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


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 3  |  Page : 576-581

Patterns of failure for early-stage glottic carcinoma: 10 years' experience in conformal radiotherapy era


1 Department of Radiation Oncology, Ege University Medical School and Hospital, Izmir, Turkey
2 Department of Otolaryngology, Ege University Medical School and Hospital, Izmir, Turkey

Date of Web Publication29-May-2019

Correspondence Address:
Dr. Fatma Sert
Department of Radiation Oncology, Ege University Medical School and Hospital, Izmir
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_692_17

Rights and Permissions
 > Abstract 


Purpose: Larynx cancer is the most common head-and-neck cancer in Turkey. Vocal cords are involved nearly 70%–80% of laryngeal carcinomas. We aim to present our 10 years' experience and failure patterns of the patients with T1 and T2 glottic laryngeal carcinoma by same manner, technique, doses, and physician in conformal radiotherapy (RT) era.
Methods: Between January 2005 and December 2015, a total of 143 patients treated with definitive RT for early-stage glottis laryngeal cancer were selected. The total dose was 65.25 Gy in 29 fractions.
Results: The median follow-up time was 64 (range: 12–150) months. All of the patients had a complete clinical response to the treatment. A 5-year local control (LC) rates were 84.5%, 91.8%, 74%, and 56% for overall, T1a, T1b, and T2, respectively. Ultimate LC rates (after salvage treatment) for 5 years were 90%, 95%, 92%, and 75% for overall, T1a, T1b, and T2, respectively. Regional neck control for the whole group was 92% for 5 years. After the initial RT, a total of 22 (15.4%) patients had disease recurrence at any site of the neck or larynx. Median time to disease recurrence was 59.5 months (range: 5–150).
Conclusion: This study represents a large and long-term analysis of early-stage glottic carcinoma treated by same manner, technique, doses, and physician in conformal RT era. Definitive RT provides a high LC rate, tolerable toxicity, and favorable voice quality. Extension beyond the vocal cords and T2 stage are the most important unfavorable prognostic factors regarding LC.

Keywords: Failure patterns, glottic laryngeal carcinoma, middle-income country, radiotherapy


How to cite this article:
Sert F, Kaya I, Ozturk K, Esassolak M. Patterns of failure for early-stage glottic carcinoma: 10 years' experience in conformal radiotherapy era. J Can Res Ther 2019;15:576-81

How to cite this URL:
Sert F, Kaya I, Ozturk K, Esassolak M. Patterns of failure for early-stage glottic carcinoma: 10 years' experience in conformal radiotherapy era. J Can Res Ther [serial online] 2019 [cited 2019 Jun 17];15:576-81. Available from: http://www.cancerjournal.net/text.asp?2019/15/3/576/237253




 > Introduction Top


Larynx cancer is the most common head-and-neck cancer in Turkey, with 5655 new cases diagnosed within the male population in 2014.[1] Vocal cords are involved nearly 70%–80% of laryngeal carcinomas.[2] As distinct from many other head-and-neck carcinomas, glottic carcinomas are seen in early stages because of the mucosal lymphatic drainage paucity.[3]

The treatment choices are both definitive radiotherapy (RT) and transoral laser resection. The applied procedure changes the tumor factors, physician choice, and patient preference. The literature shows similar local control (LC), survival results, and complications between RT and resection.[3],[4] However, voice quality following resection depends on the extent of surgical procedures.[5]

Different dose fractionation schedules and irradiation techniques can be used for the treatment of early-glottic carcinomas.[6],[7] Recommended schedules are 64–70 Gy with 2 Gy per fraction over 6.5–7 weeks and 63–65.25 Gy over 5.5–6 weeks.[8] The most commonly used and recommended one is employing 2.25 Gy per fraction to a total dose of 63–65.25 Gy.[6],[9] Some reports showed that involved single vocal cord irradiation could be adequate, especially for T1 carcinomas.[10] Irradiation of the involved single vocal cord irradiation has dosimetric advantages; however, it has some uncertainties and difficulties in daily life.

We aim to present our 10 years' experience and failure patterns of the patients with T1 and T2 glottic laryngeal carcinomas by the same manner, technique, doses, and physician in conformal RT era.


 > Methods Top


Between January 2005 and December 2015, a total of 143 patients with early-stage glottic laryngeal carcinoma were evaluated for this retrospective data analysis. All included patients had biopsy-proven malignancy and only diagnostic minor surgery such as stripping allowed.

Thermoplastic masks were used for patient immobilization. Computed tomography (CT)-based simulation was used, and all included patients treated with three-dimensional (3D) conformal RT techniques. Due to the department protocol, intensity-modulated RT (IMRT) techniques were not used.

According to the International Commission on Radiation Units and Measurements (ICRU) definitions, visible and detectable tumor sites were contoured as gross tumor volume, and all laryngeal structures which were at risk of microscopic tumor infiltration were contoured as clinical target volume (CTV), and in addition, a 0.3 cm margin was added to CTV for planning target volume. Opposed lateral photon fields were standard treatment protocol of our department. Standard field borders in protocol were similar to those previously determined:[11] for superior, mid thyroid notch; for inferior, bottom of cricoid cartilage; for anterior, 1 cm anterior to the skin of the neck; and for posterior, anterior to the vertebral body. Due to the rare nodal metastasis to the neck, elective nodal irradiation was not applied. RT was given with 6 MV photons, and the dose was prescribed to the ICRU reference point in accordance with the ICRU 50 report.[12] The total dose was 65.25 Gy in 29 fractions according to the National Comprehensive Cancer Network recommendations.[9] Posttreatment follow-ups were done 3 monthly for 2 years, 6 months for latter 3 years, and further follow-ups were done once a year. All local and/or regional recurrences were marked in neck lymphatic levels for recurrent patients. Metastasis and second primary malignancies were recorded.

Statistical analysis was performed using SPSS version 18 (IBM, Somers, NY). Survival and recurrence outcomes were calculated from the day when the cancer diagnosis was proven. LC, regional control (RC), disease-specific survival, (DSS) and overall survival (OS) rates were analyzed using Kaplan–Meier curves. Log-rank and Cox regression analysis were done for detecting prognostic factors.


 > Results Top


A total of 143 patients were included in this retrospective data analysis. The median follow-up time was 64 (range: 12–150) months. All patients had a lesion located at laryngeal glottis, and the biopsy results were squamous cell carcinoma. According to the American Joint Committee on Cancer (AJCC) staging system, 86 (60.1%), 35 (24.5%), and 21 (15.4%) of the patients had T1a, Tb, and T2 disease, respectively. All patients had N0 disease. Patients and disease characteristics were shown in [Table 1].
Table 1: Patient and disease characteristics

Click here to view


All patients received the prescribed total RT dose of 65.25 Gy in 29 fractions with 2.25 Gy per day. Acute and late toxicities were evaluated using RT Oncology Group (RTOG) toxicity scoring criteria. During treatment, the most commonly seen problems were Grade I–II dysphagia and hoarseness. Only 20 (13.9%) patients had Grade II skin toxicity, and these were healed after 2 months from the treatment course. We did saw neither acute nor late Grade III–IV toxicity. None of the patients required long-term enteral feeding. About 106 (74%) patients reported an improvement of their voice quality after RT and the remaining 38 (26%) noticed neither improvement nor impairment of their voices.

All of the patients had a complete clinical response to the treatment. A 5-year LC rates were 84.5%, 91.8%, 74%, and 56% for overall, T1a, T1b, and T2, respectively. Ultimate LC rates (after salvage treatment) for 5 years were 90%, 95%, 92%, and 75% for overall, T1a, T1b, and T2, respectively. Regional neck control for the whole group was 92% for 5 years.

After the initial RT, total 22 (15.4%) patients had disease recurrence at any site of the neck or larynx. Median time to disease recurrence was 59.5 months (range: 5–150). Recurrence patterns were shown in [Table 2]. Recurrences at any site of laryngeal structures were accepted as isolated local recurrence. Isolated local recurrences were seen in 15 (68%) patients. Regional lymphatic metastasis was detected in 7 (32%) patients. Regional lymphatic nodal metastases without laryngeal lesion were accepted as isolated lymphatic recurrences, and it was seen in only 2 (9%) patients. Concomitant local and regional lymphatic recurrences were identified in 5 (23%) patients. Salvage surgery was applied to 19 (87%) patients, and the remaining 3 (13%) patients were treated with reirradiation with concomitant chemotherapy.
Table 2: Recurrence patterns of patients

Click here to view


During follow-up, totally 26 (18%) deaths were recorded, and 10 (7%) of those were accepted as disease-specific deaths. A 5-year DSS and OS were 93% and 85%, respectively. The survival curves for 5-year LC, DSS, and OS were shown in [Figure 1].
Figure 1: Kaplan–Meier curves of local recurrence, disease-specific, and overall survival of all patients

Click here to view


In univariate analysis for LC, advanced T stage (P ≤ 0.001), impaired vocal cord motion (P = 0.018), and extension beyond vocal cords (P = 0.010) were determined as unfavorable prognostic factors. In multivariate analysis, only having advanced T-stage disease (T1a vs. T1b vs. T2) was significantly associated with worse LC rates (91% vs. 74% vs. 56%, P = 0.001).

In univariate analysis for OS, advanced T stage (P ≤ 0.001), impaired vocal cord motion (P = 0.001), and extension beyond vocal cords (P < 0.001) were determined as unfavorable prognostic factors similar with LC. In multivariate analysis, only having advanced T-stage disease (T1a vs. T1b vs. T2) was significantly affecting OS unfavorably like LC rates (90% vs. 86% vs. 49%, P = 0.023).

Second primary malignancies were seen in 20 (14%) patients during follow-up. Lung and prostate cancer were the most common second primary cancer origins. Both lung and prostate cancer was detected in 4 (2.8% of whole group) patients. The distribution of the type of second primary cancers was shown in [Table 3].
Table 3: The distribution of the type of second cancers

Click here to view


Thyroid function tests were examined in 107 (73.3%) patients. Thyroid function problems were seen only in 4 (2.8%) patients, and they were consulted to an endocrinology physician. After medical treatment, they followed up with normal thyroid function tests results.

We treat many patients from rural areas. Those patients prefer their previous physician for follow-up. Due to this reason, we have some missing follow-up period due to those patients. Hence, our median follow-up time was 64 months, and this could be a limitation for this retrospective data.


 > Discussion Top


The main goal of early-stage glottic carcinoma is to eliminate the disease with organ preservation. The secondary aims are voice quality and swallowing function after treatment. Both organ preservation surgery and definitive RT can be used for those purposes. There is no randomized trial comparing conservative surgery with RT regarding LC rates and survival outcomes in the present literature. All comparisons are done according to retrospective data. The present trial is also a retrospective analysis of definitive RT and patterns of failure for early-stage glottis carcinomas. It must be kept in mind that we evaluated the long-term survival, toxicity, recurrence patterns, and treatment results obtained with only 3D conformal radiation techniques from a reference center of a middle-income country.

Anterior commissure involvement is known as a factor indicating the tendency of tumor to spread thyroid cartilage and resulting early recurrences. In 1999, Marshak et al.[13] evaluated 207 patients with early-stage glottic carcinoma regarding the prognostic factors affecting LC rates. They found that the 5-year LC rates for anterior commissure involvement 74% and for others 89% (P = 0.002). Anterior commissure involvement was accepted as a negative factor. At that point, one should evaluate the anterior commissure involvement directly with laryngoscope due to the insufficient radiologic imaging for this location. In 2011, Tong et al.[14] emphasized that the insufficient radiological imaging and underdosage of the extent of the tumor involvement could result with a negative impact of the LC rates for the tumors with anterior commissure involvement. We found 5-year LC rates of the tumors with and without anterior commissure involvement were 82% and 86%, respectively, (P = 0.116). Due to the fact that not having clear evidence regarding this issue, anterior commissure involvement should be evaluated with direct examination and the radiation fields of those patients should be determined larger for anterior border. On the other hand, the effect of anterior commissure involvement over staging system remains controversial. We suggest that the present staging system can be used in the light of current evidence regarding anterior commissure status.

T stage is an important prognostic factor for glottic carcinomas. The current AJCC staging system divides early-glottic carcinomas according to cord mobility and tumor extension. Mourad et al.[15] reported the treatment results of their 253 T1–T2 glottic cancer patients. They gave 5-year LC rates for T1 and T2 tumors were 99.5% and 91%, respectively.[14] Another retrospective study from Nur et al.[16] evaluated the prognostic factors of 114 patients with early-stage glottic carcinoma in 2005. In this trial, 5-year LC rates for T1 (including is situ tumors) and T2 tumors were 97.7% and 84.2%, respectively. They determined T stage as a single independent prognostic factor for LC.[16] Burke et al.[17] demonstrated that T stage was significant for LC (P = 0.009) and also they emphasized that the patients with T2 tumors had inferior tumor control with RT.[17] In our trial, we found that 5-year LC rates affected unfavorably with the impaired vocal cord mobility, tumor extension toward the glottic space (both subglottic and supraglottic) and T2 disease (P = 0.006, P = 0.003, and P < 0.001, respectively). In multıvariable analyses of our results, T stage was the only factor affecting both LC and OS rates unfavorably (P = 0.003 and P = 0.023, respectively).

With respect to patterns of failure, local recurrences are commonly seen at or near the primary tumor subsite. Ermiş et al.[18] evaluated the recurrence patterns of early-stage glottic carcinoma treated with hypofractionated RT. They found that 14 (11%) patients recurred at or near the primary tumor subsite. In their report, only 3 (2%) patients had regional lymphatic metastasis alone.[18] Their results supported the present literature. Similar with Ermiş et al., Lim et al.[19] examined the recurrence patterns of the same group of patients. They included 222 patients, and they saw 34 (15%) recurrences at or near the primary tumor subsite. The regional recurrences were seen only 3 (8%) patients in their report.[19] In our study, we found that 15 (10%) patients had isolated local recurrences without any lymphatic metastasis and only 3 (2%) patients had regional lymphatic metastasis. Our results are similar with current literature. From this point of view, direct examination of vocal cords with laryngoscope should be the most important follow-up rule for early-stage glottic carcinomas. Most of the recurrences can be detect by this manner. The other important point is the coverage of the irradiation field. Nowadays, a new technological development such as IMRT provides us to irradiate the involved cord alone. Levendag et al.[20] showed that IMRT had a significant dosimetric advantage regarding organ at risks doses. They concluded that ipsilateral vocal cord irradiation with newer technologies could be examined, especially for T1 glottic carcinomas.[20] As distinct from conventional RT techniques, those kinds of RT techniques do not treat the whole laryngeal structures. When considered the recurrence results of abovementioned trials, we should treat whole laryngeal structure with required radiation doses.

The patients with early-stage glottic carcinomas can be considered in the favorable group due to have a promising salvage therapy. Most recurrences are at or near to the laryngeal structures, and radical surgical techniques provide long-term control rates. In the data of Ermiş et al., it was reported that a total of 18 (90%) recurrent patients underwent salvage surgery.[18] They defined that 12 of the 18 patients (67%) who underwent salvage surgery were disease-free and alive. In our data, salvage surgery could be applied to 20 (90%) patients, and the remaining 2 (10%) patients could not undergo to salvage surgery due to the comorbid status of them.

In our data, 20 (14%) patients developed a second cancer during the follow-up period. This is similar rate of 17% reported by Ermiş et al.,[18] 21% by Cheah et al.,[21] and 22% by Khan et al.[22] We found that lung and prostate cancers were the most common second cancer origins. Ermiş et al. saw that the lung cancer was the most common second primary similar with our data.[18] In the recent published RTOG 9512 report, 20% deaths were due to second primary cancer.[23]

There are some limitations of this trial. The first issue that needs to be mentioned is the favorable expected survival. Similar with the other series cited in this report, it is difficult to determine the certain recurrences within the long-term follow-up period of the disease. In addition to the problems of giving the certain recurrences, voice quality is another important point in the treatment of early-stage laryngeal cancer. All our efforts are for giving an objective data regarding the last voice quality of the patients. We tried to evaluate the voice quality nearly all the visits of patients, but we know this is all subjective way. We should evaluate the voice quality with objective techniques, and this would show the exact effect of the treatment for both surgery and RT.

Our previous trial includes 83 patients treated between January 1995 and December 2004.[24] The stage of patients were 29 (34.9%) T1a, 29 (34.9%) T1b, and (30.1%) T2-stage disease. During a median follow-up of 56 months, 13 patients had failures. Five-year LC rates were 90.5% in T1 and 73.2% in T2 patients. Loco-RC rates were 89% in T1 and 70.5% in T2 patients.[24] Although some of the patients treated with Co60 machines in the previous trial, the previous results of our trial were similar with our current data. Taking into account both two data, we can say that early-stage glottic carcinomas can be treated even with older technological equipment in low- and low-middle income countries properly.


 > Conclusions Top


This study represents a large and long-term analysis of early-stage glottic carcinoma treated by same manner, technique, doses, and physician in 3D conformal RT era. Definitive RT provides a high LC rate, tolerable toxicity, and favorable voice quality. Extension beyond the vocal cords and T2 stage are the most important prognostic factors related to worse LC. Salvage surgery gives promising LC results for local recurrent patients. Majority of the recurrences are at or near to any part of laryngeal structures. As a result of this, most recurrences can be detected with direct laryngoscopic evaluation. We must be careful while changing our treatment protocol toward the local single vocal cord irradiation. The literature regarding this issue is still immature and large numbered trials with long-term follow-up are required. Second primary malignancies should be taken into account for this long-life expectancy group of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Cancer Statistics in Turkey. Available from: http://www.kanser.gov.tr/daire-faaliyetleri/kanser-istatistikleri/2106-2014-y%C4%B1l%C4%B1-t%C3%B Turkiye-kanser-istatistikleri.html. [Last accessed on 2017 Mar 13].  Back to cited text no. 1
    
2.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.  Back to cited text no. 2
    
3.
Brady JS, Marchiano E, Kam D, Baredes S, Eloy JA, Park RC, et al. Survival impact of initial therapy in patients with T1-T2 glottic squamous cell carcinoma. Otolaryngol Head Neck Surg 2016;155:257-64.  Back to cited text no. 3
    
4.
Lüscher MS, Pedersen U, Johansen LV. Treatment outcome after laser excision of early glottic squamous cell carcinoma – A literature survey. Acta Oncol 2001;40:796-800.  Back to cited text no. 4
    
5.
Mendenhall WM, Mancuso AA, Hinerman RW, Malyapa RS, Werning JW, Amdur RJ, et al. Multidisciplinary management of laryngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69:S12-4.  Back to cited text no. 5
    
6.
Yamazaki H, Nishiyama K, Tanaka E, Koizumi M, Chatani M. Radiotherapy for early glottic carcinoma (T1N0M0): Results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys 2006;64:77-82.  Back to cited text no. 6
    
7.
Gowda RV, Henk JM, Mais KL, Sykes AJ, Swindell R, Slevin NJ, et al. Three weeks radiotherapy for T1 glottic cancer: The christie and royal marsden hospital experience. Radiother Oncol 2003;68:105-11.  Back to cited text no. 7
    
8.
National Comphrehensive Cancer Network Cancer Treatments by Sites Guidelines. Available from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. [Last accessed on 2017 Mar 13].  Back to cited text no. 8
    
9.
NCCN Guidelines Version 2. Cancer of Glottic Larynx; 2017. Available from: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. [Last assessed on 2017 Oct 24].  Back to cited text no. 9
    
10.
Al-Mamgani A, Kwa SL, Tans L, Moring M, Fransen D, Mehilal R, et al. Single vocal cord irradiation: Image guided intensity modulated hypofractionated radiation therapy for T1a glottic cancer: Early clinical results. Int J Radiat Oncol Biol Phys 2015;93:337-43.  Back to cited text no. 10
    
11.
Chera BS, Amdur RJ, Morris CG, Kirwan JM, Mendenhall WM. T1N0 to T2N0 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:461-6.  Back to cited text no. 11
    
12.
ICRU 50. Prescribing, Recording, and Reporting Photon Beam Therapy. Bethesda, USA: International Commission on Radiation Units and Measurements Press; 1993.  Back to cited text no. 12
    
13.
Marshak G, Brenner B, Shvero J, Shapira J, Ophir D, Hochman I, et al. Prognostic factors for local control of early glottic cancer: The Rabin medical center retrospective study on 207 patients. Int J Radiat Oncol Biol Phys 1999;43:1009-13.  Back to cited text no. 13
    
14.
Tong CC, Au KH, Ngan RK, Chow SM, Cheung FY, Fu YT, et al. Impact and relationship of anterior commissure and time-dose factor on the local control of T1N0 glottic cancer treated by 6 MV photons. Radiat Oncol 2011;6:53.  Back to cited text no. 14
    
15.
Mourad WF, Hu KS, Shourbaji RA, Woode R, Harrison LB. Long-term follow-up and pattern of failure for T1-T2 glottic cancer after definitive radiation therapy. Am J Clin Oncol 2013;36:580-3.  Back to cited text no. 15
    
16.
Nur DA, Oguz C, Kemal ET, Ferhat E, Sülen S, Emel A, et al. Prognostic factors in early glottic carcinoma implications for treatment. Tumori 2005;91:182-7.  Back to cited text no. 16
    
17.
Burke LS, Greven KM, McGuirt WT, Case D, Hoen HM, Raben M, et al. Definitive radiotherapy for early glottic carcinoma: Prognostic factors and implications for treatment. Int J Radiat Oncol Biol Phys 1997;38:1001-6.  Back to cited text no. 17
    
18.
Ermiş E, Teo M, Dyker KE, Fosker C, Sen M, Prestwich RJ, et al. Definitive hypofractionated radiotherapy for early glottic carcinoma: Experience of 55Gy in 20 fractions. Radiat Oncol 2015;10:203.  Back to cited text no. 18
    
19.
Lim YJ, Wu HG, Kwon TK, Hah JH, Sung MW, Kim KH, et al. Long-term outcome of definitive radiotherapy for early glottic cancer: Prognostic factors and patterns of local failure. Cancer Res Treat 2015;47:862-70.  Back to cited text no. 19
    
20.
Levendag PC, Teguh DN, Keskin-Cambay F, Al-Mamgani A, van Rooij P, Astreinidou E, et al. Single vocal cord irradiation: A competitive treatment strategy in early glottic cancer. Radiother Oncol 2011;101:415-9.  Back to cited text no. 20
    
21.
Cheah NL, Lupton S, Marshall A, Hartley A, Glaholm J. Outcome of T1N0M0 squamous cell carcinoma of the larynx treated with short-course radiotherapy to a total dose of 50 gy in 16 fractions: The Birmingham experience. Clin Oncol (R Coll Radiol) 2009;21:494-501.  Back to cited text no. 21
    
22.
Khan MK, Koyfman SA, Hunter GK, Reddy CA, Saxton JP. Definitive radiotherapy for early (T1-T2) glottic squamous cell carcinoma: A 20 year Cleveland clinic experience. Radiat Oncol 2012;7:193.  Back to cited text no. 22
    
23.
Trotti A 3rd, Zhang Q, Bentzen SM, Emami B, Hammond ME, Jones CU, et al. Randomized trial of hyperfractionation versus conventional fractionation in T2 squamous cell carcinoma of the vocal cord (RTOG 9512). Int J Radiat Oncol Biol Phys 2014;89:958-63.  Back to cited text no. 23
    
24.
Esassolak M, Dubova S, Kamer S, Aydın B. Curative radiotherapy in early stage glottic laryngeal carcinoma. Türk Onkol Derg 2006;21:28-36.  Back to cited text no. 24
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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>Conclusions>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed520    
    Printed26    
    Emailed0    
    PDF Downloaded30    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]