Cancer Metastasis Research Center, Yonsei Cancer Center, Departments of 1 Internal Medicine, 2 Pathology, 3 Radiation Oncology and 4 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
* Correspondence to: Dr H. C. Chung, Yonsei Cancer Center, Cancer Metastasis Research Center, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea. Tel: +82-02-361-7623; Fax: +82-02-393-3652; E-mail: unchang8{at}yumc.yonsei.ac.kr
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Abstract |
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Patients and methods: Eighty-two LABC patients were treated with neoadjuvant iFAC chemotherapy including infusional 5-FU (1000 mg/m2, continuous intravenous infusion, days 13), adriamycin (40 mg/m2, intravenous bolus, day 1) and cyclophosphamide (600 mg/m2, intravenous bolus, day 1) every 3 weeks until maximum tumor response. Patients subsequently received surgery, adjuvant chemotherapy, radiotherapy and hormonal therapy as appropriate.
Results: Downstaging occurred in 71 of the 82 patients (86.6%). Seventy-two patients (67 patients with downstaging and five patients without downstaging) were resectable (resectability rate, 87.8%). The clinical response rate was 84.2%, with a complete response (CR) rate of 17.1% and a pathological CR rate of 7.8%. During 891 cycles of chemotherapy, the most common grade 3/4 hematological toxicity was leukopenia (36.0%). There were no treatment-related deaths. The median follow-up period was 51 months, with a median overall survival (OS) of 66 months, and a 5 year OS rate of 50.9% for all patients. The 5 year OS and disease-free survival (DFS) rates of the 64 patients who underwent surgery were 55.8% and 44.7%, respectively.
Conclusions: Neoadjuvant chemotherapy with iFAC had a comparable response rate and DFS to the conventional bolus FAC regimen, with an acceptable toxicity in LABC using the AJCC 2002 staging system. An early response to neoadjuvant iFAC was a favorable prognostic factor.
Key words: adriamycin, cyclophosphamide, infusional 5-fluorouracil, locally advanced breast cancer, neoadjuvant chemotherapy
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Introduction |
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Neoadjuvant chemotherapy followed by locoregional therapy is a standard treatment in LABC. The 5 year overall survival rate has improved from 1020% with local therapy alone to 3060% with the multidisciplinary approach [2]. The most effective regimens usually contain adriamycin. Generally, three to four treatment cycles have been reported to induce the clinical response rate of 5090% and a pathological complete response (pCR) rate <20% [3
, 4
]. A combined i.v. bolus 5-fluorouracil (5-FU), adriamycin and cyclophosphamide (FAC) regimen has been investigated in a neoadjuvant setting [5
] because it was previously reported to induce a good tumor response in metastatic breast cancer [6
, 7
]. More recently, a bolus FAC regimen has been widely used as neoadjuvant chemotherapy in LABC [5
, 8
, 9
].
The duration of 5-FU exposure is an important determinant of cytotoxicity, yet this agent has a short plasma half-life of approximately 11 min [10]. It was hypothesized that continuous i.v. infusion of 5-FU would overcome this limitation, and the prediction was validated by the observation of improved in vitro sensitivity to prolonged low-dose 5-FU exposure versus short high-dose exposure [11
]. However, only a few studies have evaluated infusional FAC (iFAC) in the neoadjuvant setting of LABC.
The present study was designed to evaluate the efficacy and safety of an iFAC regimen as neoadjuvant chemotherapy in LABC, and to identify the predictive and prognostic factors for response and survival with this regimen. The primary endpoint of this study was response rate and the secondary endpoints were downstaging rate, disease-free survival, overall survival, toxicity and dose intensity.
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Patients and methods |
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Treatment scheme
The iFAC regimen was administered according to the following schedule: 5-FU 1000 mg/m2 24 h continuous infusion on days 13, adriamycin 40 mg/m2 i.v. bolus injection on day 1 and cyclophosphamide 600 mg/m2 i.v. bolus on day 1. The treatment was repeated every 3 weeks. When the tumor response reached a maximum, as determined by there being no change in the tumor size for two consecutive treatment cycles, the resectability was assessed by an oncological surgeon. Criteria of resectability were determined as follows: no distant metastasis, no extensive involvement of the skin, no change of the inflammatory cancer and no fixation of axillary nodes to one another or to other structures. After surgery, adjuvant chemotherapy with iFAC was followed until a maximum of 12 cycles including neoadjuvant chemotherapy. Radiotherapy was performed with a dose of 50.4 Gy over 5.5 weeks. The irradiated volume included the chest wall, ipsilateral internal mammary node and ipsilateral supraclavicular node areas.
If the tumor was unresectable after iFAC, chemotherapy was continued with a salvage regimen. Hormonal treatment was added in those patients who were hormonal receptor positive or in a postmenopausal state. The treatment scheme is summarized in Figure 1.
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Toxicity was graded using the WHO criteria [13]. Granulocyte colony-stimulating factor (G-CSF) was administered in cases of grade 3/4 neutropenia, and the subsequent cycle was delayed until complete recovery. The dose administered was reduced by 25% if a grade 3/4 non-hematological toxicity occurred or was sustained for >2 weeks.
Follow-up evaluation after completion of anticancer treatment
The patients were evaluated every 6 months after completion of treatment. If possible, all suspected recurrences were confirmed by biopsy during the follow-up period. Typical nodules in the liver or the lung, indicated by imaging studies, or lytic areas on the bone indicated by radioisotope bone scan and plain radiographs, were accepted as recurrence without histological confirmation. Locoregional recurrence was defined as recurrence in the chest wall, breast, axillary node or ipsilateral supraclavicular node areas. Disease-free survival (DFS) was defined as the time from curative surgery to cancer recurrence, occurrence of a secondary primary cancer or death without evidence of recurrence. Overall survival (OS) was defined as the time from neoadjuvant chemotherapy to death from all causes.
Statistical methods
All statistical calculations were carried out using SPSS Windows version 11.0 (SPSS Inc., USA). All P-values were two-sided and the -value was set at 0.05. Survival was calculated using the KaplanMeier method. A log-rank test was used to compare survival between groups. Prognostic variables were submitted to multivariate analysis using Cox's proportional hazard regression model. Predictive factors for responsiveness were analyzed using a
2 test/Fisher's exact test and a logistic regression.
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Results |
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Ten unresectable patients received salvage chemotherapy with a platinum- or taxane-based regimen with or without radiation. Five of the 10 unresectable patients underwent surgery after salvage treatment. Figure 1 provides an overview of the treatment results.
Clinical and pathological response to iFAC chemotherapy
Clinical response was evaluated in breast tumors (82 patients), axillary nodes (69 patients) and supraclavicular nodes (10 patients). The clinical response rates were 84.4% for breast tumor (cCR, 25.6%; cPR, 58.8%), 82.8% for axillary nodes (cCR, 55.7%; cPR, 27.1%) and 100% for supraclavicular nodes (cCR, 100%). The overall response rate (ORR) was 84.2% (cCR, 17.1%; cPR, 67.1%). The pCR rates were 10.9% for breast tumor and 26.6% for axillary nodes. Five patients (7.8%, 5/64) achieved a pCR in both breast tumor and axillary nodes, and seven (10.9%) of the 64 patients who underwent surgery achieved a good pathological response (Table 3).
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Recurrence pattern and disease-free survival
At a median follow-up duration of 51 months (range 7122 months), 35 (54.7%) of the 64 operated patients experienced recurrence. The most common locoregional and distant recurrence sites were the chest wall and the bone, respectively. The locoregional, distant and combined recurrences occurred in 10 (15.6%), 17 (26.6%) and eight (12.5%) patients, respectively. Six of the 10 patients with locoregional recurrence showed a subsequent systemic recurrence, whereas a delayed locoregional recurrence was observed in only one of 17 initial systemic recurrences. The median DFS duration of the 64 operated patients was 45 months [95% confidence interval (CI) 1773]. The 5 year locoregional recurrence-free survival (LRFS), the 5 year distant recurrence-free survival (DRFS) and the 5 year DFS rates were 68.5%, 51.3% and 44.7%, respectively.
Overall survival
At a median follow-up duration of 51 months (range 7122 months), 41 (50%) of the 82 patients had died. Forty patients died from disease progression and one died from acute myocardial infarction. The median OS duration of the patients was 66 months (95% CI 4389), and their 5 and 10 year OS rates were 50.9% and 37.4%, respectively (Figure 2). The median OS duration of the 64 operated patients was 89 months (95% CI 43129), and their 5 and 10 year OS rates were 57.7% and 44.1%, respectively (Figure 2).
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Dose intensity
The median duration of the neoadjuvant chemotherapy was 10 weeks (range 723 weeks) with a median number of three cycles (range two to six). For neoadjuvant chemotherapy, the relative dose intensities (RDIs) were 1.0 (range 0.51.0), 1.0 (range 0.61.0) and 1.0 (range 0.51.0) for 5-FU, adriamycin and cyclophosphamide, respectively. For adjuvant chemotherapy, the RDIs were 0.9 (range 0.61.0), 0.9 (range 0.41.0) and 0.9 (range 0.41.0) for 5-FU, adriamycin and cyclophosphamide, respectively. The RDIs of the combined iFAC regimen in the neoadjuvant and adjuvant settings were 0.98 (range 0.581.00) and 0.91 (range 0.911.00), respectively.
Prognostic factors for recurrence and survival
Initial tumor size, IBC, initial clinical stage/response and pathological stage/response were evaluated as prognosticators. Table 4 summarizes the significant factors by univariate analysis. Multivariate analysis identified the following independent favorable prognostic factors (Table 4): clinical response for DRFS [hazard ratio (HR) = 3.6, P = 0.03] and OS (HR = 3.7, P = 0.04); early response for LRFS (HR = 4.1, P = 0.002), DRFS (HR = 3.1, P = 0.004), DFS (HR = 3.2, P = 0.01) and OS (HR = 3.6, P = 0.002).
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Discussion |
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A bolus FAC regimen is one of the most commonly used treatments in LABC, with a reported clinical response of 7288% and a pCR of 89% [5, 8
, 9
]. Even with a larger tumor size and a more advanced stage according to the AJCC 2002 staging system, the response rate and DFS of this trial with iFAC were similar to those of the M. D. Anderson Cancer Center clinical trial with a bolus FAC regimen [5
]. Another bolus FAC trial in LABC reported a 5 year OS rate of 46% [9
]. The 5 year OS rates of stage IIIA (47%) and IIIB (44%) reported by the National Cancer Institute [17
] were similar to our 5 year OS rates for stage IIIA (57.6%), IIIB (44.8%) and IIIC (47.9%) patients.
A high pCR of 16% was induced by MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) with a 5 year DFS of 51%. However, because of myelosuppression and diarrhea, only 31% of the patients in that trial were able to complete the intended six cycles of adjuvant MVAC chemotherapy [18]. CVAP (cyclophosphamide, vincristine, doxorubicin, prednisolone) also induced a high pCR of 16% but the long-term survival results are awaited [19
]. Recently, sequential docetaxel after anthracycline-based neoadjuvant chemotherapy was found to enhance the clinical response and pathological complete response rates significantly in two randomized phase III trials [19
, 20
]. However, it should be noted that the initial use of taxanes in LABC faces limitations such as loss of potential second-line drugs in the anthracycline-resistant cases. No data are yet available regarding the long-term survival of this treatment.
The randomized phase III Trial of Preoperative Infusional Chemotherapy (TOPIC1) [21] revealed that neoadjuvant continuous infusional 5-FU-based chemotherapy (5-FU, cisplatin, epirubicin) was no more effective than conventional bolus AC (adriamycin, cyclophosphamide) for early breast cancer. In TOPIC1, the inconvenience of continuous infusional 5-FU could not be justified by a non-significant increase in survival. Our trial is different from TOPIC1 in that infusional 5-FU-based chemotherapy was given to inoperable LABC patients. Infusional 5-FU-based chemotherapy might be overtreatment in cases of operable early breast cancer, and be needed instead for more advanced breast cancers, such as inoperable LABC, as reported previously in an advanced and locally advanced breast cancer trial [22
].
The toxicities of iFAC chemotherapy were generally mild and acceptable. The major toxicity was bone marrow suppression, which was manageable with G-CSF. Continuous infusion of 5-FU in the iFAC regimen did not cause severe oral mucositis or diarrhea. Handfoot syndrome was not observed. The occurrence of CHF (3.7%) was lower than in the bolus FAC trial (9.1%) [5]. Continuous infusion of 5-FU showed no evidence of enhancing anthracycline-induced CHF.
Most studies have used a fixed number of neoadjuvant chemotherapy cycles, usually three or four [5, 23
]. However, in the present study patients received treatment until the maximum clinical response was achieved, regardless of the number of cycles. The former strategy has the advantage that definitive local therapy is not unnecessarily delayed, although it also presents the disadvantage of missing an opportunity for optimal resection due to insufficient response. Our strategy might improve the response with the potential risk of development of resistant clones.
The clinical benefits of neoadjuvant chemotherapy include downstaging, induction of resectability and breast conservation. In the present study, downstaging and resectability rates were high, but breast conservation was not performed. Hortobagyi and colleagues reported that 23% of patients with stage IIB or III tumors were potential candidates for breast conservation [24]. The breasts of our patients were too small compared with the breast tumor mass to conserve, and the patients did not want to conserve the breast. This cultural trend explains the limited use of breast conservation surgery in Korea.
The limitation of this study was that the tumor measurements were made using classical methods, i.e. physical examination, mammography and/or ultrasonography and chest CT. A discrepancy was noted between cCR and pCR that was attributable to overestimation of the residual tumor from chemotherapy-induced fibrosis or difficulty in detecting microscopic residual tumor by the classical evaluation methods. MRI and positron emission tomography would be expected to increase the accuracy of the tumor response estimate [25, 26
].
A pCR is known to represent the best outcome [27, 28
]. The good pathological response group in the present study (five pCRs and two microRDs) also showed a trend toward better DFS. As reported in many other studies [5
, 29
], our investigation found that the clinical response was a favorable prognostic factor. The early response subgroup had a more favorable prognosis than the late response subgroup. This suggests that prolonged preoperative chemotherapy with the same regimen has less benefit in iFAC chemotherapy for late responders, i.e. patients with poor response after three cycles of iFAC should receive chemotherapy with an alternative regimen. Two possible explanations for better outcome in the early response subgroup are as follows: early local therapy may alter the disease course, or an early response to iFAC may represent a biologically predetermined good prognosis. In the results of the National Surgical Adjuvant Breast and Bowel Project B-18, which compared pre- and postoperative chemotherapy in operable cancer, early surgery did not alter the disease course [30
]. This finding seems to favor the second suggested explanation above. In the analysis of predictive factors, early responsiveness inversely correlated with initial tumor size. Thus tumor size can be considered to be an important parameter in selecting patients for neoadjuvant iFAC in LABC. Attempts are under way to identify the molecular predictors for early response in our patients by microarray-based comparative genomic hybridization.
In conclusion, neoadjuvant chemotherapy with iFAC had a comparable response rate and DFS to the conventional bolus FAC regimen, with an acceptable toxicity in LABC using the AJCC 2002 staging system. An early response to neoadjuvant iFAC was a favorable prognostic factor.
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Acknowledgements |
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Received for publication January 31, 2005. Revision received June 27, 2005. Accepted for publication June 28, 2005.
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