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META-ANALYSIS
Year : 2017  |  Volume : 3  |  Issue : 4  |  Page : 146-152

Efficacy and safety of paclitaxel-based therapy and nonpaclitaxel-based therapy in advanced gastric cancer


Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Date of Submission02-Jan-2017
Date of Acceptance29-Mar-2017
Date of Web Publication14-Aug-2017

Correspondence Address:
Xiaolong Qi
Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, Guangdong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_1_17

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  Abstract 

Aim: To compare the efficacy and safety of paclitaxel-based therapy versus nonpaclitaxel-based therapy in patients with advanced gastric cancer (AGC).
Methods: An adequate literature search in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, American Society of Clinical Oncology and European Society of Medical Oncology was conducted. Phase II/III randomized controlled trials that detected the efficacy and safety of paclitaxel-based therapy and nonpaclitaxel-based therapy in AGC patients were enrolled. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were included in the endpoints.
Results: A total of 632 patients in seven studies of were reviewed. There was a significant difference in ORR between paclitaxel and placebo therapy (odd ratio [OR] =2.68, 95% confidence interval [CI] = 1.05–6.86, P = 0.04), but not between paclitaxel and irinotecan, cisplatin or docetaxel. As no first-line treatment, paclitaxel-based therapy significantly increased ORR (OR = 1.55, 95% CI = 1.02–2.34, P = 0.04, I2 = 0%). No significant differences were found in PFS and OS between paclitaxel- and nonpaclitaxel-based therapies. In addition, paclitaxel-based therapy generally decreased the risk of vomiting and stomatitis while increased the risks of leukopenia and sensory neuropathy.
Conclusion: Paclitaxel-based therapy improved ORR in AGC patients as no first-line therapy, but no significant difference was observed for PFS and OS.

Keywords: Advanced gastric cancer, efficacy, paclitaxel, safety


How to cite this article:
Wu T, Yang X, An M, Luo W, Cai D, Qi X. Efficacy and safety of paclitaxel-based therapy and nonpaclitaxel-based therapy in advanced gastric cancer. Cancer Transl Med 2017;3:146-52

How to cite this URL:
Wu T, Yang X, An M, Luo W, Cai D, Qi X. Efficacy and safety of paclitaxel-based therapy and nonpaclitaxel-based therapy in advanced gastric cancer. Cancer Transl Med [serial online] 2017 [cited 2017 Sep 24];3:146-52. Available from: http://www.cancertm.com/text.asp?2017/3/4/146/210296


  Introduction Top


Gastric cancer is the fifth most common malignancy and the third leading cause of cancer death in the world.[1] Although the overall incidence of gastric cancer is declining, it remains particularly prevalent in developing countries (more than 70% of cases), most notably in Eastern Asia.[1],[2] As the most often diagnosed stage, advanced gastric cancer (AGC) has a poor prognosis.[3] Chemotherapy (fluoropyrimidine and cisplatin or oxaliplatin) is the standard first-line treatment for patients with AGC.[3] Moreover, preoperative or neoadjuvant chemotherapy could potentially reduce AGC staging and improve respectability and survival.[4] Nevertheless, overall survival (OS) with empiric chemotherapy remains unsatisfactory (< 12 months), and therefore new and effective therapeutic strategies are urgently needed.[2]

Taxane, a class of diterpenes with a taxadiene core, represents a well-established class with a specific chemical structure and mechanism of action.[5] Paclitaxel, a member of the classical taxane, was discovered as part of a National Cancer Institute screening program in 1960, in search for plant extracts with antitumor activity.[6] The main induction of apoptosis of paclitaxel is by targeting tubulin.[7],[8] In addition, paclitaxel targets the mitochondria and inhibits the function of the apoptosis inhibitor protein B-cell leukemia 2.[8] Since paclitaxel is excreted through the bile, it is usually the prior anticancer therapy for patients with impaired creatinine clearance or renal disease.[9] However, some studies were conducted to discover that paclitaxel has several adverse effects (AEs), including peripheral sensory neuropathy, cutaneous toxicity,[10],[11] bone marrow suppression (neutropenia, anemia, and thrombopenia), hypotension [5] and an induction of multidrug resistance.[9] Even so, the increased overall response rate overwhelmed the disadvantages and paclitaxel has been applied to many antineoplastic therapy regimens.[9]

In fact, no standard chemotherapy regimen has been established at present clinical trials. Hence, several preclinical studies were undertaken, comparing paclitaxel with other anticancer agents including cisplatin, docetaxel, and irinotecan and combined with other agents including S-1, tegafur and uracil, oxaliplatin, and calcium and folinate/5-FU.[12],[13],[14],[15],[16],[17],[18] Yet it is still unknown whether the paclitaxel-based therapy could be a potential avenue for future therapy. This meta-analysis was conducted to compare the efficacy and safety of paclitaxel-based therapy and nonpaclitaxel-based therapy in patients with AGC.


  Methods Top


Literature search strategy

A comprehensive literature search was conducted in Cochrane Controlled Trials Registry, PubMed and EMBASE database. In addition, the annual meeting proceeding from European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology were also reviewed. The literature search was completed between October 10, 2016, and October 27, 2016. The search strategy was “taxol or paclitaxel” in combination with “gastric cancer or gastric carcinoma or stomach neoplasm or gastro-esophageal cancer or esophago-gastric cancer,” “metastatic or advanced or unresectable or recurrent or stage IV” and “RCTs or randomized controlled trials.” We retrieved all eligible studies and checked corresponding reference lists for additional related publications.

Inclusion criteria

Studies researching comparison of efficacy and safety of paclitaxel-based and nonpaclitaxel-based therapy in patients with AGC were enrolled. The criteria of studies were as follows: (i) articles in English; (ii) studies reporting efficacy and safety profile of paclitaxel- and nonpaclitaxel-based therapy in patients with AGC; (iii) studies design of Phase II/III randomized controlled trials (RCTs); (iv) sufficient data to calculate odds ratio (OR) and hazard ratio (HR).

Exclusion criteria

Studies that met all the following criteria were excluded: (i) not Phase II/III RCTs; (ii) on-going studies; (iii) review articles; (iv) studies not within the field of interest of this study.

Data extraction

The data extraction process was as follows: year of publication, trial phase, the first author's surname, number of subjects, the percentage of male, median age, treatment arm, efficacy and frequency of all-grade and severe AEs evaluated by the National Cancer Institute Common Toxicity Criteria in each arm. Two independent reviewers performed data extraction and information on study design and outcomes. Conflicting views were resolved by discussion and consensus with a third reviewer.

Statistical analysis

Effect estimates were conducted to analyze with Review Manager 5.2 (Cochrane Collaboration, Oxford, UK) and dichotomous data were compared using an OR. The HRs with their 95% confidence intervals (CIs) were directly obtained from the article or calculated using previously published methods.[19] We generated forest plots for graphical presentations and estimated heterogeneity across different studies by Q statistics and I2 estimates. A fixed-effects model was built to aggregate data without statistical heterogeneity. Otherwise, if the potential reasons for heterogeneous were unknown, randomized effects model were carried out. Publication bias was evaluated with Egger and Begg tests. Influence analysis was employed to the study using Stata 12.0 (Computer Resource Center, Chicago, US). The 95% CI were computed for each result.


  Results Top


Literature search

As shown in [Figure 1], 776 initial articles covering our search terms were enrolled. Among these studies, 732 were excluded for not RCTs. For the 44 potentially related RCTs remained, 36 were excluded for not meeting baseline inclusion criteria. The remaining 8 articles were retrieved for full-text review, and 1 study was further excluded for not having sufficient data. Hence, 7 studies covering 632 patients met the inclusion criteria and were enrolled in the meta-analysis.[12],[13],[14],[15],[16],[17],[18]
Figure 1: Flow diagram of study selection process

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Characteristics of included studies

The characteristics of enrolled trials are listed in [Table 1]. Seven studies were based on 4 Phase II trials,[13],[14],[15],[17] 2 Phase III trials,[12],[16] and 1 unknown phase trial.[18] The paclitaxel-based therapy were explored as the first-line chemotherapy in three studies.[15],[16],[17] In the rest of studies, the paclitaxel-based therapy were given as either first-/second-line chemotherapy in two studies [13],[18] and as second-line chemotherapy in other studies.[12],[14] Five of the trials reported the overall response rate (ORR), progression free survival (PFS), OS and AEs,[12],[13],[14],[15],[17] one reported PFS, OS and AEs,[16] and one reported OR and AEs.[18] Five studies evaluated the comparison between paclitaxel- and nonpaclitaxel-based therapy in a two-drug combined regimen [12],[13],[14],[15],[17] and the remaining two comparison in a four-drug combined regimen.[16],[18]
Table1: Characteristics of the included studies

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Meta-analyses of overall response rate

Enrolled studies all included the ORR. As presented in [Figure 2], the results indicated that there were no significant differences between paclitaxel and irinotecan (OR = 1.26, 95% CI = 0.71–2.22, P = 0.43, I2 = 6%), cisplatin (OR = 1.52, 95% CI = 0.86–2.68, P = 0.15, I2 = 0%) ordocetaxel (OR = 1.45, 95% CI = 0.58–3.67, P = 0.43), respectively, with no heterogeneity between paclitaxel and irinotecan or cisplatin, respectively. However, a significant difference was observed between paclitaxel and placebo (OR = 2.68, 95% CI = 1.05–6.86, P = 0.04).
Figure 2: Overall response rate for each subgroup, comparison between paclitaxel and placebo or irinotecan or cisplatin or docetaxel

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As shown in [Figure 3], the results of the meta-analysis indicated that paclitaxel-based therapy had significantly higher ORR than nonpaclitaxel-based therapy, when not given as the first-line treatment for AGC (OR = 1.55, 95% CI = 1.02–2.34, P = 0.04, I2 = 0%). However, no significant difference was detected in studies where paclitaxel was administrated as the first-line treatment (OR = 1.53, 95% CI = 0.53–4.37, P = 0.43, I2 = 65%).
Figure 3: Overall response rate for each subgroup, comparison between paclitaxel-based therapy and nonpaclitaxel-based therapy in first line or no first line studies

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In addition, as presented in [Supplementary Figure 1] [Additional file 1], no study had a decisive consequence on the overall effects based on the influence analysis conducted by Stata 12.0. No publication bias was examined by the Egger (P = 1.000) and Begg (P = 0.810) test.

Meta-analyses of progression free survival

Six eligible studies reported the PFS, except for the study conducted by Yang et al.[18] The results showed that there were no significant differences in PFS between paclitaxel and placebo (HR = 0.79, 95% CI = 0.53–1.18, P = 0.25, I2 = 64%), irinotecan (HR = 0.87, 95% CI = 0.69–1.09, P = 0.24, I2 = 0%), orcisplatin (HR = 0.84, 95% CI = 0.50–1.41, P = 0.51), respectively [Figure 4].
Figure 4: Progression free survival for each subgroup, comparison between paclitaxel and placebo or irinotecan or cisplatin

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As presented in [Figure 5], whether used as first-line treatment or not, no significant difference was presented in PFS between paclitaxel- and nonpaclitaxel-based therapy (HR = 0.89, 95% CI = 0.78–1.01, P = 0.06, I2 = 29%, HR = 0.87, 95% CI = 0.68–1.11, P = 0.26, I2 = 0%, respectively).
Figure 5: Progression free survival for each subgroup, comparison between paclitaxel- and nonpaclitaxel-based therapy in first line or no first line studies

Click here to view


Furthermore, it was presented that no study had a decisive consequence on the overall effects based on the influence analysis conducted by Stata 12.0 [Supplementary Figure 2] [Additional file 2], and no publication bias (Begg test, P = 0.086; Egger test, P = 0.149) was detected.

Meta-analyses of overall survival

The OS was reported in six studies, except for study conducted by Yang et al.[18] As presented in [Figure 6], the outcomes indicated that no significant difference in the term of OS was presented in the paclitaxel-based arm compared to the placebo (HR = 0.75, 95% CI = 0.45–1.25, P = 0.27, I2 = 76%), irinotecan (HR = 0.92, 95% CI = 0.73–1.15, P = 0.45, I2 = 0%), orcisplatin (HR = 0.94, 95% CI = 0.55–1.61, P = 0.82), respectively.
Figure 6: Overall survival for each subgroup, comparison between paclitaxel and placebo or irinotecan or cisplatin

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The OS in both first-line therapy (HR = 0.84, 95% CI = 0.63–1.13, P = 0.25, I2 = 55%) and secondary therapy (HR = 0.89, 95% CI = 0.70–1.14, P = 0.36, I2 = 0%) studies was comparative [Figure 7].
Figure 7: Overall survival for each subgroup, comparison between paclitaxel-based therapy and nonpaclitaxel-based therapy in first line or no first line studies

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Moreover, the influence analysis indicated that no study had a conclusive consequence on the overall effects [Supplementary Figure 3] [Additional file 3]. No publication bias was detected by the analyses of the Egger (P = 0.462) and Begg (P = 0.478) test.

Meta-analyses of adverse effects (grade ≥ 3)

As listed in [Table 2], the risk of vomiting (OR = 0.52, 95% CI = 0.30–0.89, P = 0.02) and stomatitis (OR = 0.50, 95% CI = 0.27–0.95, P = 0.03) was decreased in the paclitaxel-based arm. However, paclitaxel-based therapy was related to increased events of leukopenia (OR = 1.95, 95% CI = 1.01–3.78, P = 0.05) and sensory neuropathy (OR = 2.60, 95% CI = 1.34–5.06, P = 0.003). In addition, there was no statistical significance in neutropenia, anemia, thrombocytopenia, diarrhea, anorexia, nausea, elevated transaminase, creatinine increased, fatigue, and rash.
Table2: Adverse events of the included studies

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  Discussion Top


Patients with gastric cancer are commonly diagnosed at a relative advanced stage with distant metastasis.[3] Unfortunately, although radical gastrectomy is the only curative treatment of gastric cancer with common recurrences,[20] many patients with AGC had no chance to receive surgical resection. Taxane, used in 1990s, is one of three milestone anti-cancer drugs.[21] Paclitaxel, an alkaloid ester including a taxane system,[5] is commonly used in the second-line or later setting for gastric cancer in Japan, and it may present consistent efficacy, irrespective of the previous chemotherapy.[22]

Many studies were conducted to explore the efficacy of paclitaxel in AGC,[12],[13],[14],[15],[16],[17],[18] however, results were controversial. Thus, the aim of this study was to clarify its efficacy and safety profile. The results showed that ORR was significantly increased in paclitaxel-based therapy compared with placebo. When given as non- first ( first or secondary) line treatment, paclitaxel-based therapy significantly improved ORR compared with nonpaclitaxel-based therapy. However, no significant difference was detected in terms of PFS or OS between paclitaxel and placebo, irinotecan or cisplatin, nor between paclitaxel-based and nonpaclitaxel-based regimens as both first and no first-line ( first or secondary) therapy. Besides, paclitaxel-based chemotherapy was associated with decreased vomiting, stomatitis, and increased leukopenia, sensory neuropathy.

The highlighted strength of our meta-analysis is that we primarily compared the difference between paclitaxel and three common clinical drugs: irinotecan, cisplatin, and docetaxel. As no significant difference between paclitaxel and irinotecan, orcisplatin was presented, it is suggested that the clinical practice of these three drugs are all feasible options for AGC patients, nevertheless, more large RCTs need to be conducted to provide robust evidence. Moreover, we performed two subgroup analyses based on paclitaxel and nonpaclitaxel agents, and first or no first ( first or secondary) line, respectively. In addition, all eligible studies were RCTs.

However, this study has several limitations. First, few studies were enrolled, especially for a certain subgroup. Second, the treatments of patients in some studies included first and second line therapy, which may confound the results. Finally, synthesized analysis, such as the impact on dosage and gender, was not conducted because the direct data of patients were not available.

In conclusion, paclitaxel-based therapy was associated with significantly higher ORR versus nonpaclitaxel-based therapy as no first line ( first or secondary) treatment and versus placebo, but no such superiority was found when compared to irinotecan, cisplatin, or docetaxel. It was indicated that paclitaxel was a potential and effective substitute for AGC patients with resistance to first-line therapy. In addition, no significant difference was observed between paclitaxel- and nonpaclitaxel-based therapy in terms of OS and PFS, whether as first-line treatment or not, which might be conditional and resulted from the fewer database and literature. Paclitaxel-based therapy was not superior to nonpaclitaxel-based therapy in terms of OS and PFS as either first or secondary therapy. In the future, paclitaxel should be evaluated further in more RCTs, including randomized Phase III trials.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136 (5): E359–86.  Back to cited text no. 1
    
2.
Pectasides E. Genomic alterations and targeted therapy in gastric and esophageal adenocarcinoma. Clin Ther 2016; 38 (7): 1589–99.  Back to cited text no. 2
    
3.
Digklia A, Wagner AD. Advanced gastric cancer: current treatment landscape and future perspectives. World J Gastroenterol 2016; 22 (8): 2403–14.  Back to cited text no. 3
    
4.
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet 2009; 374 (9688): 477–90.  Back to cited text no. 4
    
5.
Joerger M. Treatment regimens of classical and newer taxanes. Cancer Chemother Pharmacol 2016; 77 (2): 221–33.  Back to cited text no. 5
    
6.
Wani MC, Horwitz SB. Nature as a remarkable chemist: a personal story of the discovery and development of Taxol. Anticancer Drugs 2014; 25 (5): 482–7.  Back to cited text no. 6
    
7.
Ganansia-Leymarie V, Bischoff P, Bergerat JP, Holl V. Signal transduction pathways of taxanes-induced apoptosis. Curr Med Chem Anticancer Agents 2003; 3 (4): 291–306.  Back to cited text no. 7
    
8.
Ferlini C, Raspaglio G, Mozzetti S, Distefano M, Filippetti F, Martinelli E, Ferrandina G, Gallo D, Ranelletti FO, Scambia G. Bcl-2 down-regulation is a novel mechanism of paclitaxel resistance. Mol Pharmacol 2003; 64 (1): 51–8.  Back to cited text no. 8
    
9.
Barbuti AM, Chen ZS. Paclitaxel through the ages of anticancer therapy: exploring its role in chemoresistance and radiation therapy. Cancers (Basel) 2015; 7 (4): 2360–71.  Back to cited text no. 9
    
10.
Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med 1995; 332 (15): 1004–14.  Back to cited text no. 10
    
11.
Hanna YM, Baglan KL, Stromberg JS, Vicini FA, Decker DA. Acute and subacute toxicity associated with concurrent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy. Breast J 2002; 8 (3): 149–53.  Back to cited text no. 11
    
12.
Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 2013; 31 (35): 4438–44.  Back to cited text no. 12
    
13.
Mochiki E, Ogata K, Ohno T, Toyomasu Y, Haga N, Fukai Y, Aihara R, Ando H, Uchida N, Asao T, Kuwano H, North Kanto Gastric Cancer Study Group. Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer. Br J Cancer 2012; 107 (1): 31–6.  Back to cited text no. 13
    
14.
Park SH, Lee WK, Chung M, Lee Y, Han SH, Bang SM, Cho EK, Shin DB, Lee JH. Paclitaxel versus docetaxel for advanced gastric cancer: a randomized phase II trial in combination with infusional 5-fluorouracil. Anticancer Drugs 2006; 17 (2): 225–9.  Back to cited text no. 14
    
15.
Sugimoto N, Fujitani K, Imamura H, Uedo N, Iijima S, Imano M, Shimokawa T, Kurokawa Y, Furukawa H, Goto M. Randomized phase II trial of S-1 plus irinotecan versus S-1 plus paclitaxel as first-line treatment for advanced gastric cancer (OGSG0402). Anticancer Res 2014; 34 (2): 851–7.  Back to cited text no. 15
    
16.
Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, Tanabe K, Takahashi N, Imamura H, Tatsumoto N, Hara A, Nishikawa K, Fukushima R, Nozaki I, Kojima H, Miyashita Y, Oba K, Buyse M, Morita S, Sakamoto J. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol 2014; 15 (8): 886–93.  Back to cited text no. 16
    
17.
Wang X, Wang ML, Zhou LY, Lu XY, Yang JF, Yu HG. Randomized phase II study comparing paclitaxel with S-1 vs. S-1 as first-line treatment in patients with advanced gastric cancer. Clin Transl Oncol 2013; 15 (10): 836–42.  Back to cited text no. 17
    
18.
Yang JW, Chen YG, Chen Q, Fan NF, Guo ZQ, Cai XC, Wu XA, Xu S, Lu X, Zhang YH, Ouyang XN. A randomized controlled trail of taxol-based combination regimens for advanced gastric cancer. Ai Zheng 2005; 24 (12): 1531–6. (in Chinese)  Back to cited text no. 18
    
19.
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8: 16.  Back to cited text no. 19
    
20.
Buzzoni R, Bajetta E, Di Bartolomeo M, Miceli R, Beretta E, Ferrario E, Mariani L. Pathological features as predictors of recurrence after radical resection of gastric cancer. Br J Surg 2006; 93 (2): 205–9.  Back to cited text no. 20
    
21.
Li XD, Shen H, Jiang JT, Zhang HZ, Zheng X, Shu YQ, Wu CP. Paclitaxel based vs. oxaliplatin based regimens for advanced gastric cancer. World J Gastroenterol 2011; 17 (8): 1082–7.  Back to cited text no. 21
    
22.
Shimoyama R, Yasui H, Boku N, Onozawa Y, Hironaka S, Fukutomi A, Yamazaki K, Taku K, Kojima T, Machida N, Todaka A, Tomita H, Sakamoto T, Tsushima T. Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin. Gastric Cancer 2009; 12 (4): 206–11.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
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