicities except for persistent high-frequency hearing loss after CCVP.15 At a median follow-up of 61 months, there were no cases of secondary myelodysplasias or leukemias.
Prognostic and Predictive Factors All tumor- and treatment-related parameters, regardless of whether they were statistically significant in univariate analysis, were included in the multivariate analysis. Then variables having statistically significant effects were retained and others were dropped, except for age. The resulting age-adjusted multivariate analysis revealed that RFS was improved in patients with ER- or PR-positive tumors (P = .002) and those who had fewer than four involved axillary nodes before DICT (P = .01). Treatment-related positive predictors of outcome were radiation treatment (P = .001), doxorubicin-containing DICT (given either as single-cycle DICT or tandem DICT with a doxorubicin-containing regimen [P = .03]), and tandem DICT in patients who actually received both cycles (P = .049); tandem DICT, when analyzed by intent-to-treat, was not associated with statistically significant improvement of RFS. OS was improved in patients with ER- or PR-positive tumors (P = .004), with fewer than four involved axillary nodes before DICT (P = .01); treatment-related positive predictors of outcome included radiation treatment (P = .002) and doxorubicin-containing DICT (P = .01). Tandem DICT did not yield improved OS (P = .15). Age-adjusted multivariate analysis resulted in a final model of two prognostic and three predictive variables for RFS and two prognostic and two predictive variables for OS. Models generated based on the presence or absence of these variables were then constructed to assess relative risk of relapse and death. Table 4 lists relative risk reductions associated with the above prognostic and predictive features.
Figure 2A and B show RFS and OS in groups of patients separated by the presence of both favorable, either (intermediate group), or neither (unfavorable group) of the two tumor-related prognostic features (receptor status and the number of involved axillary nodes before DICT) that were found to be significant in multivariate analysis. RFS at 5 years is 64% (95% CI, 35% to 92%) for the favorable group, compared with 28% (95% CI, 12% to 43%) for the unfavorable group (P = .02). Five-year OS is 91% (95% CI, 74% to 100%) for the favorable group, compared with 41% (95%CI, 23% to 59%) for the unfavorable group (P = .006). When we assessed the effect of tandem DICT in patients (who actually received both cycles) with favorable (receptor positivity, fewer than four involved axillary nodes before DICT) and intermediate biologic prognostic markers (receptor positivity and four involved axillary nodes or receptor-negative tumors with fewer than four involved axillary nodes) in comparison with favorable/intermediate-group patients receiving single-cycle DICT, RFS was significantly better (P = .02; relative risk, 0.28; 95% CI, 0.1 to 0.9). There was no statistically significant benefit for OS (P = .14) after tandem DICT (Fig 3A and B).
Patients with breast cancer presenting with high-risk features (< 50% projected 5-year RFS and OS) constitute approximately 10% to 15% of all newly diagnosed cases of primary breast cancer. Only 3% of all newly diagnosed breast cancer patients are diagnosed with the most aggressive form of high-risk disease: IBC. In our estimate, the 116 patients treated for IBC with DICT at the COHNMC between 1989 and 2002 represented 3% to 4% of the potentially eligible IBC patient population in Southern California.1,4 Hence the results of this retrospective analysis are deduced from findings generated from a selected patient population. Because of our strict eligibility criteria, the patient population is quite homogenous from the biologic point of view. There is to some degree inherent and unavoidable heterogeneity of treatment-related factors as a result of the long time line, sequential availability of newer therapeutic agents (taxanes), and change in protocols. However, the majority of patients received doxorubicin-containing neoadjuvant (79%) or neoadjuvant and adjuvant (99%) conventional-dose chemotherapy, and 40% received a taxane before DICT, during a median time period of 7 months (4 to 12 months) from diagnosis to DICT. Hence there is a relative homogeneity of pre-DICT interventions. The patients described here do represent the majority (approximately two thirds) of all stage IIIB IBC cases treated at the COHNMC, a major regional National Cancer Institute–designated comprehensive cancer center, between 1989 and 2002.
Treatment of patients with high-risk breast cancer continues to be a major clinical challenge. Administration of the newer agents such as taxanes either sequentially or in combination has benefited patients with relatively small-volume stage II disease, but outcome in patients with RFS and OS in patients with stage IIIB IBC has been especially unsatisfactory with standard therapy. Attempts to improve outcome have included dose-intense/high-dose chemotherapy as adjuvant treatment.20–24 Other investigators have focused on improving neoadjuvant therapy in locally advanced breast cancer in general, with the assumption that increasing the complete pathologic response rate before surgery may translate into longer survival. Indeed, weekly paclitaxel in addition to standard fluorouracil, doxorubicin, and cyclophosphamide,2 the addition of docetaxel to doxorubicin and cyclophosphamide,25 and metronomic administration of low-dose cyclophosphamide and weekly doxorubicin have yielded encouraging complete responses in patients with locally advanced breast cancer.26 The median follow-up of patients with stage IIIB IBC in previously published reports of dose-intense/high-dose chemotherapy has been relatively short (up to 47 months). Studies with long follow-up report less than 30% 5- to 10-year survival rates in patients with IBC treated with conventional chemotherapy.1,2,27 Our population of 120 patients represents a mature cohort with a median follow-up for living patients of 61 months (range, 21 to 161 months). We set out to define prognostic and predictive markers of outcome in this relatively rare patient population. We have found that the biology of the tumor (receptor status and grade and metastatic potential as measured by the number of axillary lymph nodes with metastasis) is still the most powerful predictor of outcome. We and others previously identified PR negativity as well as ER and PR negativity as independent predictors for relapse in high-risk breast cancer, in addition to high tumor grade.4 However, some patient- and treatment-related characteristics lacked statistically significant predictive value as a result of a lack of power with a limited sample size. HER-2/neu overexpression and high grade have been associated with negative predictive value in the setting of dose-intense therapy, both in our prior experience with high-risk patients and in series published by others.4,28 In this series of patients, we did find that a substantial percentage of patients (65%) presented with high-grade features. Because of a lack of substantial numbers of available tissue specimens suitable for testing, we were unable to confirm the prognostic/predictive value of HER-2/neu or other molecular markers. The incidence of HER-2 overexpression in our limited sample was found to be no different from the general breast cancer patient population. Mutated p53 was found to be expressed in a higher percentage of patients with IBC in one series, and p53 overexpression was associated with worse outcome in our previous series of high-risk primary breast cancer patients.4,28,29 We are attempting to procure additional paraffin blocks to proceed with further analysis, both by immunohistochemical and polymerase chain reaction analysis, to assess and confirm the prognostic and predictive value of other molecular markers, such as p53, p21, p27, Akt, E-cadherin, HER-2 and ErbB-1,30,31 markers of microvascular density, COX2, and cyclin-D1. Whether IBC is uniquely characterized by the expression of transcripts of novel molecular markers is the subject of further investigations.32 The RFS and OS in our cohort of selected DICT-treated patients compare favorably with our historical cohort of IBC patients treated with conventional therapy.3 Only limited data are available from patients treated concomitantly and in a nonrandomized fashion at the COHNMC with non-DICT containing regimens.4 We did find that treatment-related factors such as the achievement of complete pathologic response after neoadjuvant therapy and the actual delivery of tandem DICT are associated with improved RFS. The single-cycle regimens in our previous analysis as well as in the current study did not yield substantially different outcomes, although doxorubicin-containing regimens seemed to be associated with better RFS. The robustness of our conclusions is limited by the fact that IBC is a rare entity, hence we could not carry out a prospective randomized study. Patients were selected for DICT as a result of referral and institutional bias, and treatment-associated heterogeneity was unavoidable because of the length of time required to accrue large numbers of patients with stage IIIB IBC. Our patients were continuously accrued on sequential studies just as those studies became available through completion of accrual of earlier trials. There exists a time-related bias in this report, because most of the recently accrued patients received tandem-cycle DICT. Treatment of patients with IBC continues to be a major challenge. Because of its rarity, diagnosis is often delayed, leading to larger tumors and extensive lymph node metastasis in the majority of patients. Intuitively, as well as based on data from us and others, more effective neoadjuvant therapy to achieve enhanced pathologic complete response rates, as well as further improvements in adjuvant and consolidation therapy, are needed. More frequent (dose-dense) administration of standard-dose neoadjuvant therapy up-front, followed by surgery, and adjuvant therapy inclusive of tandem DICT may be one reasonable strategy for patients with receptor-negative, suboptimally responsive IBC who have four or more positive nodes.
Recent data from a prospectively randomized, phase III trial from the Netherlands for patients with Of the two United States randomized trials reported to date, one compared adjuvant chemotherapy followed by high-dose chemotherapy (STAMP-I) versus dose-intense consolidation with the same drugs (carmustine, cisplatin, and cyclophosphamide), whereas the second trial administered cyclophosphamide and thiotepa.35,36 Neither of these trials found a difference in outcome between the two arms, possibly as a result of the inherent toxicities associated with the regimens, although the more recent study by Tallman et al36 did reveal a potential RFS advantage in the subset of patients analyzed after excluding those with minor/major protocol violations from analysis.
A study of metronomic, weekly, or dose-dense sequential administration of an anthracycline, cyclophosphamide, and taxane followed by modified radical mastectomy and prospective randomization between dose-dense and a thoroughly tested single- or tandem-cycle alkylator-containing DICT33,37 may be required to further improve outcome for patients with IBC, especially if their tumors are receptor-negative, high-grade, HER-2/neu-overexpressing, and have persistently (
The authors indicated no potential conflicts of interest.
We thank our data managers and our secretary, Sunny Aure.
Supported by grant Nos. CA 33572 and CA 62505 from the National Cancer Institute, a General Research Center grant from the National Institutes of Health (grant No. M01 RR00043), Bethesda, MD, and an unrestricted grant from Bristol-Myers and Squibb Co, Princeton, NJ. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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16. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983, 2003 17. Nabholtz JM, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5 fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:36, 2002 (abstr 141) 18. Mamounas EP, Bryant J, Lembersku BC, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)
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28. Nieto Y, Cagnoni PJ, Nawaz S, et al: Evaluation of the predictive value of Her-2/neu overexpression and p53 mutations in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplantation. J Clin Oncol 18:2070–2080, 2000 29. Aziz SA, Pervez S, Kham S, et al: Case control study of prognostic markers and disease outcome in inflammatory carcinoma breast: A unique clinical experience. Breast J 7:398–404, 2001[CrossRef][Medline] 30. Guerin M, Gabillot M, Mathieu MC, et al: Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: Prognostic significance. Int J Cancer 43:201–208, 1989[Medline] 31. Bacus SS, Altomare DA, Lyass L, et al: AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival. Oncogene 21:3532–3540, 2002[CrossRef][Medline]
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36. Tallman MS, Gray R, Robert NJ, et al: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349:17–26, 2003 37. Nitz UA, Frick M, Mohrmann S, et al: Tandem high dose chemotherapy versus dose-dense conventional chemotherapy for patients with high risk breast cancer: Interim results from a multicenter phase III trial. Proc Am Soc Clin Oncol 22:832, 2003 (abstr 3344) Submitted October 22, 2003; accepted February 27, 2004. This article has been cited by other articles:
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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
65 years old and had a Karnofsky performance status of 
