Abstract
Purpose
To assess the efficacy and safety of primary systemic treatment with doxorubicin and paclitaxel in patients with early breast cancer.
Patients and methods
Forty patients with newly diagnosed, histologically confirmed breast cancer (T2, N0–1, M0) received primary chemotherapy with doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) in 3-week intervals for up to four courses.
Results
A total of 151 cycles were administered. The clinical response rate as assessed by sonographic measurement was 70%, and complete remissions of the primary tumor occurred in two patients. Eight patients (20%) had histologically confirmed complete responses. Predominant toxicity was myelosuppression with grade 3/4 neutropenia in 70% of patients. Non-hematological toxicity was generally moderate. Grade 4 non-hematological toxicities were not observed and grade 3 toxicity was reported with alopecia (98%) and stomatitis (10%).
Conclusions
The combination of doxorubicin and paclitaxel is safe and highly active in patients with early breast cancer. The evaluated schedule is suitable for phase III studies.
Keywords: Primary chemotherapy, Neoadjuvant, Early breast cancer, Paclitaxel, Doxorubicin, Adjuvant treatment
Introduction
Perioperative systemic treatment has had a major impact on relapse-free and overall survival of pre- and postmenopausal women with early-stage breast cancer [1, 2]. Conventionally, perioperative systemic therapy is administered after local treatment. However, in recent years, the application of chemotherapy before the treatment of the primary lesions with surgery or radiation has become increasingly common. This approach is referred to as primary or neoadjuvant therapy.
This approach was first applied to patients with locally advanced breast cancer in order to downstage the primary breast tumor, facilitate radical locoregional treatment, and improve the outcome in this high-risk population. After it became the standard treatment for locally advanced tumors, primary systemic therapy was introduced in the management of patients with earlier stages of breast cancer. The rationale for its use in operable breast cancer is based on observations of accelerated metastatic growth following tumor resection in animal models. It was suspected that primary chemotherapy might achieve better eradication of possible distant micrometastatic disease through early initiation of systemic treatment before the development of resistant clones and while potential antiangiogenic factors secreted by the primary are still present. In addition, neoadjuvant chemotherapy provides an effective means to test tumor chemo-sensitivity in vivo and to study breast cancer biology and its influence on response to treatment.
Primary systemic treatment has been evaluated in a number of randomized trials comparing neoadjuvant and adjuvant anthracycline-based chemotherapy [3, 4, 5, 6, 7, 8, 9, 10]. Although primary chemotherapy was generally associated with a higher rate of breast-conserving surgery, it failed to increase disease-free or overall survival. Several trials showed, however, that response to neoadjuvant chemotherapy is correlated with survival. Patients who experience complete disappearance of their primary tumor seem to obtain the greatest advantage from neoadjuvant chemotherapy regarding survival.
Since only a minority of patients are reported to achieve a complete response, current approaches for primary systemic therapy focus on increasing the pathologic response rate. One strategy is the incorporation of taxanes into anthracycline-based neoadjuvant chemotherapy. Paclitaxel and docetaxel have proved to be highly active in the treatment of early and advanced breast cancer. In metastatic breast cancer, combinations of taxanes and anthracyclines have shown superior efficacy compared to non-taxane containing anthracycline-based combinations.
At the time when this trial was initiated, no data were available on the use of paclitaxel in the neoadjuvant setting. Therefore, this trial was initiated to evaluate the safety and efficacy of primary systemic treatment with doxorubicin and paclitaxel in patients with early breast cancer.
Patients and methods
Objectives
The objectives of this study were to assess the efficacy and safety of primary systemic treatment with doxorubicin and paclitaxel in patients with early breast cancer. The primary study objective was to determine the clinical and pathological response to doxorubicin and paclitaxel. Secondary end points included tolerability, the rate of breast-conserving surgery, and quality of life.
Patient eligibility
Previously untreated patients aged 18–75 years with newly diagnosed, histologically confirmed breast cancer with T2 N0–1 M0 disease were included in the trial. Patients were required to have measurable disease by physical examination or diagnostic breast imaging, adequate hematological, renal, hepatic and cardiac function (ANC >1.5×109/l; platelets >100×109/l; bilirubin, serum transaminase, and creatinine levels within normal range; left ventricular ejection fraction of at least 50%), a Karnofsky performance status of at least 70, a negative pregnancy test, and appropriate contraception throughout the study (in premenopausal women only). Written, informed consent was required.
Exclusion criteria included previous systemic or local treatment for breast cancer (including surgery, radiotherapy, cytotoxic and endocrine treatments), evidence of distant metastases, a history of prior other malignancies, preexisting peripheral neuropathy greater than grade 1 (NCI Common Toxicity Criteria), cardiac arrhythmias greater than Lown II, congestive heart failure, active infection or other severe concurrent medical conditions. Pregnant or lactating women were ineligible.
Treatment regimen and study design
Eligible patients received doxorubicin 60 mg/m2 IV over 15 min, followed by paclitaxel 200 mg/m2 IV over 3 h. Premedication consisted of dexamethasone 20 mg, clemastin 2 mg, and cimetidine 300 mg, given intravenously 30 min before paclitaxel. If required, antiemetic treatment was extended in compliance with the standards of the center. Hematopoietic growth factors were used to treat patients with grade 4 neutropenia or febrile neutropenia but were not applied prophylactically.
Treatment was repeated in 3-week intervals for up to four courses. Continuation of treatment was delayed as a result of hematologic toxicity (ANC <1.5×109/l and/or platelet count <100×109/l) on day 1 of any cycle. Subsequent doses of paclitaxel were to be reduced to 175 mg/m2 in cases of febrile neutropenia, grade 4 thrombocytopenia, grade 3–4 gastrointestinal side effects or grade 2 neurotoxicity. No dose reduction of doxorubicin was permitted. Treatment was stopped in case of persistent toxicity despite dose reduction, grade 3 to 4 neurotoxicity, cardiac arrhythmia, a ≥10% decrease of left ventricular ejection fraction to a final value below normal, any grade 3 non-hematologic toxicity except for nausea, vomiting, gastrointestinal side effects, alopecia and myalgia, or in case of any grade 4 non-hematologic toxicity.
Patients were scheduled to undergo surgery approximately 3–4 weeks after the last chemotherapy cycle. Surgery was performed earlier in case of disease progression, stable disease after two courses, complete clinical response or inadequate or prolonged toxicity. Surgery consisted of either a modified radical mastectomy or breast-conserving surgery in order to provide tumor-free margins of at least 1 cm. Standard axillary lymph node surgery with excision of at least ten lymph nodes was to be performed in all cases. Patients with breast-conserving surgery received adjuvant irradiation of the breast. Adjuvant systemic treatment (hormonal treatment and/or chemotherapy) was administered in accordance with the consensus guidelines for primary breast cancer applicable at that time.
Patient evaluation and follow-up
Before entry into the study, all patients underwent staging work-up including a complete history and physical examination, complete blood count, chemistry profile, chest X-ray, abdominal ultrasound and/or a computed tomography, bone scan, and mammograms of both breasts. Primary tumor size and axillary lymph node involvement were assessed by clinical, X-ray, and sonographic evaluation. Histologic confirmation of the invasive tumor was performed by core needle biopsy.
Clinical tumor size and nodal status were estimated before each cycle of chemotherapy and within 4 weeks after the last chemotherapy cycle by both palpation and ultrasound. The product of the two greatest perpendicular diameters was used to compare tumor size before and after chemotherapy.
A clinical complete response (cCR) was considered to be complete disappearance of all clinically detectable malignant disease by palpation as well as imaging techniques. Clinical partial response was defined as a 50% or more decrease in total tumor size (cPR). A decrease in tumor size of less than 50% or an increase of less than 25% was classified as stable disease (SD). An increase of 25% in tumor size at any time was considered to be progressive disease (PD). In patients with clinically negative nodes at study entry, the development of palpable nodes during preoperative chemotherapy was considered evidence of PD.
Surgical specimens were evaluated for pathologic tumor status. Samples with no histologic evidence of invasive tumor at the primary site and in the axillary lymph nodes were classified as pathologic complete responses (pCR). Pathologic findings represented in this report are those reported by institutional pathologists.
Adverse events and toxicities were recorded for every cycle. They were graded using the NCI Common Toxicity Criteria (CTC). Quality of life was evaluated using the EORTC questionnaire QLQ-Q30.
During follow-up a clinical assessment for each patient was performed at 3-month intervals for the first 2 years and every 6 months thereafter. In addition to the routine physical examination—with particular attention to local recurrence and lymph nodes—which was performed at each visit, an extended search for relapse and metastases (mammography, chest X-ray, abdominal ultrasound, skeletal X-ray, bone scintigraphy) was applied every 6 months during the first year and once a year thereafter.
Regular independent monitoring was performed for source data verification and in order to ensure treatment according to the protocol. The relevant local ethics boards reviewed and approved the study protocol and all amendments. The study was conducted in accordance with the Declaration of Helsinki, ICH Harmonized Tripartite Guidelines for Good Clinical Practice, and any local regulations.
Statistical analysis
The sample size was estimated at 40 patients assuming an objective response rate ≤40% as null hypothesis, a true response rate of ≥60%, a power of 90%, and a significance level of 5%. Standard descriptive methods were applied. Survival and recurrence-free survival were estimated by the Kaplan-Meier method. Categorical variables were described by contingency table methods and percentages. Continuous variables were described by mean and median values, standard deviations, and minimum and maximum values.
Results
Patient characteristics
Forty patients with newly diagnosed, early breast cancer were enrolled at five different centers. All patients were assessable for efficacy and safety analysis. Median follow-up was 63 weeks (range, 29–109 weeks).
Patient characteristics at the time of study registration are listed in Table 1. The median age of patients was 50 years (range, 30–69 years). Half of the patients had clinical stage IIA disease and stage IIB or IIIA disease, respectively.
Table 1.
Patient baseline characteristics
| Patients | (n) | 40 |
|---|---|---|
| Age (years) | [median (range)] | 50(30–69) |
| Initial clinical tumor size | ||
| 2–<3 cm | [n (%)] | 9(22.5%) |
| 3–5 cm | [n (%)] | 31(78.5%) |
| Initial clinical nodal status | ||
| N0 | [n (%)] | 20(50.0) |
| N1 | [n (%)] | 15(37.5) |
| Nx | [n (%)] | 5(12.5) |
| ECOG Performance Status | ||
| Grade 0 | [n (%)] | 39(97.5) |
| Grade 1 | [n (%)] | 1(2.5) |
| Menopausal state | ||
| Pre- and perimenopausal | [n (%)] | 21(52.5) |
| Postmenopausal | [n (%)] | 19(47.5) |
| Hormone receptor status | ||
| ER and/or PgR positive | [n (%)] | 20(50.0) |
| ER and PgR negative | [n (%)] | 19(47.5) |
| Not available | [n (%)] | 1(2.5) |
| Histology | ||
| Ductal carcinoma | [n (%)] | 34(85.0) |
| Lobulary carcinoma | [n (%)] | 3(7.5) |
| Not further specified | [n (%)] | 3(7.5) |
| Histological grade | ||
| G1 | [n (%)] | 2(5.0) |
| G2 | [n (%)] | 17(42.5) |
| G3 | [n (%)] | 12(30.0) |
| Not available | [n (%)] | 9(22.5) |
A total of 151 cycles of chemotherapy were administered during the study. The mean (median) number of cycles per patient was 3.8 (4). All patients received at least two cycles. Three patients were withdrawn after two and three cycles respectively with stable disease. The remaining 34 patients received the intended maximum number of four courses. The median cumulative doxorubicin and paclitaxel doses were 240 mg/m2 (range, 120–240 mg/m2) and 800 mg/m2 (range 400–800 mg/m2), respectively.
Toxicity
The tolerability and toxicity of the regimen was evaluated in 150 documented courses. No treatment delays were carried out in any patient. Dose reductions were required in only one cycle in a patient experiencing grade 4 thrombocytopenia during the 3rd course. No patient had to be taken off the trial due to toxicity.
Although hematopoetic growth factors were not used prophylactically, myelosuppression was only moderate. Predominant hematological toxicity was neutropenia with grade 3 or 4 toxicity in 37.3% of courses and 28 of 40 patients, respectively (Table 2). Neutropenia was generally uncomplicated and rapidly reversible. No relevant infections occurred during the trial. In accordance with the protocol, seven patients received G-CSF to treat grade 4 neutropenia.
Table 2.
Incidence of hematologic toxicities during study treatment (by patient and by cycle)
| Patients | Cycles | |||||||
|---|---|---|---|---|---|---|---|---|
| Total | Grade 3/4 | Total | Grade 3/4 | |||||
| n | % | n | % | n | % | n | % | |
| Neutropenia | 32 | 80.0 | 28 | 70.0 | 69 | 59.0 | 56 | 37.3 |
| Leucopenia | 37 | 92.5 | 22 | 55.0 | 114 | 76.0 | 47 | 31.3 |
| Anemia | 33 | 82.5 | 0 | 0 | 79 | 52.6 | 0 | 0 |
| Thrombocytopenia | 14 | 35.0 | 1 | 5.0 | 32 | 21.4 | 2 | 1.3 |
Anemia was frequent but generally mild with grade 1 and 2 in 24 (60.0%) and nine patients (22.5%), respectively, and no grade 3 or 4 toxicity. Thrombocytopenia was noted in 14 patients but was grade 3/4 in one patient only.
Acute nonhematologic toxicities were usually mild (Table 3). No grade 4 episodes of acute nonhematologic toxicity were reported. Grade 3 toxicities were reported for stomatitis (four patients) and alopecia, which was complete in nearly all patients (39 patients; 97.5%). Further common toxicities included peripheral neuropathy (grade 2:35%), asthenia (grade 2:27.5% of patients), and musculoskeletal pain (grade 2:25% of patients). Mild to moderate nausea and vomiting (grade 1 and 2) were reported in 11 and seven patients, respectively, but remained under control with a combination of 5-HT3-antiemetics and corticosteroids. No cases of cardiac, hepatic, renal or pulmonary toxicity were reported throughout the study.
Table 3.
Incidence of non-hematologic toxicities during study treatment (by patient and by cycle)
| Patients | Cycles | |||||||
|---|---|---|---|---|---|---|---|---|
| Total | Grade 3/4 | Total | Grade 3/4 | |||||
| n | % | n | % | n | % | n | % | |
| Nausea | 26 | 65.0 | 0 | 0 | 77 | 51.4 | 0 | 0 |
| Vomiting | 18 | 45.0 | 0 | 0 | 37 | 24.7 | 0 | 0 |
| Stomatitis | 20 | 50.0 | 4 | 10.0 | 44 | 29.3 | 6 | 4.0 |
| Diarrhea | 3 | 7.5 | 0 | 0 | 6 | 4.0 | 0 | 0 |
| Asthenia | 16 | 40.0 | 0 | 0 | 43 | 28.7 | 0 | 0 |
| Periph. neuropathy | 23 | 57.5 | 0 | 0 | 60 | 40.0 | 0 | 0 |
| Myalgia | 6 | 15.0 | 0 | 0 | 12 | 8.0 | 0 | 0 |
| Arthralgia | 9 | 22.5 | 0 | 0 | 16 | 10.7 | 0 | 0 |
| Skeletal pain | 15 | 37.5 | 0 | 0 | 40 | 26.7 | 0 | 0 |
| Cardiotoxicity | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Infection | 6 | 15.0 | 0 | 0 | 7 | 4.7 | 0 | 0 |
| Febrile neutropenia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Fever | 6 | 15.0 | 0 | 0 | 7 | 4.7 | 0 | 0 |
Efficacy
The overall clinical response rate assessed by sonographic evaluation was 70% [95% Confidence Interval (CI), 55.8%–84.2%]. Partial and complete responses were achieved in 26 patients (65%) and two patients (5%), respectively (Table 4). Disease was stable in 12 patients. No patient progressed on study treatment.
Table 4.
Clinical and pathological response
| Patients | (n) | [% (95% Confidence Interval)] |
|---|---|---|
| Clinical assessment | ||
| Complete response | 2 | 5.0 |
| Partial response | 26 | 65.0 |
| Objective response (CR & PR) | 28 | 70.0 (55.8–84.2%) |
| Stable disease | 12 | 30.0 |
| Progression | 0 | 0.0 |
| Histologic assessment | ||
| Histologic complete response | 8 | 20.0 (7.6–32.4%) |
| Residual invasive tumor | 32 | 80.0 |
Histologic evaluation confirmed complete disappearance of the tumor in the two patients with clinical complete responses. In addition, six patients with clinical partial responses had no evidence of invasive tumor tissue on pathologic evaluation, accounting for an overall pathologic response (pCR) rate of 20% (95% CI, 7.6%–32.4%).
Quality of life
Baseline evaluation of quality of life (QoL) showed generally normal median physical, role, and cognitive functioning (Table 5). The most affected aspect of QoL was emotional functioning (median score 65.4±28.2). Social functioning (median score 78.8±21.9) and global health status (median score 75.3±22.9) were moderately affected.
Table 5.
Quality of life
| Pretreatment | Change from baseline to end of treatment | |
|---|---|---|
| (median±standard deviation) | (median±standard deviation) | |
| Physical functioning | 96.2±10.9 | −13.1±21.9 |
| Role functioning | 96.2±13.6 | −33.3±37.4 |
| Emotional functioning | 65.4±28.2 | 5.1±30.0 |
| Cognitive functioning | 96.2±10.9 | −12.8±24.2 |
| Social functioning | 78.9±21.9 | 1.9±27.2 |
| Global health status | 75.3±22.9 | −8.3 ±26.4 |
During preoperative chemotherapy, physical (median change from baseline −13.1±21.9), role (median change from baseline −33.3±37.4), and cognitive functioning (median change from baseline −12.8±24.2) decreased markedly. In contrast, social and emotional functioning remained mainly unaffected. Standard deviations were large for all function scales reflecting wide interindividual variability.
Locoregional and adjuvant treatment
Breast-conserving surgery was performed in 27 patients. Of 15 patients with clinical lymph node involvement at the beginning of the study, 12 patients had clinically uninvolved lymph nodes after primary chemotherapy. On histologic evaluation, 20 patients were node-negative.
Twenty-five patients received adjuvant treatment (Table 6). Chemotherapy was administered in 12 patients. All patients with hormone-receptor positive tumors received endocrine treatment.
Table 6.
Locoregional and adjuvant treatment
| Patients | (n) | (%) |
|---|---|---|
| Surgery | ||
| Breast-conserving surgery | 27 | 67.5 |
| Modified radical mastectomy | 13 | 32.5 |
| Adjuvant radiotherapy | 24 | 60.0 |
| Adjuvant systemic treatment | ||
| Endocrine therapy only | 13 | 32.5 |
| Chemotherapy only | 5 | 12.5 |
| Chemo-endocrine treatment | 7 | 17.5 |
| None | 15 | 37.5 |
Follow-up
With a median follow-up of 15.7 months there have been five recurrences. Median time to relapse was 11 months.
Discussion
Primary chemotherapy offers an effective means to evaluate novel therapies. At the time when this trial was initiated, no data were available on the use of paclitaxel in the neoadjuvant setting. Since then, however, several trials have proved the efficacy of taxane-based neoadjuvant single-agent and combination therapy in both locally advanced and operable primary breast cancer.
When used as single agent neoadjuvant therapy, paclitaxel showed comparable efficacy to the combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in patients with stage II or IIIA breast cancer. Clinical response rate was 80% with 18% experiencing pathologic complete responses (pCR) [11]. Other trials confirm the efficacy of both single agent paclitaxel and docetaxel for primary chemotherapy [12, 13, 14] with pCR rates ranging from 3% to 25%.
The sequential use of single agent docetaxel can significantly improve clinical and pathologic response in patients who have already received anthracycline-based primary polychemotherapy. In the NSABP B-27 trial, which included more than 2,400 patients, the addition of preoperative docetaxel to four cycles of doxorubicin and cyclophosphamide increased the clinical response rate from 85% to 91%, and the number of pCRs from 14% to 25% [15]. The Aberdeen neoadjuvant trial showed that this effect is given both in anthracycline-sensitive and anthracycline-refractory patients. The benefit appears to be more related to the introduction of a non-cross-resistant drug than to the duration of treatment [16].
In the present trial, the efficacy of a combination of paclitaxel and doxorubicin was evaluated. The clinical response rate as assessed by sonographic measurement was 70% and histologic evaluation revealed a 20% pCR-rate. Although a considerable number of other clinical trials have evaluated combinations of taxanes and anthracyclines, only a few trials have been published in full text so far. In a phase II trial, 79 patients with operable or locally advanced breast cancer received four cycles of primary chemotherapy with paclitaxel (200 mg/m2) and doxorubicin (60 mg/m2) [17]. The overall clinical response was 88% with 31% of patients with stage IIIB and 20% of patients with stage II or IIIA breast cancer, respectively, experiencing clinical complete response. Pathologic complete response rate was 7%.
Similar results were obtained in a multicenter phase II study using the combination of paclitaxel (175 mg/m2) and pegylated liposomal doxorubicin (35 mg/m2) in 3-week intervals for up to six cycles [18]. A total of 35 patients with stage III primary breast cancer were enrolled. Twenty-five patients (71%) responded clinically. Nine percent of patients achieved a pCR.
Another phase II study evaluated the combination of docetaxel (75 mg/m2) and doxorubicin (50 mg/m2) in 42 patients with primary breast cancer of at least 2 cm size [19]. The overall response rate as assessed by sonographic evaluation was 67%. Pathologically confirmed compete response of the primary tumor occurred in 5% of patients.
These trials show a similar clinical response compared to the present trial but resulted in considerably lower pathologic response rates ranging from 5% to 9%. In contrast to the present trial, however, they included more patients at advanced stages. This might have influenced pathologic response rates since small tumor size has been identified as an independent predictor of response to primary chemotherapy.
The results of the present trial are further confirmed by several phase II and III trials, which have only been published in abstract form so far. They report pCR-rates ranging from 5% to 25% for paclitaxel combined with doxorubicin or epirubicin [20, 21, 22, 23], and from 5% to 32% for docetaxel-anthracycline combinations [24, 25, 26, 27, 28, 29, 30, 31, 32]. Higher response rates were generally seen in trials including patients at earlier stages. Compared to non-taxane-containing anthracycline-based regimens, combinations of anthracycline and taxanes seem to result in superior response rates, as has been shown in randomized trials [21, 30, 32].
A potential additional benefit might be derived from dose-dense regimens. In a phase III trial, patients with stage II or III primary breast cancer were randomized to neoadjuvant treatment with either 12 courses of weekly paclitaxel or four cycles every 3 weeks [33]. At a preliminary analysis including 127 patients, the pCR rate was higher in the weekly arm (31%) compared to the 3-weekly arm (18.5%). Similar results were obtained in a randomized trial comparing a dose-dense sequential regimen and a standard dose combination of paclitaxel and epirubicin [23]. Preliminary data demonstrate a significantly higher pCR rate with the dose-dense regimen. Final results are awaited before definite conclusions can be made.
In the present study, the combination of doxorubicin and paclitaxel was well tolerated. As expected, leukopenia and neutropenia were the predominant side effects. They were, however, easily manageable and did not require discontinuation of therapy. The absence of febrile neutropenia or relevant infections during the trial confirm the decision not to use hematopoetic growth factors prophylactically.
Non-hematologic toxicity was mild throughout the study. Grade 3 toxicities were reported for stomatitis and alopecia only. Common grade 2 toxicities included peripheral neuropathy, nausea and vomiting, asthenia, and musculoskeletal pain. The toxicity profile was comparable to other neoadjuvant trials using combinations of anthracyclines and taxanes. Furthermore, there were no apparent differences in tolerability between patients receiving taxane-based combinations for primary breast cancer and metastatic disease, respectively.
In contrast to most trials published to date, the present study reports data on QoL. Reflecting the psychological impact of the diagnosis, at baseline, patients appeared to be mainly affected in their emotional and social functioning, whereas physical functioning was generally normal. During chemotherapy, however, median physical functioning and the related role functioning decreased, whereas emotional and social functioning remained generally at the same level. Interestingly, there was no correlation between response to primary chemotherapy and emotional and social functioning. Despite limitations due to the small number of patients and wide interindividual variability, these results are interesting. Future studies are, however, required to further evaluate the influence of primary chemotherapy on QoL.
In conclusion, the present trial confirms the efficacy and tolerability of the combination of paclitaxel and doxorubicin in the neoadjuvant setting. Together with data from phase II and III trials, there is now substantial evidence that the incorporation of taxanes into anthracycline-based primary chemotherapy can increase the pCR rate. The impact on disease-free and overall survival, however, has yet to be defined.
Footnotes
This study was supported by a grant from Bristol Myers Squibb, Munich, Germany
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