Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 4  |  Page : 638-643

Efficacy of neoadjuvant chemotherapy in down staging locally advanced pre-menopausal breast cancer in Eastern Nigeria: Is four courses adequate?


Department of Surgery, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria

Date of Web Publication11-Feb-2014

Correspondence Address:
Ochonma Amobi Egwuonwu
Department of Surgery, Nnamdi Azikiwe University Teaching Hospital, Nnewi
Nigeria
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.126463

Rights and Permissions
 > Abstract 

Context: Breast cancer is the most frequent cancer among women in most part of the world and in Nigeria. Neoadjuvant chemotherapy (NAC) has been demonstrated to be a helpful strategy in the context of locally advanced breast cancer (LABC).
Aims: To determine if the use of four courses of doxorubicin based neoadjuvant chemotherapeutic regimen will result in significant primary tumor down-staging.
Settings and Design: One year prospective study of premenopausal breast cancer patients presenting to the specialty breast clinic.
Methods: The patients were recommended for four courses of doxorubicin based NAC and response assessed using response evaluation criteria in solid tumors (RECIST) methodology.
Statistical Analysis Used: Simple frequency and descriptive statistics were used to analyze data using SPSS statistical software.
Results: One hundred and fourteen patients presented with breast cancer. Their ages ranged from 26 to 51 years with a mean age of 42.1 years ± 7.7 years. Thirty-one patients completed the four courses of NAC. At the end of NAC, 23 (74.2%) patients had more than 30% reduction in primary tumor size and 8 (25.8%) had no response (NR). The response according to the modified RECIST methodology was 12.9% for a complete clinical response, 61.3% for partial response, and 25.8% for NR. Significant clinical response was seen in 74.2% of patients (P < 0.0001) (one sample t-test).
Conclusions: Four courses of antracycline based NAC is effective in premenopausal patients with LABC in our environment

Keywords: Chemotherapy, efficacy, neoadjuvant


How to cite this article:
Egwuonwu OA, Anyanwu SN, Nwofor AM. Efficacy of neoadjuvant chemotherapy in down staging locally advanced pre-menopausal breast cancer in Eastern Nigeria: Is four courses adequate?. J Can Res Ther 2013;9:638-43

How to cite this URL:
Egwuonwu OA, Anyanwu SN, Nwofor AM. Efficacy of neoadjuvant chemotherapy in down staging locally advanced pre-menopausal breast cancer in Eastern Nigeria: Is four courses adequate?. J Can Res Ther [serial online] 2013 [cited 2019 Dec 12];9:638-43. Available from: http://www.cancerjournal.net/text.asp?2013/9/4/638/126463


 > Introduction Top


Breast cancer is still a major problem in most parts of the world. In Nigeria, breast cancer is the most frequent cancer among women. [1],[2] African women with breast cancer present at a young age. [3],[4] Nigerian women with breast cancer present with advanced disease, [5],[6],[7]] and survival is noted to be poor compared to their white counterpart. [5],[8] Local and distant disease control in locally advanced breast cancer (LABC), which may improve survival is still a challenge. Neoadjuvant chemotherapy (NAC) has been shown to be a useful strategy in the multimodal treatment of LABC, because it results in tumor down staging benefits. [9],[10],[11] A study in our patient population revealed that the number of patients on NAC progressively declined to 46% by the last cycle during a six-course treatment regimen. This was mainly due to financial reasons as the hospital is operated on a fee for service. [12] The optimal NAC regimen has not been explicitly defined. However, the typical approach consists of at least 4-6 cycles of an anthracycline based regimen, [13],[14] usually doxorubicin and cyclophosphamide with or without addition of taxane-based agents. If administration of lesser cycles of doxorubicin based neoadjuvant chemotherapeutic regimen results in tumor down-staging that is equivalent to full course of 6 cycles then adherence to NAC could possibly be improved within our population.

The present study was designed to determine the optimal number of chemotherapy cycle for tumor down-staging in Nigerian women with LABC and investigate the correlation, if any, with primary tumor size and disease stage at presentation.


 > Methods Top


This is a prospective study conducted in Nigeria. It spanned for a 12-month period starting from June 2009 to May 2010. All pre-menopausal patients presenting with cytology/histologically confirmed LABC, Stage III (A, B and C) breast cancer and T3N0M0 subset of Stage IIB who had not received any form of intervention except fine needle aspiration cytology or biopsies were eligible. The staging investigations done before and after NAC was chest X-ray, liver function test, abdomino-pelvic ultrasound scan and X-ray of the site of bone pain, if present. All pre-menopausal patients with evidence of distant metastasis demonstrable before the onset of NAC or shortly thereafter (<1 month) were excluded. Before initiation of NAC, a full blood count was done, and the body surface area was determined. These were repeated on each visit for subsequent cycles of chemotherapy.

All eligible patients presenting to the specialty breast clinic were counselled on the benefits for NAC as regards downstaging the primary tumor before mastectomy. The patients were expected to have hemoglobin concentration hemoglobin concentration of ≥10 g/dl, white blood cell count white blood cell of ≥ 2500/mm 3 with absolute neutrophil count of ≥1000/mm 3 and platelet count of ≥100,000/mm 3 . The size of the primary breast tumor was measured in its two greatest diameters using a calliper and clinical regional lymph node assessment was done before each course of chemotherapy and three weeks after the 4 th course of NAC. A doxorubicin containing regimen was used. The regimen cyclophoshamide, doxorubicin and 5-fluorouracil (CAF) consisted of cyclophosphamide 500 mg/m 2 , Doxorubucin 50 mg/m 2 , and 5-Fluorouracil 500 mg/m 2 all given on day 1. The fluorouracil and cyclophosphamide were given as bolus injection in a free flowing intravenous line and the doxorubicin was given as an infusion. The cycles of the CAF were repeated at 3 weekly intervals. Cycles were deferred if hematologic parameters were inadequate. All eligible patients who consented were offered four courses of CAF.

Treatment response was assessed using a modification of the RECIST methodology. [15],[16] The response was assessed as a complete clinical response (cCR), when there was an absence of residual tumor on examination anytime during the period of NAC or by the end of the NAC before loco-regional treatment. Partial response, was defined as a reduction of at least 30% in the longest diameter of the target lesion. No response (NR) was defined as no evidence of decrease in tumor size or any decrease in the longest diameter of target lesion <30%, or any evidence of appearance of new lesion (i.e., stable and progressive disease in RECIST methodology)- Furthermore, the primary tumor response was categorized into tumors ≤10 cm and >10 cm to determine their response to NAC. Facility for histochemistry was not available for hormone receptor and human epidermal growth factor receptor human epidermal growth factor receptor human epidermal growth factor receptor-2 (HER-2) neu status. The study was proposed to the ethics committee as a policy change study. The Research and Ethical Committee approved the study.

The data was recorded and analyzed using the SPSS Statistical software (Statistical Package for Social Sciences SPSS Inc. 233 S Wacker Drive No 1100 Chicago, IL 60606) version 15.0 S. Simple frequency and descriptive statistics and one sample T-test was used while assessing response using RECIST methodology.



To determine N, the surgical outpatients' record was used to determine the number of new breast cancer patients seen in the preceding 12 months.


 > Results Top


One hundred and fourteen patients presented with breast cancer, 65 had LABC, 44 of whom gave consent to be part of the study. The remaining 21 patients were not included because they were post-menopausal women. Their ages ranged from 26 to 51 years with a mean age of 42.1 years ± 7.7 years. Most patients, 27 (61.4%) had at least some high school education, 9 (20.4%) had only primary school education and 8 (18.2%) had no formal education.

Of the 44 patients who consented to be part of this study, 3 women did not receive any chemotherapy because they lacked funds to procure the drugs. Seven patients defaulted after the first course, 3 of these because they preferred to proceed with mastectomy and the remaining 4 patients due to lack of funds. Three patients dropped out after the second course also due to lack of funds. Of the 41 patients that commenced NAC 31 (75.6%) patients completed the four courses of NAC. Four patients discontinued further treatment after NAC on achieving cCR when they were expected to have mastectomy.

The mean longest diameter of the pre-chemotherapy tumor size was 11.5 cm (range 5-25 cm). The mean size decreased progressively to 7.5 cm (range 0-28 cm) at the end of the NAC. Most of the decrease was noticed following the first and second course [Table 1] and [Figure 1]. The clinical stage distributions of the breast cancer by AJCC, TNM at presentation and at the end of chemotherapy are as shown in [Table 2].
Figure 1: Mean tumor size during neoadjuvant chemotherapy

Click here to view
Table 1: Tumour sizes during neoadjuvant chemotherapy

Click here to view
Table 2: Clinical stage

Click here to view


At the end of the NAC, 23 (74.2%) patients had more than 30% reduction in the primary tumor size and 8 (25.8%) had NR. The response according to the modified RECIST methodology was 12.9% for cCR, 61.3% for PR and 25.8% for NR. Therefore, significant clinical response was seen in 74.2% of the patients. This is statistically significant (P < 0.0001) (one-sample T-test). The four patients who achieved cCR absconded when it was time for surgery.The four patients who achieved cCR absconded when it was time for surgery.

Of the 8 (25.8%) patient who was classified as NR according to the modified RECIST methodology, it was observed that 4 (12.9%) of the patients progressed to stage IV disease. At presentation 15 (48.4%) patients had breast masses of ≤10 cm and 16 (51.6%) had lump of >10 cm. Of the 15 patients who had tumor sizes of ≤10 cm, 12 (80%) achieved significant clinical response but 3 (20%) did not and of the 16 patients with tumor sizes >10 cm, 11 (68.8%) had significant clinical response while 5 (31.2%) had no significant response. There was no statistically significant correlation between pre-chemotherapy primary tumor size and clinical response (P = 0.613) (Chi-square). The relationship between clinical stages at presentation with response to NAC is shown in [Table 2]. This relationship is not statistically significant (P = 0.595) (Chi-square test).


 > Discussion Top


The mean age of the study population was 42.1 years with a range from 26 to 51 years. This is similar to 42.8 years reported in a previous study on premenopausal patients in our environment. [12] The mean age reported by other researchers are those of study population comprising pre-menopausal and post-menopausal patients, it ranged between 42.7 and 48 years. [17],[18]

The number of patients who completed the four courses of NAC were 31 (75.6%) out of 41 that commenced it. A study on NAC in our environment revealed that only 46% completed the six courses prescribed due to lack of funds to procure the chemotherapeutic agents as the hospital operated a fee for service. [12] This increase rate of adherence may be due to reduction in the number of courses required.

The use of anthracycline based regimen for NAC results in clinical response rate ranging from 50% to 80%. [19],[20] The result of this study demonstrated a statistically significant clinical response to NAC of 74.2% in pre-menopausal women receiving four courses of CAF regimen with a cCR of 12.9%. Though, in the earlier study in our environment the partial clinical response rate was higher, 89% (25 patients), 20% reduction in primary tumor diameter were used [12] as against the 30% used in this study, based on the RECIST methodology. Despite this the cCR noted in this present study is superior to that reported when six courses was used. [12] Also, the statistically significant clinical response observed is within the clinical response rate of 50-80% that have been documented by other researchers. [19],[20] This would mean that prescribing six courses of NAC does not confer any significant advantage over the use of four courses in our patient population, but could result in reduced adherence to NAC in the treatment of LABC.

This study agrees with what Chintamani et al.[21] found in India in a study population with similar characteristics and same chemotherapy regimen. They documented objective clinical response of 70%. However, they used at least 50% tumor reduction as evidence of clinical response while this study used 30% tumor reduction as an objective clinical response. Moon et al. in their study in Korea, documented a clinical response rate of 84.4% for breast tumor with a cCR rate of 25.6%. [22] This response rate is higher than that in this study. In their study Stage IIIA comprised 51.3% while in this study most of the patients were in Stage IIIB (71%) with Stage IIIA making up only 9.7% of the study population. Furthermore, their sample size was quite larger than in this study (82 vs. 31). This too may have contributed to the difference, especially with the cCR.

Fisher et al. [23] and Rastogi et al. [9] reporting on the clinical responses in the National Surgical Adjuvant Breast and Bowel Projects B18 and B27, noted that the clinical responses were 79% and 85% respectively with cCR rates of 36% and 40% respectively after the initial 4 cycles of AC NAC. These responses were better than what is observed in this study despite their using >50% reduction in size as cut-off for the clinical response. The higher clinical response and cCR may be due to the smaller size of their primary tumors. In B18, only 13% had tumor size >5 cm and 26% with positive clinical nodal status while in B27, 70% of their study population had the primary breast tumor of <4 cm and 70% were node negative. Small size primary tumor and node negativity are known predictor of better response, especially pathological complete response (pCR). [9],[14] Buzdar et al. [24] also reported clinical response of 79.3% in the patients that received CAF chemotherapy. In the retrospective study by Gajdos et al., [25] the clinical response was 53% with cCR of 8%. This is lower than reported in this study. The reason may be because some of the patients received cyclophosphomide, methotrexate and 5-fluorouracil (CMF) and others received CAF, which is known to give a better clinical response than CMF. But in this study all patients received CAF chemotherapy.

Many patients receive NAC, but some do not respond well. The ability to predict a response to NAC would be beneficial. Gajdos et al. [25] compared the clinical responses of patients with primary breast tumor of <5 cm and >5 cm in greatest diameter. They reported clinical response being 71% and 42% respectively, which was statistically significant (P = 0.038), they concluded that smaller tumors <5.0 cm are more likely to respond than larger tumors.

One aim of this study was to determine the relationship between clinical responses with pre-treatment primary tumor size. However, none of the study populations had tumor size <5.0 cm hence it could not be determined whether tumors <5.0 cm are more likely to respond to NAC in this study. Nevertheless, this study did not find any statistically significant relationship between clinical response to NAC and tumor sizes 5-10 cm and >10 cm.

Chintamani et al. also did not demonstrate significant difference in response to NAC between tumor sizes 5-8 cm, 8-10 cm and > 10 cm. [21] Their finding appears to agree with this study. However, th e work by Moon et al. found a statistically significant relationship between response and tumor size; tumors ≤ 10 cm are more likely to respond to NAC than those > 10 cm. [22] This finding was statistically significant. The discrepancy between the findings by Moon et al. and Chintamani et al. may be due to the fact that the latter had smaller sample size (n = 50) and further stratified the size < 10 cm into three groups < 5 cm, 5-8 cm and 8-10 cm while Moon had just two groups < 10 cm and > 10 cm and much larger sample size (n = 82).

Eight (25.8%) patients showed no clinical response (NR) as defined by the modified RECIST methodology used in this study; that is, either the size of the primary tumor remained unchanged or reduction in size was < 30% or the primary tumor increased in size. Three patients had a tumor that increased in size, 2 remained unchanged while 3 had a reduction in size that was < 30%. Of the eight patients with NR, four patients (two with tumor increasing in size, one with tumor size unchanged and one with reduction in size < 30%) had evidence of metastasis at the end of NAC. This means that four (12.9%) patients from the study population progressed to Stage IV of which 2 (6.5%) also showed an increase in their tumor size.

Though, it has been reported that only 2-3% of patients receiving NAC have signs of progression, this study noted a higher rate of progression. [14] Moon et al. in their study noted disease progression in 7 (8.5%) of the 82 patients who is still lower than observed in this study. [22] In their study 51.3% had Stage IIIA disease while in this study, most (71%) of the patients had Stage IIIB disease with only 9.7% in Stage IIIA. This may imply that the patients in this study have more advanced disease and hence, probably higher burden of micro-metastasis. [26]

Bone scan, and computed tomography scans were not used for staging in this study because the facility was not available in our centre. The nearest centre where it could be done was about 600 km from our centre.

The multimodal treatment policy for LABC in our centre involves administering six courses of CAF in the neoadjuvant setting or until cCR if achieved before the sixth course. The initial decision to use NAC for 6 cycles was designed on the success of adjuvant chemotherapy using 6 cycles as reported by other workers. It was during the course of the work that a consensus developed around 4 cycles for NAC. The NAC is followed by mastectomy with level two axillary dissection followed by radiotherapy to chest wall and supraclavicular area and followed by four courses of adjuvant chemotherapy. This study was not designed to follow the patients up on all the treatment modalities.

Breast oncologists in Nigeria accept that NAC is a useful strategy in the management of LABC; this study may be the first that has demonstrated that four courses of antracycline based NAC is adequate for primary tumor downstaging in our patient population. It also noted that maximum reduction in tumor size was after the second course. This response is not dependent on the primary tumor size or the disease stage at presentation. This is good for our environment considering that most of our patients present with advanced disease. Hence, reducing the number of courses to two or three may result in improved adherence with early surgical intervention without compromising the benefits that NAC confers on these patients.


 > Conclusion Top


This study may be the first in Nigeria to be demonstrated that the use of four courses of doxorubicin based neoadjuvant chemotherapeutic regimen results in tumor down-staging that is equivalent to full course of 6 cycles and independent of primary tumor size and disease stage at presentation. With maximum tumor downstaging noted after the second course, administering two or three courses of NAC could possibly improve adherence within our patient population.

 
 > References Top

1.Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, cancer incidence and mortality: IARC cancer base No 10. Lyon France: International Agency for Research on Cancer; 2010. Available from: http://www.globocan.iarc.fr.  Back to cited text no. 1
    
2.Solanke TF, Adebamowo CA. Report of the state of the art in oncology in Ibadan and Ife. UCH Ibadan: National headquarters of cancer registries in Nigeria;; 1996.  Back to cited text no. 2
    
3.Fregene A, Newman LA. Breast cancer in sub-Saharan Africa: How does it relate to breast cancer in African-American women? Cancer 2005;103:1540-50.  Back to cited text no. 3
[PUBMED]    
4.Oluwole SF, Fadiran OA, Odesanmi WO. Diseases of the breast in Nigeria. Br J Surg 1987;74:582-5.  Back to cited text no. 4
[PUBMED]    
5.Adesunkanmi AR, Lawal OO, Adelusola KA, Durosimi MA. The severity, outcome and challenges of breast cancer in Nigeria. Breast 2006;15:399-409.  Back to cited text no. 5
[PUBMED]    
6.Atoyebi OA, Atimomo CE, Adesanya AA, Beredugo BK, da Rocha-Afodu JT. An appraisal of 100 patients with breast cancer seen at the Lagos University Teaching Hospital. Nig. Q J Hosp Med 1997;7:104-8.  Back to cited text no. 6
    
7.Anyanwu SN. Temporal trends in breast cancer presentation in the third world. J Exp Clin Cancer Res 2008;27:17.  Back to cited text no. 7
[PUBMED]    
8.Anyanwu SN. Survival following treatment of primary breast cancer in eastern Nigeria. East Afr Med J 2000;77:539-43.  Back to cited text no. 8
[PUBMED]    
9.Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26:778-85.  Back to cited text no. 9
[PUBMED]    
10.Maráz R, Boross G, Svébis M, Gyánti R, Vizhányó R, Hajnal L, et al. Response rates following neoadjuvant chemotherapy and breast preserving treatment in patients with locally advanced breast cancer. Magy Seb 2005;58:225-32.  Back to cited text no. 10
    
11.Beriwal S, Schwartz GF, Komarnicky L, Garcia-Young JA. Breast-conserving therapy after neoadjuvant chemotherapy: Long-term results. Breast J 2006;12:159-64.  Back to cited text no. 11
[PUBMED]    
12.Anyanwu SN, Nwose P, Ihekwoaba E, Mbaeri AT, Chukwuanukwu TO. Neoadjuvant chemotherapy for locally advanced premenopausal breast cancer in Nigerian women: Early experience. Niger J Clin Pract 2010;13:215-7.  Back to cited text no. 12
[PUBMED]  Medknow Journal  
13.Powles TJ, Hickish TF, Makris A, Ashley SE, O′Brien ME, Tidy VA, et al. Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 1995;13:547-52.  Back to cited text no. 13
[PUBMED]    
14.Lee MC, Newman LA. Management of patients with locally advanced breast cancer. Surg Clin North Am 2007;87:379-98.  Back to cited text no. 14
[PUBMED]    
15.Skeel RT. Systemic assessment of the patient with cancer and long-term consequences of treatment. In: Skeel RT, editor. Handbook of Cancer Chemotherapy. 7 th ed. philadelphia: Lippincott William and Wilkin; 2008. p. 32-46.  Back to cited text no. 15
    
16.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16.  Back to cited text no. 16
[PUBMED]    
17.Adesunkanmi AR, Lawal OO, Adelusola KA, Durosimi MA. The severity, outcome and challenges of breast cancer in Nigeria. Breast 2006;15:399-409.  Back to cited text no. 17
[PUBMED]    
18.Ikpat OF, Ndoma-Egba R, Collan Y. Influence of age and prognosis of breast cancer in Nigeria. East Afr Med J 2002;79:651-7.  Back to cited text no. 18
[PUBMED]    
19.Hortobagyi GN, Singletary SE, Strom EA. Treatment of locally advanced and inflammatory breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, editors. Harris Disease of Breast. 2 nd ed. philadelphia???: Lippman, Lippincott Williams and Wilkins; 2000. p. 645-60.  Back to cited text no. 19
    
20.Valero V, Hortobagyi GN. Primary chemotherapy: A better overall therapeutic option for patients with breast cancer. Ann Oncol 1998;9:1151-4.  Back to cited text no. 20
[PUBMED]    
21.Chintamani M, Singhal V, Singh JP, Lyall A, Saxena S, Bansal A. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer?-a prospective clinical study. BMC Cancer 2004;4:48.  Back to cited text no. 21
    
22.Moon YW, Rha SY, Jeung HC, Yang WI, Suh CO, Chung HC. Neoadjuvant chemotherapy with infusional 5-fluorouracil, adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer: An early response predicts good prognosis. Ann Oncol 2005;16:1778-85.  Back to cited text no. 22
[PUBMED]    
23.Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483-93.  Back to cited text no. 23
    
24.Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, et al. Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 1999;17:3412-7.  Back to cited text no. 24
    
25.Gajdos C, Tartter PI, Estabrook A, Gistrak MA, Jaffer S, Bleiweiss IJ. Relationship of clinical and pathologic response to neoadjuvant chemotherapy and outcome of locally advanced breast cancer. J Surg Oncol 2002;80:4-11.  Back to cited text no. 25
    
26.Rustogi A, Budrukkar A, Dinshaw K, Jalali R. Management of locally advanced breast cancer: Evolution and current practice. J Cancer Res Ther 2005;1:21-30.  Back to cited text no. 26
[PUBMED]    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Methods>Results>Discussion>Conclusion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed1567    
    Printed46    
    Emailed3    
    PDF Downloaded102    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]