1Division of Medical Oncology, 2Pathology Department, 3Biometrics Department and 4Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Received 31 October 2001; revised 18 February 2002; accepted 8 March 2002.
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Abstract |
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The aim of this study was to present an update of overall (OS) and disease-free survival (DFS) and to evaluate the correlation between outcome and pathological findings at surgery in a randomized trial of high-dose chemotherapy following neoadjuvant chemotherapy and surgery in high-risk breast cancer patients.
Patients and methods
Ninety-seven women <60 years of age with breast cancer and extensive axillary lymph node involvement received three courses of FE120C (5-fluorouracil 500 mg/m2, epirubicin 120 mg/m2, cyclophosphamide 500 mg/m2) followed by surgery. Eighty-one patients were randomized to receive either a fourth FE120C course alone or a fourth FE120C course followed by high-dose chemotherapy (cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, carboplatin 1600 mg/m2). We performed a univariate analysis on possible prognostic factors and analyzed the sites of relapse.
Results
After a median follow-up of 6.9 years, 47 (48%) patients were alive, of whom 36 (38%) were without disease. Sixty patients relapsed after treatment. One patient died of myelodysplastic syndrome, without a relapse. In intention-to-treat analysis, the 5-year DFS rates were 47.5% in the conventional treatment arm and 49% in the high-dose arm, and the 5-year OS rates were 62.5% and 61%, respectively. In the univariate analysis, the clinical T-stage before chemotherapy and the number of tumor-positive axillary lymph nodes after induction chemotherapy (P = 0.027) were significant prognostic factors for OS. The same factors (both P = 0.06) plus the estrogen receptor (P = 0.08) were borderline significant factors for DFS.
Conclusions
After a median follow-up of 6.9 years there was no difference in OS or DFS rates between the two treatment groups. The number of tumor-positive axillary lymph nodes after induction chemotherapy and the clinical T-stage before chemotherapy were significant factors for OS.
Key words: breast cancer, hematopoietic progenitor-cell support, high-dose chemotherapy, randomized trial
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Introduction |
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Of the remaining five randomized studies, only the Dutch National study (preliminary analysis of the first 284 patients) [1] showed a modest survival benefit from high-dose chemotherapy. The American Intergroup study [2] was updated at the American Society of Clinical Oncology (ASCO) meeting in 2001 and did not show a survival advantage of high-dose therapy compared with intermediate-dose therapy. They found fewer relapses in the high-dose therapy group, but this was compensated by a high early toxicity mortality rate. The other three randomized studies have been published in peer-reviewed journals and showed no advantage of high-dose treatment [35]. One of these randomized trials was performed in our institute, and the results with a median follow-up of 4 years were published in 1998 [5]. In this report, we present the updated results of this trial with a median follow-up of >6.9 years and a lead follow-up of almost 10 years. The more mature data allow not only an update of survival, but also an evaluation of risk of second malignancies and possible long-term side effects of high-dose chemotherapy.
In this study, surgery was performed following three courses of chemotherapy, which gave the opportunity to analyze prognostic significance of the response to neoadjuvant chemotherapy. As well as response, we also analyzed other possible prognostic factors [estrogen (ER), progesterone receptor (PR) [7], tumor size, the axillary nodal status [8], HER-2/neu protein expression [9], proliferation markers] in order to identify patients that will benefit most from high-dose chemotherapy.
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Patients and methods |
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Written informed consent was obtained from all patients before enrolment in the study, according to institutional guidelines. Patients again gave their consent before up-front chemotherapy, before surgery and before randomization. The protocol was approved by The Netherlands Cancer Institutes protocol review committee and the Committee for Medical Ethics of The Netherlands Cancer Institute.
Study design
The study was designed as a single-institution phase II study. Earlier results concerning efficacy and feasibility have been published previously [5, 13]. The treatment sequence started with three up-front courses of FE120C (5-fluorouracil 500 mg/m2, epirubicin 120 mg/m2, cyclophosphamide 500 mg/m2) (Figure 1). After the third course, all patients underwent surgery. The type of surgery (mastectomy or breast-conserving therapy and axillary lymph node dissection) had been decided before the start of chemotherapy. After surgery, patients with a response to chemotherapy or stable disease were randomized to either conventional chemotherapy (a fourth course of FE120C, followed by radiotherapy and tamoxifen) or high-dose chemotherapy [the same treatment but with additional high-dose chemotherapy and peripheral-blood progenitor cell (PBPC) support]. In the high-dose arm, the fourth FE120C course was used for mobilization of stem cells. For this purpose granulocyte colony stimulating factor (filgrastim 300 µg, daily subcutaneous dose) was started 24 h after the chemotherapy. PBPCs were harvested by leukocytaphereses, starting when the white blood cells exceeded 3 x 109/l and continued until at least 3 x 106 CD34-positive cells per kilogram of body weight had been collected. High-dose chemotherapy started preferentially 21 days after the fourth FE120C course. The high-dose regimen consisted of cyclophosphamide 6 g/m2, thiotepa 480 mg/m2 and carboplatin 1600 mg/m2, divided over 4 days [14]. The PBPC reinfusion was performed 2 days after the end of the chemotherapy. The prophylactic use of anti-emetics and antibiotics has been described elsewhere [5]. Anti-emetics were used prophylactically and then as needed. All patients received prophylactic antibiotics, including oral ciprofloxacin (500 mg bd) and oral amphotericin B (500 mg qds), starting 4 days before high-dose treatment. Penicillin (1 x 106 U qds) was administered 2 days before reinfusion and amphotericin B (0.25 mg/kg daily) on the day of reinfusion. All antibiotics were discontinued when the neutrophil cell count exceeded 0.5 x 109/l. Patients who were positive for antibodies to herpes simplex virus were given oral aciclovir 400 mg twice daily. Irradiated platelet transfusions were administered to maintain platelet count above 10 x 109/l and irradiated leukocyte-free red blood cells were given if hemoglobin was <5.5 mmol/l. The chemotherapy was followed by radiation therapy (to the chest wall, parasternal, axilla and supraclavicular and infraclavicular fields) and by tamoxifen (40 mg/day for 2 years).
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Pathological examination
All breast specimens were handled according to institutional protocols. Tumor size was measured in fresh specimen, and the largest diameter was used to assess pathological tumor stage (pT). pT was checked microscopically by complete cross sections of the gross tumor. At least 10 lymph nodes were harvested from the axillary specimens; all lymph nodes were completely embedded and evaluated by hematoxylineosin (HE) and immunohistochemical staining using cam 5.2. Immunohistochemistry was performed in case of residual carcinoma to assess ERs and PRs, HER2/neu, p53 overexpression, Ki-67 and BCL-2. Pathological response was evaluated and scored as complete in case of absence of invasive tumor in the breast and lymph nodes. Histological classification was carried out according to the WHO criteria. Grading was carried out according to criteria described by Elston and Ellis [15]. The results of the proliferation markers (Ki-67 and BCL-2) and the pathological response will be published elsewhere.
Immunohistochemistry
Formalin-fixed, paraffin-embedded tissue samples were stained with antibodies against HER-2/neu (3B5; 1:10 000), p53 (D07; 1:8000; mouse IgG2b; DAKO, Copenhagen, Denmark), ER (1D5; 1:150; mouse IgG1; DAKO), Ki-67 (MIB-1; 1:1000; DAKO) and BCL-2 (clone 124; 1:100 mouse IgG1; DAKO). The methods of the immunohistochemical staining will be published elsewhere. Briefly, 5-µm sections were deparaffinized in xylol and alcohol, and endogenous peroxidase was quenched in methanolperoxide (3%; 20'). Slides were pre-treated (antigen retrieval) in citrate buffer, blocked with normal goat serum and then incubated with the primary antibody overnight at 4°C. Binding of the monoclonal antibody was detected with biotin-labeled goat anti-mouse IgG (1:200; 30' DAKO) and horseradish peroxidase avidinbiotin complex (1:100; 30' DAKO). Bound peroxidase was developed with 3,3'-diaminobenzidine tetrachloride (Sigma, St. Louis, MO, USA) and 0.02% H2O2 in phosphate-buffered saline (PBS). All reagents were diluted in a 1% bovine albumin solution in PBS. Anti-mouse IgG solution was admixed with 10% normal human serum to prevent non-specific binding. Replacement of the primary antibody with 1% bovine albumin solution in PBS served as negative control.
Immunohistochemical results were mostly scored semi-quantitatively on a six-point scale for percentage of positively staining tumor cells (0; 1, <10%; 2, 10% to 25%; 3, 25% to 50%; 4, 50% to 75%; 5, 75% to 100%). HER-2/neu was scored according to the system that has recently come into use for clinical testing (0; 1+ >10% cells weakly positive; 2+ moderate homogenous staining; 3+ strong homogenous staining).
Statistical analysis
This report is an update of our study published in 1998 [5]. Treatment assignment was done by the minimization technique with stratification for cCR (yes or no) and postmenopausal status (yes or no). The primary endpoints were overall survival (OS) and relapse-free survival.
The treatment comparisons were done by intention-to-treat analysis. Survival curves were constructed by the KaplanMeier method and compared by the log-rank test. We used Coxs model to analyze the factors predictive of progression or death and to adjust the comparison of treatment for the patients baseline characteristics.
In the univariate analysis, possible prognostic factors for relapse and overall disease-free survival (DFS) from the start of treatment were examined. For each variable, KaplanMeier curves and the graph of the log (log survival function) versus log (time) were plotted and checked for proportionality of hazards. For these plots, each variable was screened univariately by means of Coxs proportional hazards model. Discrete variables with more than two categories were analyzed by means of the categories or indicator variables. A forward stepwise procedure was planned with those variables found to be significant in the screening. No variable passed this step.
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Results |
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Feasibility, toxicity and data on PBPC mobilization have been described in earlier reports [5, 16].
Overall and progression-free survival
At the time of this analysis, 47 (48%) of the 97 patients were alive, of whom 11 (11%) had disease and 36 (37%) were without disease (Table 1). The 5-year DFS and OS were 45% and 59%, respectively.
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Long-term side effects and second tumors
The median follow-up of 6.9 years after registration with a lead follow-up of 9.8 years is still too short for a complete evaluation of risk of second tumors (particularly solid tumors) and long-term side effects (Table 7). Radiation pneumonitis is a relatively early side effect. Five patients (four in the high-dose group and one in the conventional therapy arm) developed a radiation pneumonitis between 3 and 12 weeks after radiation therapy; all were reversible after treatment with prednisone. Cardiac problems were reported with expected frequency: one patient had a myocardial infarction. Van Dam et al. [22] have evaluated cognitive toxicity in these patients, and found that cognitive function impairment was more frequent after high-dose treatment for breast cancer.
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Discussion |
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After a median follow-up of 6.9 years and a lead follow-up of almost 10 years in 97 patients with breast cancer and extensive lymphadenopathy, there was no statistically significant relapse-free survival advantage for high-dose chemotherapy over conventional therapy in this study. Since the study was small and did not have the power to detect a difference of >30% in (relapse-free) survival between the treatment groups, a smaller but clinically important advantage for high-dose therapy may have been missed. In fact, 27 of 40 patients randomized to the conventional treatment died or relapsed, while there were only 23 (22 deaths from or relapse of disease, and one death from myelodysplasia) of 41 patients in the high-dose group who experienced such an event. At the time of writing, 32% of the conventionally treated patients remain alive and free of disease compared with 44% of the patients who received high-dose therapy as a consolidation. This corresponds to a reduction in hazard rate of almost 20%. Although statistically not significant, this is consistent with preliminary data of the large Dutch National study, which were reported at the ASCO meeting in 2000 [1]. This study showed a reduction of odds of relapse of 20% in 885 patients at a median follow-up of 35 months after randomization. Thus, the present study cannot be regarded as negative, because it is too small to reject an equivalence hypothesis.
A second possible reason for the absence of an effect of high-dose therapy could be the fact that chemotherapy was interrupted for an appreciable amount of time to allow surgery. Substantial regrowth of tumor cells might take place between the third and the fourth FE120C courses, thereby losing some of the beneficial effect of the induction chemotherapy. It is of interest that a similar interval between conventional dose induction chemotherapy and high-dose therapy was present in the Philadelphia study [25], which showed no advantage for high-dose therapy. Mathematical models of tumor growth suggest that this could eliminate most of the benefit of the induction therapy [26, 27].
The high-dose chemotherapy regimen used in this study and in the Dutch National study [1] is related but not identical to the STAMP-V or CTCb regimen, which was employed in the Philadelphia study [25] and in the Scandinavian randomized adjuvant trial [3]. The main differences are that the carboplatin dose in the Dutch regimen is twice as high (1600 mg/m2), and the three alkylating agents are administered as short-term infusions rather than as 96-h continuous infusions. The latter difference could be important, since we have shown recently that even low concentrations of thiotepa can inhibit the activation route of cyclophosphamide [28]. If thiotepa is continuously present in the circulation, a sustained reduction of 4-hydroxycyclophosphamide formation may be present, accounting for less active metabolites of cyclophosphamide, less toxicity and possibly a lower efficacy.
Although our study failed to show an advantage for high-dose therapy, the OS is appreciably better than that of a similar series of patients reported from our institute [29]. This could result from factors such as patient selection [30, 31] and stage migration. Moreover, these patients were treated with the CMF (cyclophosphamide, methotrexate and 5-fluoruracil) regimen instead of FE120C. It is likely, however, that some real improvements in adjuvant therapy, such as the prolonged administration of tamoxifen after chemotherapy and radiation therapy of the chest wall, have contributed to the better OS.
An important disadvantage of high-dose therapy or other forms of intensive chemotherapy in the adjuvant treatment of breast cancer is long-term side effects, including the risk of therapy-induced second malignancies. After a lead follow-up of 10 years we identified five neoplasms: two MDS and three solid tumors. Both cases of MDS developed in the high-dose therapy arm, but one of these patients retrospectively had signs of a myelodysplastic syndrome in her bone marrow before high-dose therapy. This incidence is comparable to the results of Sobecks et al. [32], who reported an incidence of 0.3%, and Laughlin et al. [33], who reported a 4-years probability of developing MDS/acute leukemia of 1.6% after high-dose therapy. In the study by Bergh et al. [3], no cases of MDS/acute leukemia were seen in the high-dose therapy arm, but in the 251 patients treated with tailored FEC (dose adjusted to tolerance), six cases of acute myelogenous leukaemia and three cases of MDS were diagnosed. This high incidence was probably caused by the high cumulative dose of epirubicin in the conventional arm.
Since MDS and leukemia usually develop within 6 years after treatment [33, 34], we believe that the incidence will not appreciably rise with further follow-up in the present study.
Only three solid tumors have been diagnosed in our patient group: one basal cell carcinoma (high-dose treatment) and two colorectal tubular/tubulovillous adenomas (one in the high-dose arm and one in the conventional treatment arm). These malignancies are also common in the normal population. We found only one contralateral second breast tumor in the conventional dose arm. This is remarkable, because the incidence of second contralateral breast tumors is 78 per 1000 women-years of follow-up [3537]. In this group of 97 patients with 670 women-years of follow-up, one would expect 45 cases of contralateral breast cancers. So, it could be that the adjuvant hormonal and chemotherapeutic treatment has a protective effect for contralateral breast cancer. At this time it is difficult to estimate the number of second malignancies after high-dose therapy in breast cancer, since there is insufficient follow-up in all of the available studies.
A potential complication of high-dose therapy in breast cancer is radiation pneumonitis. We observed this complication in 5% of our patients: four patients in the high-dose group and one in the conventional arm, all responding well to prednisone without developing clinically significant long-term pulmonary toxicity. This is an important difference with the cisplatinBCNUcyclophosphamide regimen used in the American Intergroup study [2]. In this trial, pulmonary toxicity was an important cause of therapy-related death.
We recently reported that neuropsychological disorders may be present after high-dose chemotherapy, although their clinical importance is as yet unclear [22]. At this point, it is not known whether or not abnormalities at neuropsychological testing are also present after one of the other high-dose regimens used in breast cancer. This would be interesting to determine, while theoretically it is possible that the higher dose carboplatin in our regimen has influence on neuropsychological functioning.
If high-dose chemotherapy proves to benefit patients with breast cancer, it is quite likely that this benefit will be limited to a (possibly small) subgroup of patients. It would be important to identify or confirm prognostic factors that characterize this patient group. In the present study, pathological specimens were taken both before and after induction chemotherapy, allowing the study of a range of potential prognostic factors in relation to treatment outcome. Pathological characteristics of primary tumors have been reported to have predictive value [1821] and similar results have been obtained in small series of patients receiving intensive chemotherapy [79]. In the present study, only clinical T-stage and the number of tumor-positive axillary lymph nodes were prognostic factors for OS. Clinical T-stage, the number of tumor-positive axillary lymph nodes and positivity for the ER were of borderline prognostic value for DFS. Unfortunately, it was not possible to identify a patient group that specifically benefited from high-dose therapy. Clearly, the number of patients in our study may have been too small to investigate this in a meaningful way, and similar analyses will be crucial when the large American and European studies of high-dose therapy and the adjuvant chemotherapy of breast cancer have reached sufficient follow-up time.
Although this study did not show a benefit of high-dose therapy in patients with high-risk breast cancer, the Dutch National study [1] has reported preliminary results that could be consistent with a modest benefit for high-dose therapy. An update of the American Intergroup study [2] presented at ASCO 2001 showed fewer relapses in the high-dose therapy group compared with the intermediate-dose group. This did not result in a survival advantage, probably because of the high early toxicity rate. The maturation of these and other ongoing large studies should be awaited before the validity of the high-dose concept in breast cancer is abandoned or adopted.
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Acknowledgements |
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Footnotes |
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Present address: Division of Medical Oncology, Academical Medical Centre, Amsterdam, The Netherlands.
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