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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 1069-1076

A randomized controlled Phase II trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline-pretreated women with metastatic breast cancer


1 Department of Breast Oncology, Cancer Hospital of Tianjin, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
2 Department of Oncology, Hebei Province Xingtai People's Hospital, Hebei Medical University Affiliated Hospital, Xingtai, China
3 Department of Oncology, Xiamen No. 2 Hospital, Xiamen, China

Date of Submission17-Oct-2019
Date of Decision01-Jan-2020
Date of Acceptance06-Apr-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Yongsheng Jia
Huanhuxi Road, Tiyuanbei, Hexi, Tianjin, 300060
China
Zhongsheng Tong
Huanhuxi Road, Tiyuanbei, Hexi, Tianjin, 300060
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_792_19

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 > Abstract 


Background: Previous studies have shown that vinorelbine/capecitabine (NX) and docetaxel/capecitabine (TX) chemotherapy has a certain effect in advanced breast cancer. However, there are few clinical studies directly comparing TX and NX regimen chemotherapy, especially in patients with advanced breast cancer previously treated with anthracycline and taxane. The purpose of this Phase II study was to compare survival and side effects between patients with anthracycline- and taxane-resistant advanced breast cancer treated with NX and those treated with TX chemotherapy.
Patients and Methods: From February 2012 to March 2014, a total number of 97 patients were randomly assigned to NX (n = 55) or TX (n = 42). Baseline characteristics were relatively well-balanced in the two treatment arms. The clinical trial registration number (clincaltrials.gov) is NCT01635465.
Results: After a median follow-up of 46.0 months, there was no significant difference between the NX and TX arms in objective response rate (17.9% vs. 21.1%; P = 0.686) and progression-free survival (6 months vs. 7 months; P = 0.560). The overall survival period of the TX arm was longer than that of the NX arm (32 months vs. 27 months) but without statistical significance. Both regimens were well-tolerated. The main toxicities were neutropenia, leukopenia, and anemia. In the TX arm, hand-foot syndrome occurred more frequently than in the NX arm (P < 0.01), but frequencies of other minor adverse effects were similar between the two arms.
Conclusion: NX and TX regimens are both alternative treatments for patients with anthracycline- and taxane-resistant advanced breast cancer, but the safety profile was more favorable and manageable with the NX regimen.
Trial Registrations: ClinicalTrials.gov NCT01635465. Registered 09 July 2012.

Keywords: Anthracycline-pretreated, capecitabine, docetaxel, metastatic breast cancer, vinorelbine


How to cite this article:
Li S, Meng W, Zhang J, Xie X, Hao C, Jia Y, Tong Z. A randomized controlled Phase II trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline-pretreated women with metastatic breast cancer. J Can Res Ther 2020;16:1069-76

How to cite this URL:
Li S, Meng W, Zhang J, Xie X, Hao C, Jia Y, Tong Z. A randomized controlled Phase II trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline-pretreated women with metastatic breast cancer. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1069-76. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1069/296446

Shufen Li, Wenjing Meng and Jibo Zhang contributed equally to this work





 > Introduction Top


Breast cancer is one of the most common malignant tumors in women, which is also the most common cause of female death.[1] Although early detection and good management are expected to prolong overall survival (OS), few contemporary randomized clinical trials have demonstrated statistically significant OS.[2],[3] However, with the use of anthracycline and taxane in early-stage breast cancer or first-line treatment of advanced breast cancer, the risk of recurrence and metastasis of breast cancer has been decreased by 30%–50%; thus, the survival rate has improved. Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options.

Currently, there are no standard treatment recommendations for patients with anthracycline- and taxane-resistant advanced breast cancer. The National Comprehensive Cancer Network (NCCN) guidelines have recommended a single-drug chemotherapy, including capecitabine, vinorelbine, and gemcitabine; however, studies have observed an efficiency of 9%–14% and 25% following administration of single-drug capecitabine and vinorelbine, respectively, in patients with anthracycline- and taxane-resistant advanced breast cancer.[4],[5],[6] In contrast, a combination of chemotherapy is associated with a significant survival advantage for all stages of operable breast cancer.[7] In a small sample vinorelbine/capecitabine (NX) chemotherapy study, it has been found that the objective response rate (ORR) was 49%, and the median time to progress (TTP) and OS reached 7.6 months and 27.2 months, respectively.[8] In another study including 40 patients with metastatic breast cancer, who had undergone anthracycline and taxane chemotherapy, NX regimen chemotherapy was adopted, and an ORR of 20% and a median progression-free survival (PFS) and OS of 3.4 months and 11.3 months were observed, respectively.[9] Docetaxel plus capecitabine in anthracycline-pretreated metastatic breast cancer is currently a recommended scheme in the NCCN guideline. Studies have shown that the combination of docetaxel and capecitabine has a significant effect on breast cancer and is not cross-resistant to anthracycline drugs.[10] A randomized Phase III trial including 511 patients with metastatic breast cancer with anthracycline-based drug treatment failure has shown that the median TTP and OS was 6.1 months and 14.5 months, respectively, and the effective rate reached 42% with TX regimen chemotherapy.[11]

Based on the current results of clinical trials, it is necessary to explore more effective chemotherapy regimens for patients with anthracycline- and taxane-resistant advanced breast cancer. Previous studies have shown that NX and TX chemotherapy has a certain effect in advanced breast cancer. However, there are few clinical studies directly comparing TX and NX regimen chemotherapy, especially in patients with advanced breast cancer previously treated with anthracycline and taxane. We conducted a randomized, Phase II trial to compare survival and side effects between patients with anthracycline- and taxane-resistant advanced breast cancer treated with NX or TX regimen chemotherapy.


 > Patients and Methods Top


Trial design

This is a prospective, randomized, Phase II trial comparing NX combination therapy versus TX combination therapy for anthracycline- and taxane-resistant advanced breast cancer. Using the online randomization http://www.graphpad.com/quickcalcs/index.cfm, we generate a randomization plan for treatment assignment to patients. The primary endpoint was PFS, defined as the time interval between the day of randomization and the day of diagnosis of disease progression, secondary malignant disease, or death from any cause. The second endpoints were OS, defined as the time interval between randomization and death, ORR according to the RECIST criteria, tolerability, including incidence and severity of adverse events graded according to the National Cancer Institute Common Toxicity Criteria version 2.0 (National Cancer Institute, Bethesda, Maryland, USA), and the quality of life (QOL; EORTC-QLQ-C30). This study was established at the Key Laboratory of Breast Cancer Prevention and Therapy in Tianjin Medical University Cancer Institute and Hospital, from February 2012 to March 2014. The clinical trial registration number (clincaltrials.gov) is NCT01635465.

Patients

Inclusion criteria were as follows: women with 18 to 70 years of age; histologically confirmed MBC, showing disease progression during or following a previous anthracycline- and taxane-based regimen in the (neo) adjuvant or first-line metastatic setting; patients with at least one measurable lesion according to the RECIST criteria, version 1.0 (The RECIST Working Group, Brussels. Belgium); ECOG performance status ≤2; life expectancy ≥3 months; adequate hepatic, renal, and hematologic function; and no prior capecitabine exposure. Prior hormonal therapy was allowed, and prior (neo) adjuvant 5-fluorouracil or taxane therapy was permitted if completed 12 months before study entry. All the patients provided written informed consent before any study-specific procedures were performed.

Exclusion criteria were as follows: prior chemotherapy for MBC, except for anthracycline-containing regimens; adjuvant chemotherapy within the previous 12 months; metastases limited to the bone; symptomatic brain metastases; secondary carcinomas, except for curatively treated basal cell carcinomas of the skin or cervical carcinoma in situ; psychiatric disorders; and participation in another clinical trial within the previous 4 weeks.

Drug administration

Patients were randomized to NX (days 1–14, every 3 weeks: vinorelbine 25 mg/m 2 intravenous (IV) on days 1 and 8 plus capecitabine 950 mg/m 2 twice PO). Patients were randomized to TX (days 1–14, every 3 weeks: docetaxel 75 mg/m 2 IV on day 1 plus capecitabine 950 mg/m 2 twice PO). Treatment was administered until the documented disease progression, unacceptable toxicity, or patient's refusal. In the case of documented progression occurring before the first disease evaluation (3 weeks after start of treatment), the treatment was discontinued and the response to treatment was recorded as early progression. If one drug of the combination arm was discontinued because of toxicity before disease progression, the patient was considered “off treatment.” The other drug could be further given at the recommended dose in monotherapy at the discretion of the investigator.

Dose modifications

If patients experienced febrile neutropenia, Grade 4 leukopenia, or Grade 3 thrombocytopenia, treatment was interrupted until recovery of neutrophil count of ≥1.5 × 109/L and platelet count of ≥100 × 109/L. The dose of the next cycle was reduced to 75%. If Grade 3 or 4 hematologic toxicity recurred, treatment was interrupted and then continued at a resolution with hematopoietic growth factor support. Doses of drugs were reduced if patients experienced Grade 2 or neurologic toxicity, and treatment was discontinued in case of Grade 3 or 4 sensory neuropathy. Dose omissions of capecitabine or vinorelbine were not replaced or restored. If one drug had to be discontinued in one arm because of a specific toxicity, the patient was off treatment.

Study assessments

Before initiating therapy, a medical history, physical examination, complete blood count, biochemical profile, chest radiograph, ultrasound or computed tomography scan of the liver, and a bone scan were performed (the latter two investigations were optional for Stage I patients). QOL was assessed using the EORTC QOL questionnaire C30. Patients completed questionnaires before administration of any treatment, every 2 cycles (before treatment administration), and at the time of treatment discontinuation. During the treatment, hematologic tests were performed every week. Before each cycle of therapy, patients underwent physical examination. ECOG performance status, clinical chemistry, and toxicities were recorded. Tumors were assessed every 2 cycles according to the RECIST criteria 1.1. A final assessment was performed 4 weeks after completing the study therapy and included clinical examination, assessment of toxicities, laboratory tests, and tumor assessment. Patients were followed up every 3 months for the first 2 years after the last cycle and every 6 months thereafter.

Statistical methods

Descriptive data are expressed as frequency and central tendency measures. We analyzed frequency tables with the Fisher's exact test or the Chi-square test. To compare PFS and OS between the two arms, we used the Kaplan–Meier life-table method. We also compared treatment arms using a Cox proportional-hazards model adjusted for tumor size, nodal status, and ER status; to determine the statistical significance of each variable in the model, we used the Wald Chi-square test. The proportional-hazards assumption was verified using the Schoenfeld residuals. The analyses were performed using SPSS version 21.0 (SPSS Inc, Chicago, Illinois, USA) and Stata 12 (StataCorp LLC, College Station, Texas, USA). Estimates were considered statistically significant for two-tailed values of P < 0.05.


 > Results Top


Patient population

This was a prospective, open, and randomized Phase II study in a single center. From February 2012 to March 2014, 97 patients were randomly assigned to chemotherapy, 55 of whom were randomized to NX and 42 to TX. Overall, in the NX group, 232 cycles of NX were applied (4.2 cycles per person) and 196 cycles in the TX group (4.7 cycles per person). The median number of cycles for both the NX and TX groups was 4 (range, 1–12 cycles and 0–12 cycles, respectively). The most common reason for discontinuing the treatment prematurely was disease progression [42/55, 76.4% in the TX group, and 22/42, 52.4% in the NX group; [Figure 1]. In total, 97 anthracycline-pretreated women with metastatic breast cancer were enrolled, including 55 in the NX group and 42 in the NX group (median age, 52 years in each group). The majority of patients had visceral metastases (76.4% in the NX group and 69.0% in the TX group). Baseline characteristics were relatively well-balanced in the two treatment arms [Table 1].
Figure 1: Patient disposition throughout the study

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Table 1: Baseline patient characteristics

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Efficacy

The median follow-up at the time of this final analysis was 46.0 months. There was no significant difference between the NX and TX arms in ORR [17.9% vs. 21.1%; [Table 2]. [Figure 2] shows PFS, which was very similar between the two arms (P = 0.560); the median PFS was 6 months in the NX group and 7 months in the TX group. The OS period of the TX arm was longer than that of the NX arm [32 months vs. 27 months; P = 0.766; [Figure 3] but without statistical significance. There was no significant difference in both 1-year PFS and 1-year OS or both 2-year PFS and 2-year OS between the NX and TX arms [Table 3].
Table 2: The comparison of response to treatment between the two groups

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Figure 2: The comparison of progression-free survival between vinorelbine/capecitabine and docetaxel/capecitabine arms

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Figure 3: The comparison of overall survival between vinorelbine/capecitabine and docetaxel/capecitabine arms

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Table 3: The comparison of survival between vinorelbine and capecitabine and docetaxel and capecitabine arms

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Adverse events

The safety of both treatments is relatively acceptable [Table 4]. The explorative data analysis reported in [Figure 4], regarding the differences in the incidence of side effects between the NX and TX arms, was conducted as follows: the incidence of each side effect was calculated over the number of treated patients in each treatment group. If a given side effect occurs twice or more in the same patient, only the highest level of toxicity is considered. The main toxicities were neutropenia, leukopenia, and anemia. In the TX arm, hand-foot syndrome occurred more frequently than in the NX arm (11/42 vs. 1/55; P < 0.001), but frequencies of other minor adverse effects were similar in both the arms. The incidence of myelosuppression in the NX group was higher than in the TX group, but no statistical significance was observed. Myelosuppression could be recovered using granulocyte-colony-stimulating factor (G-CSF). Hepatic dysfunction was more frequent in the TX group than in the NX group but with no statistical significance. Other diverse events, including oral ulcers and nosebleed, occurred in the TX group but not in the NX group. There were four patients in the NX group who had withdrawn from the treatment: two patients with Grade 3 myelosuppression, one patient with Grade 4 hand-foot syndrome, and one patient with Grade 4 gastrointestinal reaction. In the TX group, 6 patients were withdrawn from the treatment. Five patients had Grade 4 hand-foot syndrome and one patient had Grade 3 myelosuppression.
Table 4: Summary of adverse events per patient

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Figure 4: Difference in the incidence of adverse events between vinorelbine/capecitabine and docetaxel/capecitabine. The vertical line is used to determine whether the results are statistically significant. The diamond sign represents the integrated effect and confidence interval, with a synthesis of results. The intersection of the diamond sing and vertical lines indicates that there is no significant difference in the incidence of a given side effect between vinorelbine/capecitabine and docetaxel/capecitabine

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 > Discussion Top


Breast cancer is one of the most common malignant tumors in women, which is also the most common cause of female death.[1] A substantial number of patients with breast cancer eventually develop incurable metastasis. Systemic chemotherapy is one of the main treatment options for patients with advanced breast cancer. Anthracycline and taxane are the most frequently used drugs for the treatment of advanced breast cancer in the setting of adjuvant or first-line chemotherapy. Unfortunately, many patients with advanced breast cancer will develop resistance to these drugs and have to switch to second- and third-line therapies. The efficacy of chemotherapy for anthracycline- and taxane-pretreated patients with advanced breast cancer remains at a low level of 33.0%–38.3%.[12] Several toxic drugs, such as vinorelbine, cisplatin, capecitabine, and gemcitabine, are recommended for the treatment of anthracycline- and/or taxane-resistant advanced breast cancer. However, no optimal regimen by far has been proved to be more effective or less toxic than the conventional ones, due to their different mechanisms of action and toxicity profiles. Thus, new effective arms should be explored to treat the patients with anthracycline- and/or taxane-resistant advanced breast cancer.

In advanced breast cancer, there are many ways to shift to another chemotherapy regimen.[13] Capecitabine is an active drug in MBC. Currently, a combination drug regimen based on capecitabine is one of the preferred drugs for anthracycline- and/or taxane-resistant advanced breast cancer.[14],[15] The response rate is 20%–26% with the second-line treatment of single capecitabine.[16] The combination of capecitabine is also effective and may be superior to a single drug.[17] This trial evaluated the feasibility and tolerability of vinorelbine plus capecitabine versus docetaxel plus capecitabine as a second-line treatment for anthracycline-pretreated women with metastatic breast cancer. The median follow-up at the time of this final analysis was 46.0 months. There was no significant difference between the NX and TX arms in ORR [17.9% vs. 21.1%; [Table 2]. [Figure 2] shows PFS, which was very similar between the two arms (P = 0.560). The median PFS was 6 months and 7 months in the NX and TX groups, respectively. The OS period of the TX arm was longer than in the NX arm (32 months vs. 27 months; P = 0.766) [Figure 3] but without statistical significance. Estévez et al.[8] showed that following NX chemotherapy, the ORR was 49%, and the median TTP and OS reached 7.6 months and 27.2 months, respectively. In another study, NX regimen chemotherapy was adopted, with an ORR of 20% and a median PFS and OS of 3.4 months and 11.3 months, respectively.[9] A randomized Phase III trial including 511 patients with metastatic breast cancer with anthracycline-based drug treatment failure has shown that the TTP and OS were 6.1 months and 14.5 months, respectively, and the effective rate reached 42% with TX regimen chemotherapy.[11] There are few clinical studies directly comparing TX and NX, especially in patients with advanced breast cancer previously treated with anthracycline and taxane. However, a Phase III randomized trial on capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer has shown that the TX group achieved longer median PFS than the NX group (8.4 months vs. 7.1 months; P = 0.0026, HR = 1.65) and had better median DOR (7.8 months vs. 6.6 months; P = 0.0451), even for patients who had previously received taxane in (neo) adjuvant settings.[18] This trial was not powered to demonstrate major differences in PFS or OS. Moreover, due to the small number of patients per arm, the result may be due to accidental imbalance.

The safety profile of both regimens was relatively acceptable. In the TX arm, hand-foot syndrome occurred more frequently than in the NX arm (11/42 vs. 1/55; P < 0.01), but frequencies of other minor adverse effects were similar in both the arms. This phenomenon may be due to the synergistic effect of docetaxel and capecitabine. Furthermore, Heo et al.[19] established risk factor analyses and showed that combined use of docetaxel and preceding chemotherapy-related stomatitis were significant risk factors for the development of hand-foot syndrome.[19] The incidence of myelosuppression in the NX group was higher than that in the TX group but with no statistical significance. Myelosuppression can be recovered by G-CSF administration. Hepatic dysfunction was more frequent in the TX group than in the NX group but with no statistical significance. Other diverse events, including oral ulcers and nosebleed, occurred in the TX group but not in the NX group. There were four patients in the NX group who withdrew the treatment: two for Grade 3 myelosuppression, one for Grade 4 hand-foot syndromes, and one for Grade 4 gastrointestinal reactions. Moreover, there were six patients in the TX group who withdrew the treatment: five for Grade 4 hand-foot syndromes and one for Grade 3 myelosuppression. A Phase III randomized trial has confirmed that adverse reactions in the TX combination group were mostly gastrointestinal reactions and hand-foot syndrome, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel.[20] Xu et al.[21] showed that hand-foot syndrome occurred more frequently in the TX group than in the NX group (47% vs. 16.7%; P < 0.0001), but the frequencies of other minor adverse effects were similar in both the groups. The most common side effect leading to an interruption of treatment was hand-foot syndrome.[18],[21] A three-arm randomized Phase II study has demonstrated that the NX regimen was less related with neutropenia, infection, hand-foot syndrome, fatigue/asthenia, and alopecia than the TX regimen, whereas gastrointestinal side effects were less associated with the TX regimen for metastatic breast cancer previously treated with anthracyclines.[22] A randomized Phase III JO21095 trial has reported that Grade ≥3 treatment-related toxicities occurred in 74% of TX-treated patients with anthracycline-pretreated HER2-negative metastatic breast cancer, which included hand-foot syndrome (7.3%), fatigue/malaise (2.4%), and peripheral edema (1.2%).[23]

The primary conclusion is that NX has less risk of side effects than TX. Our drug regimens are as follows: NX (days 1–14, every 3 weeks: vinorelbine 25 mg/m 2 IV on days 1 and 8 plus capecitabine 950 mg/m 2 twice PO) and TX (days 1–14, every 3 weeks: docetaxel 75 mg/m 2 IV on day 1 plus capecitabine 950 mg/m 2 twice PO). A Phase I study conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of vinorelbine and capecitabine in patients affected with metastatic breast cancer reported that the MTD of capecitabine in combination with vinorelbine at 25 mg/m 2 dosage on days 1 and 8 of a 3-week schedule is 2000 mg/m 2/day for 14 consecutive days.[24] Another Phase I study reported that NX (days 1–14, every 3 weeks: vinorelbine 25 mg/m 2 IV on days 1 and 8 plus capecitabine 2000 mg/m 2 twice PO) regimen cannot be recommended as first-line treatment of metastatic breast cancer because capecitabine presented with a DLT.[25] However, TX (days 1–14, every 3 weeks: docetaxel 75 mg/m 2 IV on day 1 plus capecitabine 950 mg/m 2 twice PO) regimen is recommended by the NCCN guideline for advanced breast cancer. We choose TX dosages according to standard doses of advanced breast cancer recommended in the NCCN guideline. The dosage of the NX regimen was designed for both the results of the Phase I study and the dosage regulation of capecitabine in the TX regimen of the NCCN guideline. The safety profile of both regimens was relatively acceptable, and the dosages of vinorelbine and docetaxel used in this trial were rational.

There is a limitation to our study. The sample size was relatively small. However, our results demonstrate that NX combination regimen should be considered as an alternative in anthracycline-pretreated women with metastatic breast cancer.


 > Conclusion Top


This study did not identify significant differences in ORR, PFS, and OS between the NX and TX arms. Both the arms were well-tolerated. NX has less risk of side effects, especially hand-foot syndrome and other diverse events, including oral ulcers and nosebleed, than TX. NX and TX regimens are both alternative treatments for patients with anthracycline- and taxane-resistant advanced breast cancer; however, the safety profile was more favorable and manageable with the NX regimen. Additional large-scale trials will be necessary to confirm this finding.

Declaration

This study was reviewed and approved by the relevant independent ethics committees/institutional review boards at Tianjin Medical University Cancer Institute and Hospital and was conducted in accordance with the Declaration of Helsinki, good clinical practice guidelines, and applicable laws. All patients provided written informed consent.

Availability of data and materials

The datasets generated and/or analyzed during the present study are not publicly available in order to protect patient information in the clinical trial database, but they are available from the corresponding author on reasonable request.

Financial support and sponsorship

This work was supported by grants from Science Foundation of Tianjin Medical University (2016KYZQ05), Anticancer Key Technologies R&D Program of Tianjin (12ZCDZSY16200).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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